Corpus
Pmc
Racine
Corpus
Checkpoint
Pmc
Racine
Pmc
Exploration
Accueil
Racine
Racine

Serveur d'exploration Chloroquine

Attention, ce site est en cours de développement !
Attention, site généré par des moyens informatiques à partir de corpus bruts.
Les informations ne sont donc pas validées.

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness

Identifieur interne : 000094 ( Pmc/Corpus ); précédent : 000093; suivant : 000095

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness

Auteurs : Janet B. Mcgill ; Mariko Johnson ; Stacy Hurst ; William T. Cade ; Kevin E. Yarasheski ; Richard E. Ostlund ; Kenneth B. Schechtman ; Babak Razani ; Michael B. Kastan ; Donald A. Mcclain ; Lisa De Las Fuentes ; Victor G. Davila-Roman ; Daniel S. Ory ; Samuel A. Wickline ; Clay F. Semenkovich

Source :

RBID : PMC:6664523

Abstract

Background

Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome.

Methods

Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment.

Results

For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups.

Conclusions

These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.

Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007


Url:
DOI: 10.1186/s13098-019-0456-4
PubMed: 31384309
PubMed Central: 6664523

Links to Exploration step

PMC:6664523

Le document en format XML

<record>
<TEI>
<teiHeader>
<fileDesc>
<titleStmt>
<title xml:lang="en">Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness</title>
<author>
<name sortKey="Mcgill, Janet B" sort="Mcgill, Janet B" uniqKey="Mcgill J" first="Janet B." last="Mcgill">Janet B. Mcgill</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Johnson, Mariko" sort="Johnson, Mariko" uniqKey="Johnson M" first="Mariko" last="Johnson">Mariko Johnson</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hurst, Stacy" sort="Hurst, Stacy" uniqKey="Hurst S" first="Stacy" last="Hurst">Stacy Hurst</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cade, William T" sort="Cade, William T" uniqKey="Cade W" first="William T." last="Cade">William T. Cade</name>
<affiliation>
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Program in Physical Therapy,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Yarasheski, Kevin E" sort="Yarasheski, Kevin E" uniqKey="Yarasheski K" first="Kevin E." last="Yarasheski">Kevin E. Yarasheski</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ostlund, Richard E" sort="Ostlund, Richard E" uniqKey="Ostlund R" first="Richard E." last="Ostlund">Richard E. Ostlund</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schechtman, Kenneth B" sort="Schechtman, Kenneth B" uniqKey="Schechtman K" first="Kenneth B." last="Schechtman">Kenneth B. Schechtman</name>
<affiliation>
<nlm:aff id="Aff3">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Biostatistics,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Razani, Babak" sort="Razani, Babak" uniqKey="Razani B" first="Babak" last="Razani">Babak Razani</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kastan, Michael B" sort="Kastan, Michael B" uniqKey="Kastan M" first="Michael B." last="Kastan">Michael B. Kastan</name>
<affiliation>
<nlm:aff id="Aff5">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0004 1936 7961</institution-id>
<institution-id institution-id-type="GRID">grid.26009.3d</institution-id>
<institution>Department of Pharmacology & Cancer Biology,</institution>
<institution>Duke University,</institution>
</institution-wrap>
Durham, NC USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mcclain, Donald A" sort="Mcclain, Donald A" uniqKey="Mcclain D" first="Donald A." last="Mcclain">Donald A. Mcclain</name>
<affiliation>
<nlm:aff id="Aff6">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2185 3318</institution-id>
<institution-id institution-id-type="GRID">grid.241167.7</institution-id>
<institution>Department of Internal Medicine,</institution>
<institution>Wake Forest School of Medicine,</institution>
</institution-wrap>
Winston-Salem, NC USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="De Las Fuentes, Lisa" sort="De Las Fuentes, Lisa" uniqKey="De Las Fuentes L" first="Lisa" last="De Las Fuentes">Lisa De Las Fuentes</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Davila Roman, Victor G" sort="Davila Roman, Victor G" uniqKey="Davila Roman V" first="Victor G." last="Davila-Roman">Victor G. Davila-Roman</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ory, Daniel S" sort="Ory, Daniel S" uniqKey="Ory D" first="Daniel S." last="Ory">Daniel S. Ory</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wickline, Samuel A" sort="Wickline, Samuel A" uniqKey="Wickline S" first="Samuel A." last="Wickline">Samuel A. Wickline</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Semenkovich, Clay F" sort="Semenkovich, Clay F" uniqKey="Semenkovich C" first="Clay F." last="Semenkovich">Clay F. Semenkovich</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff7">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Department of Cell Biology & Physiology,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt>
<idno type="wicri:source">PMC</idno>
<idno type="pmid">31384309</idno>
<idno type="pmc">6664523</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664523</idno>
<idno type="RBID">PMC:6664523</idno>
<idno type="doi">10.1186/s13098-019-0456-4</idno>
<date when="2019">2019</date>
<idno type="wicri:Area/Pmc/Corpus">000094</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000094</idno>
</publicationStmt>
<sourceDesc>
<biblStruct>
<analytic>
<title xml:lang="en" level="a" type="main">Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness</title>
<author>
<name sortKey="Mcgill, Janet B" sort="Mcgill, Janet B" uniqKey="Mcgill J" first="Janet B." last="Mcgill">Janet B. Mcgill</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Johnson, Mariko" sort="Johnson, Mariko" uniqKey="Johnson M" first="Mariko" last="Johnson">Mariko Johnson</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hurst, Stacy" sort="Hurst, Stacy" uniqKey="Hurst S" first="Stacy" last="Hurst">Stacy Hurst</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cade, William T" sort="Cade, William T" uniqKey="Cade W" first="William T." last="Cade">William T. Cade</name>
<affiliation>
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Program in Physical Therapy,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Yarasheski, Kevin E" sort="Yarasheski, Kevin E" uniqKey="Yarasheski K" first="Kevin E." last="Yarasheski">Kevin E. Yarasheski</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ostlund, Richard E" sort="Ostlund, Richard E" uniqKey="Ostlund R" first="Richard E." last="Ostlund">Richard E. Ostlund</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Schechtman, Kenneth B" sort="Schechtman, Kenneth B" uniqKey="Schechtman K" first="Kenneth B." last="Schechtman">Kenneth B. Schechtman</name>
<affiliation>
<nlm:aff id="Aff3">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Biostatistics,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Razani, Babak" sort="Razani, Babak" uniqKey="Razani B" first="Babak" last="Razani">Babak Razani</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kastan, Michael B" sort="Kastan, Michael B" uniqKey="Kastan M" first="Michael B." last="Kastan">Michael B. Kastan</name>
<affiliation>
<nlm:aff id="Aff5">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0004 1936 7961</institution-id>
<institution-id institution-id-type="GRID">grid.26009.3d</institution-id>
<institution>Department of Pharmacology & Cancer Biology,</institution>
<institution>Duke University,</institution>
</institution-wrap>
Durham, NC USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mcclain, Donald A" sort="Mcclain, Donald A" uniqKey="Mcclain D" first="Donald A." last="Mcclain">Donald A. Mcclain</name>
<affiliation>
<nlm:aff id="Aff6">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2185 3318</institution-id>
<institution-id institution-id-type="GRID">grid.241167.7</institution-id>
<institution>Department of Internal Medicine,</institution>
<institution>Wake Forest School of Medicine,</institution>
</institution-wrap>
Winston-Salem, NC USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="De Las Fuentes, Lisa" sort="De Las Fuentes, Lisa" uniqKey="De Las Fuentes L" first="Lisa" last="De Las Fuentes">Lisa De Las Fuentes</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Davila Roman, Victor G" sort="Davila Roman, Victor G" uniqKey="Davila Roman V" first="Victor G." last="Davila-Roman">Victor G. Davila-Roman</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ory, Daniel S" sort="Ory, Daniel S" uniqKey="Ory D" first="Daniel S." last="Ory">Daniel S. Ory</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wickline, Samuel A" sort="Wickline, Samuel A" uniqKey="Wickline S" first="Samuel A." last="Wickline">Samuel A. Wickline</name>
<affiliation>
<nlm:aff id="Aff4">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Semenkovich, Clay F" sort="Semenkovich, Clay F" uniqKey="Semenkovich C" first="Clay F." last="Semenkovich">Clay F. Semenkovich</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff7">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Department of Cell Biology & Physiology,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Diabetology & Metabolic Syndrome</title>
<idno type="eISSN">1758-5996</idno>
<imprint>
<date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<sec>
<title>Background</title>
<p id="Par1">Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome.</p>
</sec>
<sec>
<title>Methods</title>
<p id="Par2">Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment.</p>
</sec>
<sec>
<title>Results</title>
<p id="Par3">For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups.</p>
</sec>
<sec>
<title>Conclusions</title>
<p id="Par4">These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.</p>
<p id="Par5">
<italic>Trial registration</italic>
ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007</p>
</sec>
</div>
</front>
<back>
<div1 type="bibliography">
<listBibl>
<biblStruct>
<analytic>
<author>
<name sortKey="Eckel, Rh" uniqKey="Eckel R">RH Eckel</name>
</author>
<author>
<name sortKey="Alberti, Kg" uniqKey="Alberti K">KG Alberti</name>
</author>
<author>
<name sortKey="Grundy, Sm" uniqKey="Grundy S">SM Grundy</name>
</author>
<author>
<name sortKey="Zimmet, Pz" uniqKey="Zimmet P">PZ Zimmet</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Mottillo, S" uniqKey="Mottillo S">S Mottillo</name>
</author>
<author>
<name sortKey="Filion, Kb" uniqKey="Filion K">KB Filion</name>
</author>
<author>
<name sortKey="Genest, J" uniqKey="Genest J">J Genest</name>
</author>
<author>
<name sortKey="Joseph, L" uniqKey="Joseph L">L Joseph</name>
</author>
<author>
<name sortKey="Pilote, L" uniqKey="Pilote L">L Pilote</name>
</author>
<author>
<name sortKey="Poirier, P" uniqKey="Poirier P">P Poirier</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Solinas, G" uniqKey="Solinas G">G Solinas</name>
</author>
<author>
<name sortKey="Becattini, B" uniqKey="Becattini B">B Becattini</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Look, Arg" uniqKey="Look A">ARG Look</name>
</author>
<author>
<name sortKey="Gregg, Ew" uniqKey="Gregg E">EW Gregg</name>
</author>
<author>
<name sortKey="Jakicic, Jm" uniqKey="Jakicic J">JM Jakicic</name>
</author>
<author>
<name sortKey="Blackburn, G" uniqKey="Blackburn G">G Blackburn</name>
</author>
<author>
<name sortKey="Bloomquist, P" uniqKey="Bloomquist P">P Bloomquist</name>
</author>
<author>
<name sortKey="Bray, Ga" uniqKey="Bray G">GA Bray</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Semenkovich, Cf" uniqKey="Semenkovich C">CF Semenkovich</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Schneider, Jg" uniqKey="Schneider J">JG Schneider</name>
</author>
<author>
<name sortKey="Finck, Bn" uniqKey="Finck B">BN Finck</name>
</author>
<author>
<name sortKey="Ren, J" uniqKey="Ren J">J Ren</name>
</author>
<author>
<name sortKey="Standley, Kn" uniqKey="Standley K">KN Standley</name>
</author>
<author>
<name sortKey="Takagi, M" uniqKey="Takagi M">M Takagi</name>
</author>
<author>
<name sortKey="Maclean, Kh" uniqKey="Maclean K">KH Maclean</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Mercer, Jr" uniqKey="Mercer J">JR Mercer</name>
</author>
<author>
<name sortKey="Cheng, Kk" uniqKey="Cheng K">KK Cheng</name>
</author>
<author>
<name sortKey="Figg, N" uniqKey="Figg N">N Figg</name>
</author>
<author>
<name sortKey="Gorenne, I" uniqKey="Gorenne I">I Gorenne</name>
</author>
<author>
<name sortKey="Mahmoudi, M" uniqKey="Mahmoudi M">M Mahmoudi</name>
</author>
<author>
<name sortKey="Griffin, J" uniqKey="Griffin J">J Griffin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Le Guezennec, X" uniqKey="Le Guezennec X">X Le Guezennec</name>
</author>
<author>
<name sortKey="Brichkina, A" uniqKey="Brichkina A">A Brichkina</name>
</author>
<author>
<name sortKey="Huang, Yf" uniqKey="Huang Y">YF Huang</name>
</author>
<author>
<name sortKey="Kostromina, E" uniqKey="Kostromina E">E Kostromina</name>
</author>
<author>
<name sortKey="Han, W" uniqKey="Han W">W Han</name>
</author>
<author>
<name sortKey="Bulavin, Dv" uniqKey="Bulavin D">DV Bulavin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Razani, B" uniqKey="Razani B">B Razani</name>
</author>
<author>
<name sortKey="Feng, C" uniqKey="Feng C">C Feng</name>
</author>
<author>
<name sortKey="Semenkovich, Cf" uniqKey="Semenkovich C">CF Semenkovich</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Geisel, Mh" uniqKey="Geisel M">MH Geisel</name>
</author>
<author>
<name sortKey="Bauer, M" uniqKey="Bauer M">M Bauer</name>
</author>
<author>
<name sortKey="Hennig, F" uniqKey="Hennig F">F Hennig</name>
</author>
<author>
<name sortKey="Hoffmann, B" uniqKey="Hoffmann B">B Hoffmann</name>
</author>
<author>
<name sortKey="Lehmann, N" uniqKey="Lehmann N">N Lehmann</name>
</author>
<author>
<name sortKey="Mohlenkamp, S" uniqKey="Mohlenkamp S">S Mohlenkamp</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Subramanian, S" uniqKey="Subramanian S">S Subramanian</name>
</author>
<author>
<name sortKey="Derosa, Ma" uniqKey="Derosa M">MA DeRosa</name>
</author>
<author>
<name sortKey="Bernal Mizrachi, C" uniqKey="Bernal Mizrachi C">C Bernal-Mizrachi</name>
</author>
<author>
<name sortKey="Laffely, N" uniqKey="Laffely N">N Laffely</name>
</author>
<author>
<name sortKey="Cade, Wt" uniqKey="Cade W">WT Cade</name>
</author>
<author>
<name sortKey="Yarasheski, Ke" uniqKey="Yarasheski K">KE Yarasheski</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Derosa, G" uniqKey="Derosa G">G Derosa</name>
</author>
<author>
<name sortKey="Fogari, E" uniqKey="Fogari E">E Fogari</name>
</author>
<author>
<name sortKey="D Ngelo, A" uniqKey="D Ngelo A">A D’Angelo</name>
</author>
<author>
<name sortKey="Bianchi, L" uniqKey="Bianchi L">L Bianchi</name>
</author>
<author>
<name sortKey="Bonaventura, A" uniqKey="Bonaventura A">A Bonaventura</name>
</author>
<author>
<name sortKey="Romano, D" uniqKey="Romano D">D Romano</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Derosa, G" uniqKey="Derosa G">G Derosa</name>
</author>
<author>
<name sortKey="Bonaventura, A" uniqKey="Bonaventura A">A Bonaventura</name>
</author>
<author>
<name sortKey="Bianchi, L" uniqKey="Bianchi L">L Bianchi</name>
</author>
<author>
<name sortKey="Romano, D" uniqKey="Romano D">D Romano</name>
</author>
<author>
<name sortKey="Fogari, E" uniqKey="Fogari E">E Fogari</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Azimi Nezhad, M" uniqKey="Azimi Nezhad M">M Azimi-Nezhad</name>
</author>
<author>
<name sortKey="Mirhafez, Sr" uniqKey="Mirhafez S">SR Mirhafez</name>
</author>
<author>
<name sortKey="Stathopoulou, Mg" uniqKey="Stathopoulou M">MG Stathopoulou</name>
</author>
<author>
<name sortKey="Murray, H" uniqKey="Murray H">H Murray</name>
</author>
<author>
<name sortKey="Ndiaye, Nc" uniqKey="Ndiaye N">NC Ndiaye</name>
</author>
<author>
<name sortKey="Bahrami, A" uniqKey="Bahrami A">A Bahrami</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Suarez Ortegon, Mf" uniqKey="Suarez Ortegon M">MF Suarez-Ortegon</name>
</author>
<author>
<name sortKey="Blanco, E" uniqKey="Blanco E">E Blanco</name>
</author>
<author>
<name sortKey="Mclachlan, S" uniqKey="Mclachlan S">S McLachlan</name>
</author>
<author>
<name sortKey="Fernandez Real, Jm" uniqKey="Fernandez Real J">JM Fernandez-Real</name>
</author>
<author>
<name sortKey="Burrows, R" uniqKey="Burrows R">R Burrows</name>
</author>
<author>
<name sortKey="Wild, Sh" uniqKey="Wild S">SH Wild</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Demir, E" uniqKey="Demir E">E Demir</name>
</author>
<author>
<name sortKey="Harmankaya, No" uniqKey="Harmankaya N">NO Harmankaya</name>
</author>
<author>
<name sortKey="Kirac Utku, I" uniqKey="Kirac Utku I">I Kirac Utku</name>
</author>
<author>
<name sortKey="Aciksari, G" uniqKey="Aciksari G">G Aciksari</name>
</author>
<author>
<name sortKey="Uygun, T" uniqKey="Uygun T">T Uygun</name>
</author>
<author>
<name sortKey="Ozkan, H" uniqKey="Ozkan H">H Ozkan</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Gabrielsen, Js" uniqKey="Gabrielsen J">JS Gabrielsen</name>
</author>
<author>
<name sortKey="Gao, Y" uniqKey="Gao Y">Y Gao</name>
</author>
<author>
<name sortKey="Simcox, Ja" uniqKey="Simcox J">JA Simcox</name>
</author>
<author>
<name sortKey="Huang, J" uniqKey="Huang J">J Huang</name>
</author>
<author>
<name sortKey="Thorup, D" uniqKey="Thorup D">D Thorup</name>
</author>
<author>
<name sortKey="Jones, D" uniqKey="Jones D">D Jones</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Stein, Jh" uniqKey="Stein J">JH Stein</name>
</author>
<author>
<name sortKey="Korcarz, Ce" uniqKey="Korcarz C">CE Korcarz</name>
</author>
<author>
<name sortKey="Hurst, Rt" uniqKey="Hurst R">RT Hurst</name>
</author>
<author>
<name sortKey="Lonn, E" uniqKey="Lonn E">E Lonn</name>
</author>
<author>
<name sortKey="Kendall, Cb" uniqKey="Kendall C">CB Kendall</name>
</author>
<author>
<name sortKey="Mohler, Er" uniqKey="Mohler E">ER Mohler</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="De Fuentes, L" uniqKey="De Fuentes L">L de Fuentes</name>
</author>
<author>
<name sortKey="Waggoner, Ad" uniqKey="Waggoner A">AD Waggoner</name>
</author>
<author>
<name sortKey="Mohammed, Bs" uniqKey="Mohammed B">BS Mohammed</name>
</author>
<author>
<name sortKey="Stein, Ri" uniqKey="Stein R">RI Stein</name>
</author>
<author>
<name sortKey="Miller, Bv" uniqKey="Miller B">BV Miller</name>
</author>
<author>
<name sortKey="Foster, Gd" uniqKey="Foster G">GD Foster</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Porter, Fd" uniqKey="Porter F">FD Porter</name>
</author>
<author>
<name sortKey="Scherrer, De" uniqKey="Scherrer D">DE Scherrer</name>
</author>
<author>
<name sortKey="Lanier, Mh" uniqKey="Lanier M">MH Lanier</name>
</author>
<author>
<name sortKey="Langmade, Sj" uniqKey="Langmade S">SJ Langmade</name>
</author>
<author>
<name sortKey="Molugu, V" uniqKey="Molugu V">V Molugu</name>
</author>
<author>
<name sortKey="Gale, Se" uniqKey="Gale S">SE Gale</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Yaghootkar, H" uniqKey="Yaghootkar H">H Yaghootkar</name>
</author>
<author>
<name sortKey="Lamina, C" uniqKey="Lamina C">C Lamina</name>
</author>
<author>
<name sortKey="Scott, Ra" uniqKey="Scott R">RA Scott</name>
</author>
<author>
<name sortKey="Dastani, Z" uniqKey="Dastani Z">Z Dastani</name>
</author>
<author>
<name sortKey="Hivert, Mf" uniqKey="Hivert M">MF Hivert</name>
</author>
<author>
<name sortKey="Warren, Ll" uniqKey="Warren L">LL Warren</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Simcox, Ja" uniqKey="Simcox J">JA Simcox</name>
</author>
<author>
<name sortKey="Mcclain, Da" uniqKey="Mcclain D">DA McClain</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ramm, Ga" uniqKey="Ramm G">GA Ramm</name>
</author>
<author>
<name sortKey="Powell, Lw" uniqKey="Powell L">LW Powell</name>
</author>
<author>
<name sortKey="Halliday, Jw" uniqKey="Halliday J">JW Halliday</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Matsuda, M" uniqKey="Matsuda M">M Matsuda</name>
</author>
<author>
<name sortKey="Defronzo, Ra" uniqKey="Defronzo R">RA DeFronzo</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Han, Ms" uniqKey="Han M">MS Han</name>
</author>
<author>
<name sortKey="Jung, Dy" uniqKey="Jung D">DY Jung</name>
</author>
<author>
<name sortKey="Morel, C" uniqKey="Morel C">C Morel</name>
</author>
<author>
<name sortKey="Lakhani, Sa" uniqKey="Lakhani S">SA Lakhani</name>
</author>
<author>
<name sortKey="Kim, Jk" uniqKey="Kim J">JK Kim</name>
</author>
<author>
<name sortKey="Flavell, Ra" uniqKey="Flavell R">RA Flavell</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Houstis, N" uniqKey="Houstis N">N Houstis</name>
</author>
<author>
<name sortKey="Rosen, Ed" uniqKey="Rosen E">ED Rosen</name>
</author>
<author>
<name sortKey="Lander, Es" uniqKey="Lander E">ES Lander</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Minamikawa, J" uniqKey="Minamikawa J">J Minamikawa</name>
</author>
<author>
<name sortKey="Tanaka, S" uniqKey="Tanaka S">S Tanaka</name>
</author>
<author>
<name sortKey="Yamauchi, M" uniqKey="Yamauchi M">M Yamauchi</name>
</author>
<author>
<name sortKey="Inoue, D" uniqKey="Inoue D">D Inoue</name>
</author>
<author>
<name sortKey="Koshiyama, H" uniqKey="Koshiyama H">H Koshiyama</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Koshiyama, H" uniqKey="Koshiyama H">H Koshiyama</name>
</author>
<author>
<name sortKey="Shimono, D" uniqKey="Shimono D">D Shimono</name>
</author>
<author>
<name sortKey="Kuwamura, N" uniqKey="Kuwamura N">N Kuwamura</name>
</author>
<author>
<name sortKey="Minamikawa, J" uniqKey="Minamikawa J">J Minamikawa</name>
</author>
<author>
<name sortKey="Nakamura, Y" uniqKey="Nakamura Y">Y Nakamura</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Stocker, Dj" uniqKey="Stocker D">DJ Stocker</name>
</author>
<author>
<name sortKey="Taylor, Aj" uniqKey="Taylor A">AJ Taylor</name>
</author>
<author>
<name sortKey="Langley, Rw" uniqKey="Langley R">RW Langley</name>
</author>
<author>
<name sortKey="Jezior, Mr" uniqKey="Jezior M">MR Jezior</name>
</author>
<author>
<name sortKey="Vigersky, Ra" uniqKey="Vigersky R">RA Vigersky</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Xiang, Ah" uniqKey="Xiang A">AH Xiang</name>
</author>
<author>
<name sortKey="Hodis, Hn" uniqKey="Hodis H">HN Hodis</name>
</author>
<author>
<name sortKey="Kawakubo, M" uniqKey="Kawakubo M">M Kawakubo</name>
</author>
<author>
<name sortKey="Peters, Rk" uniqKey="Peters R">RK Peters</name>
</author>
<author>
<name sortKey="Kjos, Sl" uniqKey="Kjos S">SL Kjos</name>
</author>
<author>
<name sortKey="Marroquin, A" uniqKey="Marroquin A">A Marroquin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Saremi, A" uniqKey="Saremi A">A Saremi</name>
</author>
<author>
<name sortKey="Schwenke, Dc" uniqKey="Schwenke D">DC Schwenke</name>
</author>
<author>
<name sortKey="Buchanan, Ta" uniqKey="Buchanan T">TA Buchanan</name>
</author>
<author>
<name sortKey="Hodis, Hn" uniqKey="Hodis H">HN Hodis</name>
</author>
<author>
<name sortKey="Mack, Wj" uniqKey="Mack W">WJ Mack</name>
</author>
<author>
<name sortKey="Banerji, M" uniqKey="Banerji M">M Banerji</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kaneto, H" uniqKey="Kaneto H">H Kaneto</name>
</author>
<author>
<name sortKey="Nakatani, Y" uniqKey="Nakatani Y">Y Nakatani</name>
</author>
<author>
<name sortKey="Miyatsuka, T" uniqKey="Miyatsuka T">T Miyatsuka</name>
</author>
<author>
<name sortKey="Kawamori, D" uniqKey="Kawamori D">D Kawamori</name>
</author>
<author>
<name sortKey="Matsuoka, Ta" uniqKey="Matsuoka T">TA Matsuoka</name>
</author>
<author>
<name sortKey="Matsuhisa, M" uniqKey="Matsuhisa M">M Matsuhisa</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ricci, R" uniqKey="Ricci R">R Ricci</name>
</author>
<author>
<name sortKey="Sumara, G" uniqKey="Sumara G">G Sumara</name>
</author>
<author>
<name sortKey="Sumara, I" uniqKey="Sumara I">I Sumara</name>
</author>
<author>
<name sortKey="Rozenberg, I" uniqKey="Rozenberg I">I Rozenberg</name>
</author>
<author>
<name sortKey="Kurrer, M" uniqKey="Kurrer M">M Kurrer</name>
</author>
<author>
<name sortKey="Akhmedov, A" uniqKey="Akhmedov A">A Akhmedov</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Valentin Vega, Ya" uniqKey="Valentin Vega Y">YA Valentin-Vega</name>
</author>
<author>
<name sortKey="Maclean, Kh" uniqKey="Maclean K">KH Maclean</name>
</author>
<author>
<name sortKey="Tait Mulder, J" uniqKey="Tait Mulder J">J Tait-Mulder</name>
</author>
<author>
<name sortKey="Milasta, S" uniqKey="Milasta S">S Milasta</name>
</author>
<author>
<name sortKey="Steeves, M" uniqKey="Steeves M">M Steeves</name>
</author>
<author>
<name sortKey="Dorsey, Fc" uniqKey="Dorsey F">FC Dorsey</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Madiraju, Ak" uniqKey="Madiraju A">AK Madiraju</name>
</author>
<author>
<name sortKey="Qiu, Y" uniqKey="Qiu Y">Y Qiu</name>
</author>
<author>
<name sortKey="Perry, Rj" uniqKey="Perry R">RJ Perry</name>
</author>
<author>
<name sortKey="Rahimi, Y" uniqKey="Rahimi Y">Y Rahimi</name>
</author>
<author>
<name sortKey="Zhang, Xm" uniqKey="Zhang X">XM Zhang</name>
</author>
<author>
<name sortKey="Zhang, D" uniqKey="Zhang D">D Zhang</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Zhou, K" uniqKey="Zhou K">K Zhou</name>
</author>
<author>
<name sortKey="Bellenguez, C" uniqKey="Bellenguez C">C Bellenguez</name>
</author>
<author>
<name sortKey="Spencer, Cc" uniqKey="Spencer C">CC Spencer</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Gerstein, Hc" uniqKey="Gerstein H">HC Gerstein</name>
</author>
<author>
<name sortKey="Thorpe, Ke" uniqKey="Thorpe K">KE Thorpe</name>
</author>
<author>
<name sortKey="Taylor, Dw" uniqKey="Taylor D">DW Taylor</name>
</author>
<author>
<name sortKey="Haynes, Rb" uniqKey="Haynes R">RB Haynes</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Sheikhbahaie, F" uniqKey="Sheikhbahaie F">F Sheikhbahaie</name>
</author>
<author>
<name sortKey="Amini, M" uniqKey="Amini M">M Amini</name>
</author>
<author>
<name sortKey="Gharipour, M" uniqKey="Gharipour M">M Gharipour</name>
</author>
<author>
<name sortKey="Aminoroaya, A" uniqKey="Aminoroaya A">A Aminoroaya</name>
</author>
<author>
<name sortKey="Taheri, N" uniqKey="Taheri N">N Taheri</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Wasko, Mc" uniqKey="Wasko M">MC Wasko</name>
</author>
<author>
<name sortKey="Hubert, Hb" uniqKey="Hubert H">HB Hubert</name>
</author>
<author>
<name sortKey="Lingala, Vb" uniqKey="Lingala V">VB Lingala</name>
</author>
<author>
<name sortKey="Elliott, Jr" uniqKey="Elliott J">JR Elliott</name>
</author>
<author>
<name sortKey="Luggen, Me" uniqKey="Luggen M">ME Luggen</name>
</author>
<author>
<name sortKey="Fries, Jf" uniqKey="Fries J">JF Fries</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Solomon, Dh" uniqKey="Solomon D">DH Solomon</name>
</author>
<author>
<name sortKey="Massarotti, E" uniqKey="Massarotti E">E Massarotti</name>
</author>
<author>
<name sortKey="Garg, R" uniqKey="Garg R">R Garg</name>
</author>
<author>
<name sortKey="Liu, J" uniqKey="Liu J">J Liu</name>
</author>
<author>
<name sortKey="Canning, C" uniqKey="Canning C">C Canning</name>
</author>
<author>
<name sortKey="Schneeweiss, S" uniqKey="Schneeweiss S">S Schneeweiss</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Mercer, E" uniqKey="Mercer E">E Mercer</name>
</author>
<author>
<name sortKey="Rekedal, L" uniqKey="Rekedal L">L Rekedal</name>
</author>
<author>
<name sortKey="Garg, R" uniqKey="Garg R">R Garg</name>
</author>
<author>
<name sortKey="Lu, B" uniqKey="Lu B">B Lu</name>
</author>
<author>
<name sortKey="Massarotti, Em" uniqKey="Massarotti E">EM Massarotti</name>
</author>
<author>
<name sortKey="Solomon, Dh" uniqKey="Solomon D">DH Solomon</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Diabetol Metab Syndr</journal-id>
<journal-id journal-id-type="iso-abbrev">Diabetol Metab Syndr</journal-id>
<journal-title-group>
<journal-title>Diabetology & Metabolic Syndrome</journal-title>
</journal-title-group>
<issn pub-type="epub">1758-5996</issn>
<publisher>
<publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">31384309</article-id>
<article-id pub-id-type="pmc">6664523</article-id>
<article-id pub-id-type="publisher-id">456</article-id>
<article-id pub-id-type="doi">10.1186/s13098-019-0456-4</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Research</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes" equal-contrib="yes">
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-6228-6521</contrib-id>
<name>
<surname>McGill</surname>
<given-names>Janet B.</given-names>
</name>
<address>
<phone>314.362.7617</phone>
<email>jmcgill@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Johnson</surname>
<given-names>Mariko</given-names>
</name>
<address>
<email>marikojohnson@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hurst</surname>
<given-names>Stacy</given-names>
</name>
<address>
<email>shurst@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cade</surname>
<given-names>William T.</given-names>
</name>
<address>
<email>tcade@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Yarasheski</surname>
<given-names>Kevin E.</given-names>
</name>
<address>
<email>kyarasheski@c2ndiagnostics.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ostlund</surname>
<given-names>Richard E.</given-names>
</name>
<address>
<email>rostlund@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Schechtman</surname>
<given-names>Kenneth B.</given-names>
</name>
<address>
<email>kschechtman@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Razani</surname>
<given-names>Babak</given-names>
</name>
<address>
<email>brazani@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kastan</surname>
<given-names>Michael B.</given-names>
</name>
<address>
<email>michael.kastan@duke.edu</email>
</address>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>McClain</surname>
<given-names>Donald A.</given-names>
</name>
<address>
<email>dmcclain@wakehealth.edu</email>
</address>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>de las Fuentes</surname>
<given-names>Lisa</given-names>
</name>
<address>
<email>lfuentes@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Davila-Roman</surname>
<given-names>Victor G.</given-names>
</name>
<address>
<email>vdavila@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ory</surname>
<given-names>Daniel S.</given-names>
</name>
<address>
<email>dory@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wickline</surname>
<given-names>Samuel A.</given-names>
</name>
<address>
<email>wicklines@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Semenkovich</surname>
<given-names>Clay F.</given-names>
</name>
<address>
<email>csemenko@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff7">7</xref>
</contrib>
<aff id="Aff1">
<label>1</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA</aff>
<aff id="Aff2">
<label>2</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Program in Physical Therapy,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</aff>
<aff id="Aff3">
<label>3</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Division of Biostatistics,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</aff>
<aff id="Aff4">
<label>4</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Cardiovascular Division,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</aff>
<aff id="Aff5">
<label>5</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0004 1936 7961</institution-id>
<institution-id institution-id-type="GRID">grid.26009.3d</institution-id>
<institution>Department of Pharmacology & Cancer Biology,</institution>
<institution>Duke University,</institution>
</institution-wrap>
Durham, NC USA</aff>
<aff id="Aff6">
<label>6</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2185 3318</institution-id>
<institution-id institution-id-type="GRID">grid.241167.7</institution-id>
<institution>Department of Internal Medicine,</institution>
<institution>Wake Forest School of Medicine,</institution>
</institution-wrap>
Winston-Salem, NC USA</aff>
<aff id="Aff7">
<label>7</label>
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Department of Cell Biology & Physiology,</institution>
<institution>Washington University,</institution>
</institution-wrap>
St. Louis, MO USA</aff>
</contrib-group>
<pub-date pub-type="epub">
<day>29</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release">
<day>29</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection">
<year>2019</year>
</pub-date>
<volume>11</volume>
<elocation-id>61</elocation-id>
<history>
<date date-type="received">
<day>5</day>
<month>4</month>
<year>2019</year>
</date>
<date date-type="accepted">
<day>20</day>
<month>7</month>
<year>2019</year>
</date>
</history>
<permissions>
<copyright-statement>© The Author(s) 2019</copyright-statement>
<license license-type="OpenAccess">
<license-p>
<bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1">
<sec>
<title>Background</title>
<p id="Par1">Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome.</p>
</sec>
<sec>
<title>Methods</title>
<p id="Par2">Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment.</p>
</sec>
<sec>
<title>Results</title>
<p id="Par3">For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups.</p>
</sec>
<sec>
<title>Conclusions</title>
<p id="Par4">These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.</p>
<p id="Par5">
<italic>Trial registration</italic>
ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007</p>
</sec>
</abstract>
<kwd-group xml:lang="en">
<title>Keywords</title>
<kwd>Chloroquine</kwd>
<kwd>Metabolic syndrome</kwd>
<kwd>Carotid intima-media thickness</kwd>
<kwd>Insulin sensitivity</kwd>
<kwd>Glucose disposal</kwd>
<kwd>Atheroma</kwd>
<kwd>Blood pressure</kwd>
<kwd>Lipids</kwd>
<kwd>JNK</kwd>
</kwd-group>
<funding-group>
<award-group>
<funding-source>
<institution-wrap>
<institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000050</institution-id>
<institution>National Heart, Lung, and Blood Institute</institution>
</institution-wrap>
</funding-source>
<award-id>HL083762</award-id>
<award-id>DK020579</award-id>
<award-id>DK076729</award-id>
<principal-award-recipient>
<name>
<surname>Semenkovich</surname>
<given-names>Clay F.</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group>
<custom-meta>
<meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body>
<sec id="Sec1">
<title>Introduction</title>
<p id="Par37">A combination of increased triglycerides, low HDL cholesterol, hypertension, above normal fasting glucose, and increased waist circumference constitutes the metabolic syndrome [
<xref ref-type="bibr" rid="CR1">1</xref>
], which predisposes to diabetes, cardiovascular disease, and all-cause mortality [
<xref ref-type="bibr" rid="CR2">2</xref>
]. Current therapy is directed at individual components of the syndrome, which are related to insulin resistance. Obesity-related insulin resistance is associated with low-grade systemic inflammation characterized by increased activation of a stress kinase known to induce insulin resistance, c-Jun N-terminal kinase (JNK) [
<xref ref-type="bibr" rid="CR3">3</xref>
]. Pronounced weight loss is associated with decreased cardiovascular events [
<xref ref-type="bibr" rid="CR4">4</xref>
], but there are other causes of insulin resistance besides obesity that could provide insight into relationships between insulin resistance and cardiovascular disease. DNA damage disorders including Hutchinson–Gilford progeria, Werner syndrome, Cockayne syndrome, and ataxia telangiectasia are associated with insulin resistance and vascular disease [
<xref ref-type="bibr" rid="CR5">5</xref>
]. Mice deficient in ataxia telangiectasia mutated (ATM), the kinase mutated in ataxia telangiectasia, have increased activation of JNK in macrophages, insulin resistance, hypertension, and increased atherosclerosis [
<xref ref-type="bibr" rid="CR6">6</xref>
–
<xref ref-type="bibr" rid="CR8">8</xref>
]. ATM activation by the anti-malarial drug chloroquine decreases macrophage JNK activation, blood pressure, insulin resistance, and atherosclerosis in mice [
<xref ref-type="bibr" rid="CR6">6</xref>
,
<xref ref-type="bibr" rid="CR9">9</xref>
].</p>
<p id="Par38">Since the ATM axis is associated with altered hepatic insulin sensitivity and atherosclerosis in mice, we translated these rodent data to humans with metabolic syndrome in two exploratory clinical trials: (1) A dose escalation study with a primary endpoint of insulin sensitivity and pre-specified secondary endpoints including serum lipids and blood pressure; and (2) Placebo or chloroquine treatment for 1 year with a primary endpoint of carotid intima-media thickness, a noninvasive predictor of cardiovascular events [
<xref ref-type="bibr" rid="CR10">10</xref>
]. The 1 year study utilized the lowest dose associated with improved insulin sensitivity in the dose escalation study and included pre-specified secondary endpoints such as carotid MRI, activation of JNK in isolated monocytes, serum lipids, and blood pressure.</p>
</sec>
<sec id="Sec2">
<title>Subjects and methods</title>
<sec id="Sec3">
<title>Subjects and trial design</title>
<p id="Par39">These single center studies were approved by the Washington University Human Research Protection Office. All subjects gave informed consent and were compensated for their participation. A data safety and monitoring board convened by the National Heart, Lung and Blood Institute (NHLBI) supervised the trials.</p>
<p id="Par40">For both the dose escalation and double blind trials, inclusion criteria included men and women of any ethnic group between the ages of 18–60 (Trial 1), and 18–70 (Trial 2) (the difference in age between protocols was intended to make the randomized trial more pertinent to a broader age group) who had at least 3 of the components of the metabolic syndrome: elevated fasting triglycerides (≥ 1.69 mmol/L); low HDL cholesterol (< 1.29 mmol/L in women, < 1.03 mmol/L in men); hypertension (≥ 130/85 mm Hg ≤ 160/100 mmHg) untreated, or hypertension controlled (≤ 150/90 mm Hg) on a stable medication regimen; increased waist circumference (> 89 cm in women, > 102 cm in men); elevated fasting glucose (≥ 5.6 mmol/L and < 7.0 mmol/L). For a diagnosis of hypertension, measurements were repeated on two separate days. Fasting glucose was also repeated on two separate days. Fasting lipids were performed once before enrollment but repeated throughout the interventions.</p>
<p id="Par41">Exclusion criteria were extensive and included: known prior treatment with chloroquine or hydroxychloroquine, BMI > 45 kg/m
<sup>2</sup>
, coronary artery disease or other vascular disease, history of stroke, eGFR (estimated glomerular filtration rate) < 60 ml/min/1.73 m
<sup>2</sup>
, diabetes, seizure disorder, history of psoriasis, hematological disorders (including anemia), current malignancy, asthma or COPD (chronic obstructive pulmonary disease), liver disease (including transaminases > 2× upper limit of normal), active infection (including HIV-human immunodeficiency virus), any serious illness requiring ongoing medical care, major psychiatric illness, lipid lowering medications (other than statins and < 1 g daily fish oils), severe hypertension at baseline or taking more than three antihypertensives, use of cimetidine or vitamin E, pregnancy or lactation or intention to become pregnant, inadequate use of contraception, glucose-6-phosphate dehydrogenase deficiency, auditory disease or hearing loss, retinal disease (especially presence of drusen or pigmentary changes at the macula), and any ocular disease interfering with the ability to rigorously assess the retina.</p>
<p id="Par42">A CONSORT statement flow diagram for the first trial is shown in Fig. 
<xref rid="Fig1" ref-type="fig">1</xref>
. The study design for the first trial is shown in Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
a. One hundred forty-four subjects were screened for participation in Trial 1 and 35 individuals with the metabolic syndrome qualified. Twenty-five subjects completed the protocol. Ten discontinued the study for reasons that included: starting a new medication during the protocol [
<xref ref-type="bibr" rid="CR3">3</xref>
], new diagnosis of diabetes during the protocol [
<xref ref-type="bibr" rid="CR1">1</xref>
], difficult IV access [
<xref ref-type="bibr" rid="CR1">1</xref>
], worsening joint symptoms [
<xref ref-type="bibr" rid="CR1">1</xref>
], and miscellaneous issues unrelated to the protocol (such as relocation, 4). For this single blind, placebo-controlled study, each subject took a capsule that was identical in appearance for 21 days. For the first limb, capsule contents were inert. For the second limb, three of the 21 capsules (administered at weekly intervals) contained 80 mg of chloroquine and the remaining capsules were inert. For the third and fourth limbs, capsules contained 80 or 250 mg of chloroquine, respectively. Each limb was separated by a washout period to allow recovery from the blood drawing of the clamp procedure. It was not possible to randomize limb order due to the extremely long half-life of chloroquine; ingestion during an early limb would be associated with tissue levels of the drug and its metabolites during a later placebo limb.
<fig id="Fig1">
<label>Fig. 1</label>
<caption>
<p>CONSORT statement flow diagram for subjects in dose escalation study</p>
</caption>
<graphic xlink:href="13098_2019_456_Fig1_HTML" id="MO1"></graphic>
</fig>
<fig id="Fig2">
<label>Fig. 2</label>
<caption>
<p>Chloroquine dose escalation trial design and results for hyperinsulinemic-euglycemic clamping and lipids.
<bold>a</bold>
Diagram of the dose escalation protocol. A 5–7 week washout period was required between limbs to allow for hematologic recovery following the blood drawing associated with clamps.
<bold>b</bold>
Glucose disposal rates expressed as μmol glucose/kg body weight/min. Insulin infusion rates were 0, 56, 181, or 486 pmol/m
<sup>2</sup>
/min.
<bold>c</bold>
Hepatic glucose production expressed as (μmol glucose/kg body weight/min) per pmol/L insulin.
<bold>d</bold>
Hepatic insulin sensitivity expressed as percent suppression of glucose production at 56 pmol/m
<sup>2</sup>
/min.
<bold>e</bold>
Total, non-HDL, and LDL cholesterol at the end of each limb.
<bold>f</bold>
Triglycerides and HDL cholesterol at the end of each limb. Data represent mean ± SE. *P < 0.05 by Tukey’s test for multiple comparisons after repeated measures ANOVA</p>
</caption>
<graphic xlink:href="13098_2019_456_Fig2_HTML" id="MO2"></graphic>
</fig>
</p>
<p id="Par43">A CONSORT statement flow diagram for the second trial is shown in Fig. 
<xref rid="Fig3" ref-type="fig">3</xref>
. The study design for the second trial is shown in Fig. 
<xref rid="Fig4" ref-type="fig">4</xref>
a. The blind was held by a research pharmacist, who provided the randomization sequence to the blinded research nurses or physicians who enrolled participants and assigned interventions that included study medications that were identical in appearance. Three hundred fifty-seven subjects were screened for participation in Trial 2 and 155 non-diabetic individuals with metabolic syndrome qualified at the initial screening visit. Of these, 21 withdrew consent before the second screening visit, 4 withdrew consent after the second screening visit and 14 did not qualify for randomization due to abnormal eye exams [
<xref ref-type="bibr" rid="CR4">4</xref>
], abnormal carotid imaging [
<xref ref-type="bibr" rid="CR2">2</xref>
], anemia [
<xref ref-type="bibr" rid="CR3">3</xref>
], G6PD deficiency [
<xref ref-type="bibr" rid="CR2">2</xref>
], abnormal liver function tests [
<xref ref-type="bibr" rid="CR2">2</xref>
], and psoriasis [
<xref ref-type="bibr" rid="CR1">1</xref>
]. The remaining 116 subjects were randomized to placebo or chloroquine. Of those randomized, 19 assigned to placebo and 20 assigned to chloroquine were being treated for hypertension, and were taking 1.3 ± 1.1 and 1.1 ± 1.0 antihypertensive medications respectively. 15 subjects in each group were taking a statin.
<fig id="Fig3">
<label>Fig. 3</label>
<caption>
<p>CONSORT statement flow diagram for subjects in the yearlong randomized clinical trial</p>
</caption>
<graphic xlink:href="13098_2019_456_Fig3_HTML" id="MO3"></graphic>
</fig>
<fig id="Fig4">
<label>Fig. 4</label>
<caption>
<p>Yearlong chloroquine trial design and results for carotid imaging.
<bold>a</bold>
Diagram of the vascular endpoint trial. After 12 months of placebo or chloroquine, both were stopped, then subjects returned at 24 months for limited additional studies.
<bold>b</bold>
CIMT results. Standard deviations (not included to simplify data presentation) and n values for these data follow. Chloroquine: 0, 0.76625 ± 0.17270 (n = 56); 6 months, 0.75827 ± 0.17634 (n = 56); 12 months, 0.75769 ± 0.16061 (n = 54); 24 months, 0.77450 ± 0.16540 (n = 53). Placebo: 0, 0.76900 ± 0.11653 (n = 53); 6 months, 0.76500 ± 0.13087 (n = 51); 12 months, 0.76833 ± 0.11487 (n = 50); 24 months, 0.77280 ± 0.13290 (n = 49).
<bold>c</bold>
MRI-determined contrast enhancement. P = 0.0697.
<bold>d</bold>
Representative images at baseline and at 12 months for the same vessels.
<bold>e</bold>
MRI-determined common carotid lumen area *P = 0.0033.
<bold>f</bold>
MRI-determined common carotid artery diameter. *P = 0.0019. Data represent mean ± SD in
<bold>c</bold>
,
<bold>e</bold>
,
<bold>f</bold>
. Analysis by mixed model testing in
<bold>b</bold>
, paired t tests in
<bold>c</bold>
,
<bold>e</bold>
,
<bold>f</bold>
</p>
</caption>
<graphic xlink:href="13098_2019_456_Fig4_HTML" id="MO4"></graphic>
</fig>
</p>
</sec>
<sec id="Sec4">
<title>Hyperinsulinemic–euglycemic clamp procedure</title>
<p id="Par44">At the end of each limb depicted in Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
a, subjects presented after an overnight fast. The antecubital vein was catheterized for infusion of insulin, glucose and tracer solutions, a hand vein was catheterized for blood sampling, and the hand was maintained in a hotbox at ~ 55 °C to arterialize venous sampling. Baseline samples were obtained prior to initiating infusions.</p>
<p id="Par45">Insulin sensitivity was assayed using a two-step euglycemic clamp technique as described previously [
<xref ref-type="bibr" rid="CR11">11</xref>
]. The stable isotope [6,6-
<sup>2</sup>
H
<sub>2</sub>
] glucose (22 μmol/kg prime and 0.25 μmol/kg/min constant infusion) was infused during a 90 min basal period (to allow isotope equilibration) and then continued throughout each study. Plasma glucose was measured at 5–10 min intervals following the basal period. Insulin was initially infused in two stages consisting of rates of 181 and 486 pmol/m
<sup>2</sup>
/min, but after analyzing results from the first 7 patients, the protocol was modified to include two stages consisting of insulin infusion rates of 56 and 181 pmol/m
<sup>2</sup>
/min in order to avoid nearly complete suppression of hepatic glucose production at higher insulin infusion rates. Twenty % dextrose (containing 1.5% [6,6-
<sup>2</sup>
H
<sub>2</sub>
] glucose) was infused to maintain blood glucose at 5.00 mmol/L for ~ 2 h at each stage. Plasma was assayed for 6,6-
<sup>2</sup>
H
<sub>2</sub>
-glucose enrichment by mass spectrometry. Glucose kinetics were determined using samples obtained at 10 min intervals during the last 30 min of the basal period and during each stage of the clamp.</p>
</sec>
<sec id="Sec5">
<title>Glucose tolerance testing and assays of serum or plasma</title>
<p id="Par46">Oral glucose tolerance testing was performed by administering 75 g of glucose followed by sampling at 0, 30, 60, 90 and 120 min. Samples were assayed for glucose, insulin, C peptide, and glucagon. AUC calculations were performed using the trapezoid rule for approximating integrals. Lipids, lipoproteins, serum chemistries, and blood counts were assayed by the Washington University Core Laboratory for Clinical Studies, which is CLIA-certified. Since this project addressed the effects of chloroquine on insulin resistance, the cause of which remains obscure, the laboratory also performed exploratory measurements of putative metabolic mediators that have been implicated in insulin resistance and/or its vascular complications [
<xref ref-type="bibr" rid="CR12">12</xref>
–
<xref ref-type="bibr" rid="CR16">16</xref>
]. These included adiponectin, leptin, iron, VEGF (vascular endothelial growth factor), and IL-17A. Samples for adiponectin and iron studies were assayed at the University of Utah [
<xref ref-type="bibr" rid="CR17">17</xref>
].</p>
</sec>
<sec id="Sec6">
<title>Blood pressure determinations</title>
<p id="Par47">Two techniques were employed: auscultation of seated subjects at rest was performed by a trained observer who recorded the first and fifth phases of the Korotkoff sounds; and, a portable oscillometric device (SpaceLabs Medical) recorded results every 20 min during the day and every h during the night then data were analyzed as mean values over 24 h, between 0800 and 2200 (daytime), and between 2200 and 0800 (nighttime).</p>
</sec>
<sec id="Sec7">
<title>CIMT assessments</title>
<p id="Par48">Carotid artery intima-media thickness (CIMT) was measured from B-mode images by a single sonographer using standard approaches [
<xref ref-type="bibr" rid="CR18">18</xref>
,
<xref ref-type="bibr" rid="CR19">19</xref>
]. The average of 3 measurements of the posterior wall of each common carotid ~ 1 cm proximal to the carotid bulb was determined; plaques (wall thickening > 50% of the surrounding wall) were excluded. To establish reproducibility, 10% of the images were randomly selected and re-measured in a blinded fashion by two independent observers. Intra-observer and inter-observer correlation coefficients were 0.900 and 0.992.</p>
</sec>
<sec id="Sec8">
<title>MRI assessments</title>
<p id="Par49">A contouring tool on the Philips ViewForum workstation was used to outline the inner and outer common carotid artery wall regions (right and left) in the first frame immediately below the bifurcation in the T2-weighted image, then areas and diameters of the vessel wall and lumen were calculated. The maximum thickness of the common carotid in the same frame was measured with the line tool. Similar measurements were made for the internal carotid artery in a slice just beyond the bifurcation. For common carotid artery wall contrast enhancement, which represents gadolinium leakage and late hyper enhancement, pre- and post-injection T1 weighted images were compared by dividing the artery into quadrants. The slice nearest the bifurcation manifesting the greatest signal in terms of numbers of quadrants enhanced was chosen by visual comparison with the same pre-injection slice. If the pre-injection signal in the carotid wall appeared bright in any quadrant due to signal spatial heterogeneity, and with reference to the other arterial wall segments in adjacent or contralateral arteries, then the post- injection signal was deemed nonenhancing. Concurrence of two readers was achieved in blinded interpretations.</p>
</sec>
<sec id="Sec9">
<title>Monocyte protein preparation, JNK assays, and oxysterol determinations</title>
<p id="Par50">Human monocytes were isolated using a negative selection technique employing a RosetteSep Human Monocyte Enrichment Cocktail (StemCell Technologies #15028), exactly as described by the manufacturer. Cells were lysed using a buffer containing 1% Tween 20 and 0.2% NP40 with protease and phosphatase inhibitors, and lysates were aliquoted and stored at − 80 °C.</p>
<p id="Par51">Total and phospho (Thr183/Tyr185) JNK were assayed using chemiluminescent sandwich ELISA kits (Cell Signaling Technologies #7869S and #7849S). Extracts from subjects before and 1 year following treatment were analyzed in the same assay by an observer masked to randomization status. Signals detected from 1 μg lysate protein (assayed with BCA reagents from Pierce) were determined using a Synergy 4 plate reader and the ratio of phospho-JNK to total JNK was calculated. For assays of cholestane-3β,5α,6β-triol, plasma samples stored at − 80 °C were thawed and combined with BHT (50 μg/mL). Oxysterols were purified, derivatized, then quantified by GC–MS (
<italic>m/z</italic>
456) in assays performed within the linear response range of appropriate standard curves [
<xref ref-type="bibr" rid="CR20">20</xref>
].</p>
</sec>
<sec id="Sec10">
<title>Statistical analyses</title>
<p id="Par52">Results are expressed as mean ± SD except in Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
where results are presented as mean ± SE to simplify data presentation. Statistical analyses were performed using GraphPad Prism software. For the dose escalation study, most data were analyzed using repeated measures ANOVA with post hoc testing using Tukey’s multiple comparison test for inter-group differences. For the yearlong treatment study, most data were analyzed using a mixed model approach for repeated measures to allow for dealing with missing values. P values for mixed model analyses represent an assessment of whether the dependent variable was affected by the randomization group (placebo vs. chloroquine) vs. time interaction. Some analyses in both trials involving only two groups were performed using a two-tailed Student’s t test. Spearman correlation coefficients were calculated for the relationships between baseline CIMT in the 116 randomized subjects and variables associated with atherosclerosis. Two-tailed paired t tests were used to analyze the baseline vs. 12-month results for MRI imaging and JNK activation. Binary baseline characteristics and adverse events were analyzed using contingency tables and Chi Square Test or Fisher’s Exact Test.</p>
</sec>
</sec>
<sec id="Sec11">
<title>Results</title>
<sec id="Sec12">
<title>Metabolic effects of increasing doses of chloroquine</title>
<p id="Par53">Characteristics for those completing the dose escalation study are shown in Table 
<xref rid="Tab1" ref-type="table">1</xref>
. The primary endpoint of the first trial was clamp-determined insulin sensitivity. Two-stage hyperinsulinemic euglycemic clamps were initially performed using insulin at 181 and 486 pmol/m
<sup>2</sup>
/min. However, data analysis after the first seven patients demonstrated complete suppression of glucose production at the higher dose and nearly complete suppression at the lower dose, decreasing the ability to detect differences in endogenous glucose production in this group of patients with metabolic syndrome but not diabetes. Subsequent two-stage clamps were performed using insulin infusions at 56 and 181 pmol/m
<sup>2</sup>
/min. The results from these first seven patients are included in Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
b, c; the 486 pmol/m
<sup>2</sup>
/min condition represents data points from these first patients for each limb while the 181 pmol/m
<sup>2</sup>
/min condition includes data points from these patients in addition to those from those undergoing clamps at 56 and 181 pmol/m
<sup>2</sup>
/min. There were no differences in glucose disposal rates between any of the chloroquine doses as shown in Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
b.
<table-wrap id="Tab1">
<label>Table 1</label>
<caption>
<p>Baseline characteristics of subjects in the dose escalation study</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Variable</th>
<th align="left">Results</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">Number</td>
<td align="left">25</td>
</tr>
<tr>
<td align="left">Gender (F/M)</td>
<td align="left">18/7</td>
</tr>
<tr>
<td align="left" colspan="2">Race</td>
</tr>
<tr>
<td align="left"> Black</td>
<td align="left">2</td>
</tr>
<tr>
<td align="left"> Non-hispanic white</td>
<td align="left">23</td>
</tr>
<tr>
<td align="left">Weight (kg)</td>
<td align="left">101 ± 17</td>
</tr>
<tr>
<td align="left">BMI (kg/m
<sup>2</sup>
)</td>
<td align="left">35.0 ± 4.4</td>
</tr>
<tr>
<td align="left">Waist circumference (cm)</td>
<td align="left">109 ± 13</td>
</tr>
<tr>
<td align="left">Fasting glucose (mmol/L)</td>
<td align="left">5.27 ± 0.61</td>
</tr>
<tr>
<td align="left">Systolic blood pressure (mmHg)</td>
<td align="left">135 ± 16</td>
</tr>
<tr>
<td align="left">Diastolic blood pressure (mmHg)</td>
<td align="left">80 ± 10</td>
</tr>
<tr>
<td align="left">Total cholesterol (mmol/L)</td>
<td align="left">5.25 ± 0.67</td>
</tr>
<tr>
<td align="left">Non-HDL cholesterol (mmol/L)</td>
<td align="left">4.11 ± 0.62</td>
</tr>
<tr>
<td align="left">LDL cholesterol (mmol/L)</td>
<td align="left">3.23 ± 0.57</td>
</tr>
<tr>
<td align="left">Triglycerides (mmol/L)</td>
<td align="left">1.85 ± 0.61</td>
</tr>
<tr>
<td align="left">HDL cholesterol (mmol/L)</td>
<td align="left">1.19 ± 0.26</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Data represent mean ± SD</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par54">There was a dose-dependent effect of chloroquine on hepatic glucose production (clamp-determined rate of appearance) with significant suppression at doses of 80 mg/day and 250 mg/day as determined by repeated measures ANOVA (Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
c). Figure 
<xref rid="Fig2" ref-type="fig">2</xref>
d shows that chloroquine increased hepatic insulin sensitivity based on data from the 56 pmol/m
<sup>2</sup>
/min stage.</p>
<p id="Par55">There was also an apparent dose-dependent effect of chloroquine on fasting levels of total cholesterol, non-HDL cholesterol, and LDL cholesterol with a significant decrease at 250/day as determined by repeated measures ANOVA (Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
e). Serum triglycerides and HDL cholesterol were unchanged (Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
f).</p>
<p id="Par56">Chloroquine in this dose escalation study had no effect on blood pressure determined using an ambulatory monitor as shown in Table 
<xref rid="Tab2" ref-type="table">2</xref>
. SBP, DBP, MAP, and magnitude of BP decrease overnight (“dipping” status) were unaffected in all limbs. Consistent with an effect of chloroquine on hepatic insulin sensitivity, fasting glucose at the time of the clamp was significantly decreased (Table 
<xref rid="Tab2" ref-type="table">2</xref>
). Consistent with the lack an effect of chloroquine on glucose disposal, OGTT AUC results were unaffected in all limbs (Table 
<xref rid="Tab2" ref-type="table">2</xref>
). There was also no effect on body weight, glucagon, leptin, NEFA, C-peptide or insulin (Table 
<xref rid="Tab2" ref-type="table">2</xref>
).
<table-wrap id="Tab2">
<label>Table 2</label>
<caption>
<p>Dose effect of chloroquine on blood pressure and other variables</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Variable</th>
<th align="left">Placebo</th>
<th align="left">80 mg/week</th>
<th align="left">80 mg/day</th>
<th align="left">250 mg/day</th>
<th align="left">P value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">SBP (mmHg)</td>
<td char="±" align="char">121 ± 12</td>
<td align="left">121 ± 10</td>
<td align="left">123 ± 12</td>
<td char="±" align="char">123 ± 12</td>
<td char="." align="char">0.5607</td>
</tr>
<tr>
<td align="left">DBP (mmHg)</td>
<td char="±" align="char">70 ± 7</td>
<td align="left">71 ± 7</td>
<td align="left">73 ± 8</td>
<td char="±" align="char">73 ± 9</td>
<td char="." align="char">0.1107</td>
</tr>
<tr>
<td align="left">MAP (mmHg)</td>
<td char="±" align="char">87 ± 8</td>
<td align="left">88 ± 7</td>
<td align="left">89 ± 9</td>
<td char="±" align="char">90 ± 9</td>
<td char="." align="char">0.1944</td>
</tr>
<tr>
<td align="left">Overnight MAP dip</td>
<td char="±" align="char">8.8 ± 4.2</td>
<td align="left">9.5 ± 5.3</td>
<td align="left">9.5 ± 8.8</td>
<td char="±" align="char">9.6 ± 5.0</td>
<td char="." align="char">0.9878</td>
</tr>
<tr>
<td align="left">Fasting glucose clamp</td>
<td char="±" align="char">5.77 ± 0.53</td>
<td align="left">5.83 ± 0.52</td>
<td align="left">5.83 ± 0.53</td>
<td char="±" align="char">5.44 ± 0.65</td>
<td char="." align="char">0.0010*</td>
</tr>
<tr>
<td align="left">Fasting glucose OGTT</td>
<td char="±" align="char">5.49 ± 0.57</td>
<td align="left">5.77 ± 0.56</td>
<td align="left">5.72 ± 0.62</td>
<td char="±" align="char">5.66 ± 0.62</td>
<td char="." align="char">0.0805</td>
</tr>
<tr>
<td align="left">OGTT AUC (mmol/L/h)</td>
<td char="±" align="char">16.93 ± 3.05</td>
<td align="left">17.65 ± 3.00</td>
<td align="left">17.87 ± 3.22</td>
<td char="±" align="char">17.26 ± 3.61</td>
<td char="." align="char">0.3585</td>
</tr>
<tr>
<td align="left">Weight (kg)</td>
<td char="±" align="char">104 ± 18</td>
<td align="left">103 ± 18</td>
<td align="left">104 ± 19</td>
<td char="±" align="char">103 ± 19</td>
<td char="." align="char">0.6041</td>
</tr>
<tr>
<td align="left">BMI</td>
<td char="±" align="char">35.9 ± 4.3</td>
<td align="left">35.9 ± 4.2</td>
<td align="left">35.9 ± 4.5</td>
<td char="±" align="char">35.5 ± 4.6</td>
<td char="." align="char">0.5964</td>
</tr>
<tr>
<td align="left">A1c (%)</td>
<td char="±" align="char">5.8 ± 0.4</td>
<td align="left">ND</td>
<td align="left">ND</td>
<td char="±" align="char">5.8 ± 0.4</td>
<td char="." align="char">0.9493</td>
</tr>
<tr>
<td align="left">Insulin (pmol/L)</td>
<td char="±" align="char">153 ± 94</td>
<td align="left">138 ± 62</td>
<td align="left">166 ± 107</td>
<td char="±" align="char">148 ± 80</td>
<td char="." align="char">0.4260</td>
</tr>
<tr>
<td align="left">C peptide (nmol/L)</td>
<td char="±" align="char">1.16 ± 0.44</td>
<td align="left">1.20 ± 0.38</td>
<td align="left">1.26 ± 0.44</td>
<td char="±" align="char">1.25 ± 0.36</td>
<td char="." align="char">0.5473</td>
</tr>
<tr>
<td align="left">Glucagon (pg/mL)</td>
<td char="±" align="char">110 ± 41</td>
<td align="left">101 ± 26</td>
<td align="left">111 ± 54</td>
<td char="±" align="char">102 ± 50</td>
<td char="." align="char">0.3646</td>
</tr>
<tr>
<td align="left">Leptin (μg/L)</td>
<td char="±" align="char">27.5 ± 11.6</td>
<td align="left">27.2 ± 11.1</td>
<td align="left">31.0 ± 16.4</td>
<td char="±" align="char">27.2 ± 11.9</td>
<td char="." align="char">0.2134</td>
</tr>
<tr>
<td align="left">NEFA (mmol/L)</td>
<td char="±" align="char">0.56 ± 0.15</td>
<td align="left">0.55 ± 0.10</td>
<td align="left">0.58 ± 0.19</td>
<td char="±" align="char">0.55 ± 0.16</td>
<td char="." align="char">0.8776</td>
</tr>
<tr>
<td align="left">TNFα (pg/mL)</td>
<td char="±" align="char">12.9 ± 1.8</td>
<td align="left">13.0 ± 1.7</td>
<td align="left">12.2 ± 1.9</td>
<td char="±" align="char">12.4 ± 2.0</td>
<td char="." align="char">0.0890</td>
</tr>
<tr>
<td align="left">Fibrinogen (μmol/L)</td>
<td char="±" align="char">8.44 ± 1.32</td>
<td align="left">8.38 ± 1.47</td>
<td align="left">8.14 ± 1.09</td>
<td char="±" align="char">7.94 ± 1.44</td>
<td char="." align="char">0.3563</td>
</tr>
<tr>
<td align="left">IL-6 (pg/mL)</td>
<td char="±" align="char">1.0 ± 1.6</td>
<td align="left">1.4 ± 1.5</td>
<td align="left">1.2 ± 1.6</td>
<td char="±" align="char">0.96 ± 1.3</td>
<td char="." align="char">0.4282</td>
</tr>
<tr>
<td align="left">Lp(a) (mg/dL)</td>
<td char="±" align="char">22.9 ± 17.5</td>
<td align="left">20.9 ± 16.0</td>
<td align="left">22.5 ± 17.2</td>
<td char="±" align="char">22.8 ± 18.1</td>
<td char="." align="char">0.1454</td>
</tr>
<tr>
<td align="left">CRP (mg/L)</td>
<td char="±" align="char">8.3 ± 10.8</td>
<td align="left">7.9 ± 10.6</td>
<td align="left">6.4 ± 7.2</td>
<td char="±" align="char">7.5 ± 8.0</td>
<td char="." align="char">0.7455</td>
</tr>
<tr>
<td align="left">Adiponectin (μg/mL)</td>
<td char="±" align="char">21.6 ± 8.1</td>
<td align="left">ND</td>
<td align="left">ND</td>
<td char="±" align="char">20.6 ± 5.6</td>
<td char="." align="char">0.3503</td>
</tr>
<tr>
<td align="left">Iron (μmol/L)</td>
<td char="±" align="char">12.3 ± 4.1</td>
<td align="left">ND</td>
<td align="left">ND</td>
<td char="±" align="char">11.4 ± 5.5</td>
<td char="." align="char">0.5311</td>
</tr>
<tr>
<td align="left">Iron Bind. Cap. (μmol/L)</td>
<td char="±" align="char">64.9 ± 8.7</td>
<td align="left">ND</td>
<td align="left">ND</td>
<td char="±" align="char">65.8 ± 10.0</td>
<td char="." align="char">0.6385</td>
</tr>
<tr>
<td align="left">Transferrin (mg/dL)</td>
<td char="±" align="char">300.3 ± 47.5</td>
<td align="left">ND</td>
<td align="left">ND</td>
<td char="±" align="char">303.8 ± 48.5</td>
<td char="." align="char">0.6899</td>
</tr>
<tr>
<td align="left">Transferrin Sat. (%)</td>
<td char="±" align="char">19.1 ± 6.4</td>
<td align="left">ND</td>
<td align="left">ND</td>
<td char="±" align="char">17.2 ± 6.9</td>
<td char="." align="char">0.3413</td>
</tr>
<tr>
<td align="left">Ferritin (pmol/L)</td>
<td char="±" align="char">170 ± 191</td>
<td align="left">ND</td>
<td align="left">ND</td>
<td char="±" align="char">105 ± 88</td>
<td char="." align="char">0.0155*</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Data represent mean ± SD</p>
<p>
<italic>MAP</italic>
mean arterial pressure,
<italic>NEFA</italic>
non-esterified fatty acids,
<italic>ND</italic>
not determined</p>
<p>P values determined by repeated measures ANOVA except for A1c, adiponectin, and iron studies, where P value determined by paired t test</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par57">There was a trend toward lower levels of TNFα (Table 
<xref rid="Tab2" ref-type="table">2</xref>
), but other inflammatory markers including CRP and adiponectin were unaffected (Table 
<xref rid="Tab2" ref-type="table">2</xref>
), consistent with other large studies of the relationship between this adipokine and insulin sensitivity [
<xref ref-type="bibr" rid="CR21">21</xref>
].</p>
<p id="Par58">Iron is linked to the development of diabetes [
<xref ref-type="bibr" rid="CR22">22</xref>
] and ferritin is the major storage form of iron. Chloroquine treatment was associated with a significant decrease in ferritin levels in humans (Table 
<xref rid="Tab2" ref-type="table">2</xref>
), confirming an effect seen in rodents [
<xref ref-type="bibr" rid="CR23">23</xref>
].</p>
</sec>
<sec id="Sec13">
<title>Vascular effects of chloroquine treatment</title>
<p id="Par59">Baseline characteristics for the 107 subjects who completed the second trial, a double-blind placebo controlled study are shown in Table 
<xref rid="Tab3" ref-type="table">3</xref>
. The primary endpoint of the second trial was CIMT. To validate carotid measurements in this study cohort, baseline CIMT values for the 116 subjects randomized to chloroquine or placebo were correlated with common variables associated with atherosclerosis. CIMT was positively correlated with age (r
<sub>s</sub>
 = 0.3963, P < 0.0001), systolic blood pressure (r
<sub>s</sub>
 = 0.3379, P = 0.0002), triglycerides (r
<sub>s</sub>
 = 0.2936, P = 0.0014), cholesterol (r
<sub>s</sub>
 = 0.3593, P < 0.0001), and LDL-C (r
<sub>s</sub>
 = 0.2590, P = 0.0050). There were no correlations with HDL-C, diastolic blood pressure, waist circumference, BMI, glucose, TNFα, IL-6, VEGF, or IL-17A (not shown).
<table-wrap id="Tab3">
<label>Table 3</label>
<caption>
<p>Baseline characteristics of subjects in the double-blind study</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Variable</th>
<th align="left">Chloroquine group</th>
<th align="left">Placebo group</th>
<th align="left">P value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">Gender (F/M)</td>
<td align="left">44/12</td>
<td align="left">33/18</td>
<td char="." align="char">0.1108</td>
</tr>
<tr>
<td align="left">Age</td>
<td align="left">55 ± 12</td>
<td align="left">55 ± 9</td>
<td char="." align="char">0.9999</td>
</tr>
<tr>
<td align="left">Race (AA/NHW/H/NA)</td>
<td align="left">9/45/1/1</td>
<td align="left">6/45/0/0</td>
<td char="." align="char">0.4990</td>
</tr>
<tr>
<td align="left" colspan="4">Smoking status</td>
</tr>
<tr>
<td align="left"> Current</td>
<td align="left">8</td>
<td align="left">10</td>
<td char="." align="char">0.4341</td>
</tr>
<tr>
<td align="left"> Past</td>
<td align="left">21</td>
<td align="left">23</td>
<td char="." align="char">0.2962</td>
</tr>
<tr>
<td align="left">Statin treatment</td>
<td align="left">15</td>
<td align="left">15</td>
<td char="." align="char">0.8310</td>
</tr>
<tr>
<td align="left">Hypertension treatment</td>
<td align="left">20</td>
<td align="left">19</td>
<td char="." align="char">0.9999</td>
</tr>
<tr>
<td align="left">Fish oil treatment</td>
<td align="left">5</td>
<td align="left">10</td>
<td char="." align="char">0.1632</td>
</tr>
<tr>
<td align="left">Waist circumference</td>
<td align="left">110.4 ± 10.5</td>
<td align="left">108.9 ± 11.8</td>
<td char="." align="char">0.6538</td>
</tr>
<tr>
<td align="left">BMI</td>
<td align="left">36.2 ± 5.0</td>
<td align="left">34.2 ± 5.0</td>
<td char="." align="char">0.0433*</td>
</tr>
<tr>
<td align="left" colspan="4">SBP</td>
</tr>
<tr>
<td align="left"> Screen</td>
<td align="left">137.1 ± 14.3</td>
<td align="left">140.2 ± 13.2</td>
<td char="." align="char">0.2385</td>
</tr>
<tr>
<td align="left"> Randomization</td>
<td align="left">129.2 ± 11.4</td>
<td align="left">134.0 ± 10.1</td>
<td char="." align="char">0.0237*</td>
</tr>
<tr>
<td align="left" colspan="4">DBP</td>
</tr>
<tr>
<td align="left"> Screen</td>
<td align="left">82.8 ± 9.5</td>
<td align="left">83.0 ± 9.7</td>
<td char="." align="char">0.9483</td>
</tr>
<tr>
<td align="left"> Randomization</td>
<td align="left">78.3 ± 7.4</td>
<td align="left">79.7 ± 7.2</td>
<td char="." align="char">0.3244</td>
</tr>
<tr>
<td align="left">Glucose</td>
<td align="left">5.48 ± 0.53</td>
<td align="left">5.52 ± 0.64</td>
<td char="." align="char">0.6960</td>
</tr>
<tr>
<td align="left">Triglycerides</td>
<td align="left">1.84 ± 1.04</td>
<td align="left">1.82 ± 0.93</td>
<td char="." align="char">0.9155</td>
</tr>
<tr>
<td align="left">HDL-C</td>
<td align="left">1.14 ± 0.26</td>
<td align="left">1.14 ± 0.27</td>
<td char="." align="char">0.9603</td>
</tr>
<tr>
<td align="left">Cholesterol</td>
<td align="left">5.00 ± 0.85</td>
<td align="left">5.18 ± 1.15</td>
<td char="." align="char">0.3834</td>
</tr>
<tr>
<td align="left">LDL-C</td>
<td align="left">3.04 ± 0.68</td>
<td align="left">3.28 ± 0.82</td>
<td char="." align="char">0.1073</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Data represent mean ± SD</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par60">There was no effect of chloroquine on CIMT after 12 months (Fig. 
<xref rid="Fig4" ref-type="fig">4</xref>
b). Because chloroquine has a long half-life, imaging was repeated at 24 months, following a 12-month washout period. These results also showed no difference between groups. MRI studies were performed only at baseline and at 12 months. Chloroquine did not affect contrast enhancement, a pre-specified secondary endpoint of the study (Fig. 
<xref rid="Fig4" ref-type="fig">4</xref>
c, P = 0.0697, paired two-tailed t test). Representative images of vessels at baseline and 12 months are shown in Fig. 
<xref rid="Fig4" ref-type="fig">4</xref>
d. Carotid dimensions were also assessed by MRI. Chloroquine was associated with a decrease in common carotid artery luminal area (Fig. 
<xref rid="Fig4" ref-type="fig">4</xref>
e, P = 0.0033) and diameter (Fig. 
<xref rid="Fig4" ref-type="fig">4</xref>
f, P = 0.0019).</p>
</sec>
<sec id="Sec14">
<title>Effects of chloroquine on blood pressure, lipids, and other variables</title>
<p id="Par61">Drug treatment over the first year was associated with a significantly lower diastolic blood pressure (P = 0.0252 at 12 months), results that were driven by a 4.9 mm Hg decrease at the 6 month time point (Fig. 
<xref rid="Fig5" ref-type="fig">5</xref>
a). Ambulatory monitoring results (performed at baseline, 6 months, and 12 months but not at 24 months) were consistent with a beneficial effect of chloroquine on blood pressure. Drug treatment over the first year was associated with significantly lower daytime mean arterial pressure (Fig. 
<xref rid="Fig5" ref-type="fig">5</xref>
b, P = 0.0484). Daytime (P = 0.0804) and nighttime (P = 0.0659) systolic pressures by ambulatory monitoring were not different (Fig. 
<xref rid="Fig5" ref-type="fig">5</xref>
c, d). By mixed model testing for the interaction between group and time, there was no effect of chronic chloroquine on lipids. However, at 12 months, a pre-specified secondary endpoint, total cholesterol was 9% lower (Fig. 
<xref rid="Fig5" ref-type="fig">5</xref>
e, P = 0.0089 by unpaired t test), non-HDL cholesterol was 12% lower (Fig. 
<xref rid="Fig5" ref-type="fig">5</xref>
f, P = 0.0048 by unpaired t test), and LDL-C was 13% lower (Fig. 
<xref rid="Fig5" ref-type="fig">5</xref>
g, P = 0.0038 by unpaired t test) in the chloroquine group. Glucose area under the curve (AUC) as well as HOMA-IR and the Matsuda index, measures of insulin sensitivity [
<xref ref-type="bibr" rid="CR24">24</xref>
], were not different between groups (Table 
<xref rid="Tab4" ref-type="table">4</xref>
). There was no effect of chloroquine on insulin AUC, C peptide AUC, or the insulinogenic index (the difference between insulin at 30 min and 0 min divided by the difference between glucose at 30 min and 0 min) (Table 
<xref rid="Tab4" ref-type="table">4</xref>
), suggesting that chronic chloroquine treatment at this dose does not impact insulin levels in humans. Glucagon AUC, creatinine, ALT, and hematologic variables were not different between treatment groups (Table 
<xref rid="Tab4" ref-type="table">4</xref>
).
<fig id="Fig5">
<label>Fig. 5</label>
<caption>
<p>Blood pressure and lipid responses in the yearlong chloroquine trial.
<bold>a</bold>
Diastolic blood pressure over 24 months determined by conventional testing.
<bold>b</bold>
–
<bold>d</bold>
Blood pressures over 12 months, determined by an ambulatory monitoring device.
<bold>e</bold>
–
<bold>i</bold>
Lipids and lipoproteins over 24 months. P values were determined by mixed model treatment of repeated measures</p>
</caption>
<graphic xlink:href="13098_2019_456_Fig5_HTML" id="MO5"></graphic>
</fig>
<table-wrap id="Tab4">
<label>Table 4</label>
<caption>
<p>Effects of chloroquine vs. placebo over 24 months (off either, i.e. washout, months 12–24)</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Variable</th>
<th align="left">Baseline</th>
<th align="left">6 months</th>
<th align="left">12 months</th>
<th align="left">24 months</th>
<th align="left">P value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" colspan="6">Waist (cm)</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">110.4 ± 10.5</td>
<td char="±" align="char">112.5 ± 12.6</td>
<td char="±" align="char">112.6 ± 13.6</td>
<td align="left">113.2 ± 16.6</td>
<td align="left">0.5578 (12 m)</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">108.9 ± 11.8</td>
<td char="±" align="char">110.4 ± 13.8</td>
<td char="±" align="char">109.8 ± 12.4</td>
<td align="left">108.9 ± 15.9</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">Weight (kg)</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">102.9 ± 16.7</td>
<td char="±" align="char">102.9 ± 16.7</td>
<td char="±" align="char">103.1 ± 19.2</td>
<td align="left">105.9 ± 20.4</td>
<td align="left">0.1323</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">99.7 ± 18.5</td>
<td char="±" align="char">98.7 ± 18.5</td>
<td char="±" align="char">99.2 ± 17.8</td>
<td align="left">100.5 ± 21.2</td>
<td align="left">0.1909 (t test 24 m)</td>
</tr>
<tr>
<td align="left" colspan="6">Fasting glucose</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">5.48 ± 0.53</td>
<td char="±" align="char">5.36 ± 0.55</td>
<td char="±" align="char">5.30 ± 0.51</td>
<td align="left">5.58 ± 0.73</td>
<td align="left">0.2741 (12 m)</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">5.52 ± 0.64</td>
<td char="±" align="char">5.52 ± 0.62</td>
<td char="±" align="char">5.51 ± 0.71</td>
<td align="left">5.63 ± 0.74</td>
<td align="left">0.0930 (t test 12 m)</td>
</tr>
<tr>
<td align="left" colspan="6">Glucose AUC</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">16.32 ± 2.46</td>
<td char="±" align="char">15.94 ± 2.24</td>
<td char="±" align="char">16.17 ± 2.58</td>
<td align="left">16.97 ± 3.20</td>
<td align="left">0.2537</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">16.54 ± 3.49</td>
<td char="±" align="char">16.87 ± 3.29</td>
<td char="±" align="char">16.43 ± 3.34</td>
<td align="left">17.50 ± 3.85</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">Insulin AUC</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">1202 ± 681</td>
<td char="±" align="char">1118 ± 542</td>
<td char="±" align="char">1143 ± 603</td>
<td align="left">1213 ± 716</td>
<td align="left">0.2479</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">1003 ± 524</td>
<td char="±" align="char">1054 ± 588</td>
<td char="±" align="char">995 ± 570</td>
<td align="left">1022 ± 613</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">C peptide AUC</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">7.46 ± 2.33</td>
<td char="±" align="char">7.23 ± 2.10</td>
<td char="±" align="char">7.16 ± 2.20</td>
<td align="left">7.39 ± 2.43</td>
<td align="left">0.2918</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">6.49 ± 1.80</td>
<td char="±" align="char">6.69 ± 2.06</td>
<td char="±" align="char">6.46 ± 2.00</td>
<td align="left">6.79 ± 2.06</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">HOMA-IR</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">3.89 ± 2.23</td>
<td char="±" align="char">3.85 ± 2.21</td>
<td char="±" align="char">3.57 ± 2.12</td>
<td align="left">3.72 ± 3.53</td>
<td align="left">0.8421</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">3.54 ± 2.03</td>
<td char="±" align="char">3.64 ± 2.08</td>
<td char="±" align="char">3.30 ± 2.23</td>
<td align="left">3.29 ± 2.26</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">Matsuda index</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">2.89 ± 1.72</td>
<td char="±" align="char">2.88 ± 1.55</td>
<td char="±" align="char">3.13 ± 2.31</td>
<td align="left">3.43 ± 2.84</td>
<td align="left">0.8997</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">3.21 ± 1.89</td>
<td char="±" align="char">3.07 ± 1.64</td>
<td char="±" align="char">3.50 ± 2.14</td>
<td align="left">3.56 ± 2.70</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">Insulinogenic index</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">1.40 ± 1.75</td>
<td char="±" align="char">1.17 ± 0.87</td>
<td char="±" align="char">1.24 ± 0.87</td>
<td align="left">1.12 ± 0.89</td>
<td align="left">0.4988</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">1.05 ± 0.77</td>
<td char="±" align="char">1.03 ± 0.67</td>
<td char="±" align="char">1.09 ± 0.88</td>
<td align="left">1.13 ± 1.62</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">Glucagon AUC</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">174.0 ± 63.5</td>
<td char="±" align="char">152.3 ± 60.3</td>
<td char="±" align="char">126.8 ± 43.3</td>
<td align="left">ND</td>
<td align="left" rowspan="2">0.6126</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">168.0 ± 60.6</td>
<td char="±" align="char">138.7 ± 46.7</td>
<td char="±" align="char">119.8 ± 36.2</td>
<td align="left">ND</td>
</tr>
<tr>
<td align="left" colspan="6">Creatinine (μmol/L)</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">68 ± 14</td>
<td char="±" align="char">67 ± 15</td>
<td char="±" align="char">66 ± 15</td>
<td align="left">ND</td>
<td align="left">0.7859</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">66 ± 16</td>
<td char="±" align="char">65 ± 17</td>
<td char="±" align="char">65 ± 17</td>
<td align="left"></td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">ALT</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">26 ± 16</td>
<td char="±" align="char">26 ± 19</td>
<td char="±" align="char">26 ± 15</td>
<td align="left">ND</td>
<td align="left">0.2056</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">25 ± 12</td>
<td char="±" align="char">27 ± 16</td>
<td char="±" align="char">23 ± 9</td>
<td align="left">ND</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">WBC count</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">6.7 ± 1.8</td>
<td char="±" align="char">6.3 ± 1.6</td>
<td char="±" align="char">6.0 ± 1.5</td>
<td align="left">ND</td>
<td align="left">0.7249</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">6.5 ± 1.7</td>
<td char="±" align="char">6.3 ± 1.8</td>
<td char="±" align="char">6.1 ± 1.9</td>
<td align="left">ND</td>
<td align="left"></td>
</tr>
<tr>
<td align="left" colspan="6">Hemoglobin</td>
</tr>
<tr>
<td align="left"> Chloroquine</td>
<td char="±" align="char">13.6 ± 1.1</td>
<td char="±" align="char">13.3 ± 1.1</td>
<td char="±" align="char">13.2 ± 1.2</td>
<td align="left">ND</td>
<td align="left">0.8953</td>
</tr>
<tr>
<td align="left"> Placebo</td>
<td char="±" align="char">13.8 ± 0.8</td>
<td char="±" align="char">13.5 ± 0.9</td>
<td char="±" align="char">13.5 ± 0.9</td>
<td align="left">ND</td>
<td align="left"></td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Data represent mean ± SD</p>
<p>P values determined by mixed model approach to repeated measures except where indicated</p>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="Sec15">
<title>Potential mechanistic mediators</title>
<p id="Par62">JNK is a stress kinase implicated in obesity-associated chronic inflammation [
<xref ref-type="bibr" rid="CR25">25</xref>
]. JNK activation in monocytes, a pre-specified secondary endpoint, was significantly decreased in chloroquine-treated but not placebo-treated subjects (Fig. 
<xref rid="Fig6" ref-type="fig">6</xref>
a). Reactive oxygen species activate JNK and have been implicated in the pathophysiology of obesity-associated conditions [
<xref ref-type="bibr" rid="CR26">26</xref>
]. Plasma cholesterol oxidation products are elevated in diabetes and coronary artery disease [
<xref ref-type="bibr" rid="CR20">20</xref>
]. Cholestane-3β, 5α, 6β-triol, one species that may reflect clinically relevant oxidative stress [
<xref ref-type="bibr" rid="CR20">20</xref>
], was significantly decreased in the chloroquine group at 12 months (Fig. 
<xref rid="Fig6" ref-type="fig">6</xref>
b).
<fig id="Fig6">
<label>Fig. 6</label>
<caption>
<p>Effects of placebo and chloroquine on potential mechanistic mediators.
<bold>a</bold>
Activated JNK in circulating monocytes at baseline and 12 months. *P = 0.0164; P = 0.3343 for placebo; paired t tests.
<bold>b</bold>
Plasma concentrations of the oxysterol cholestane-3β, 5α, 6β-triol at 12 months. *P = 0.0031; unpaired t test</p>
</caption>
<graphic xlink:href="13098_2019_456_Fig6_HTML" id="MO6"></graphic>
</fig>
</p>
</sec>
<sec id="Sec16">
<title>Adverse events</title>
<p id="Par63">For the dose escalation study, there were no serious adverse events (Table 
<xref rid="Tab5" ref-type="table">5</xref>
). Not unexpectedly given the rigors of a series of clamps, there were several study-related events. Of adverse events that were not directly study-related, infections were the most common.
<table-wrap id="Tab5">
<label>Table 5</label>
<caption>
<p>Adverse events in the dose escalation study</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Adverse event</th>
<th align="left">Subjects (%)</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">Total subjects with any event</td>
<td char="(" align="char">24 (69)</td>
</tr>
<tr>
<td align="left">Subjects with a serious adverse event</td>
<td char="(" align="char">0 (0)</td>
</tr>
<tr>
<td align="left">Total adverse events</td>
<td char="(" align="char">57 (100)</td>
</tr>
<tr>
<td align="left">Study related</td>
<td char="(" align="char">14 (25)</td>
</tr>
<tr>
<td align="left"> IV placement difficulties</td>
<td char="(" align="char">1 (1.8)</td>
</tr>
<tr>
<td align="left"> IV infiltration</td>
<td char="(" align="char">1 (1.8)</td>
</tr>
<tr>
<td align="left"> Phlebitis</td>
<td char="(" align="char">1 (1.8)</td>
</tr>
<tr>
<td align="left"> Skin reaction to tape</td>
<td char="(" align="char">1 (1.8)</td>
</tr>
<tr>
<td align="left"> Extremity erythema due to BP cuff</td>
<td char="(" align="char">1 (1.8)</td>
</tr>
<tr>
<td align="left"> Vasovagal episode with IV placement</td>
<td char="(" align="char">1 (1.8)</td>
</tr>
<tr>
<td align="left"> Incorrect stable isotope administered</td>
<td char="(" align="char">1 (1.8)</td>
</tr>
<tr>
<td align="left"> Nausea</td>
<td char="(" align="char">3 (5)</td>
</tr>
<tr>
<td align="left"> Anemia</td>
<td char="(" align="char">4 (7)</td>
</tr>
<tr>
<td align="left">Not study related</td>
<td char="(" align="char">43 (75)</td>
</tr>
<tr>
<td align="left"> Infectious</td>
<td char="(" align="char">15 (26)</td>
</tr>
<tr>
<td align="left"> Allergy/immunology</td>
<td char="(" align="char">3 (5)</td>
</tr>
<tr>
<td align="left"> Musculoskeletal</td>
<td char="(" align="char">8 (14)</td>
</tr>
<tr>
<td align="left"> CNS</td>
<td char="(" align="char">3 (5)</td>
</tr>
<tr>
<td align="left"> Psychiatric</td>
<td char="(" align="char">5 (9)</td>
</tr>
<tr>
<td align="left"> Cardiovascular</td>
<td char="(" align="char">2 (4)</td>
</tr>
<tr>
<td align="left"> GI</td>
<td char="(" align="char">4 (7)</td>
</tr>
<tr>
<td align="left"> Metabolic</td>
<td char="(" align="char">3 (5)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Parentheses denote %</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par64">For the double blind study, there were 7 serious events. In the placebo group, one subject presented with a new diagnosis of prostate cancer. One subject underwent a right knee replacement. In the chloroquine group, one patient developed transverse myelitis presenting with left leg weakness that subsequently improved but did not completely resolve. One subject underwent carotid endarterectomy for asymptomatic near-total carotid occlusion detected at 6 months. One subject was hospitalized for a cutaneous staphylococcus infection that resolved with appropriate therapy. One subject was treated for acute appendicitis, stopped the study medication for 1 week then resumed without incident. One subject was found to have a positive PPD without evidence of pulmonary tuberculosis.</p>
<p id="Par65">Total adverse events were similar between groups (Table 
<xref rid="Tab6" ref-type="table">6</xref>
). There were more infectious events in those randomized to chloroquine but this was not significant (51 vs. 42, P = 0.0609). No subject in either study developed retinal pigmentary changes that may occur with chloroquine. For the double blind study, observers masked to the treatment assignment examined each subject at 0, 6, 12, and 24 months. Ocular adverse events were not significantly different between treatment groups (Table 
<xref rid="Tab6" ref-type="table">6</xref>
).
<table-wrap id="Tab6">
<label>Table 6</label>
<caption>
<p>Adverse events in the double-blind study</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Adverse event</th>
<th align="left">Chloroquine subjects (%)</th>
<th align="left">Placebo subjects (%)</th>
<th align="left">P value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">Total subjects with any event</td>
<td align="left">44 (76)</td>
<td align="left">39 (67)</td>
<td align="left">0.4107</td>
</tr>
<tr>
<td align="left">Subjects with a serious adverse event</td>
<td align="left">5 (9)</td>
<td align="left">2 (3)</td>
<td align="left">0.4385</td>
</tr>
<tr>
<td align="left">Total adverse events</td>
<td align="left">109 (100)</td>
<td align="left">105 (100)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">Infectious</td>
<td align="left">51 (47)</td>
<td align="left">42 (40)</td>
<td align="left">0.0609</td>
</tr>
<tr>
<td align="left">Allergy/immunology</td>
<td align="left">5 (5)</td>
<td align="left">10 (10)</td>
<td align="left">0.2681</td>
</tr>
<tr>
<td align="left">Musculoskeletal</td>
<td align="left">17 (16)</td>
<td align="left">15 (15)</td>
<td align="left">0.8357</td>
</tr>
<tr>
<td align="left">CNS</td>
<td align="left">5 (5)</td>
<td align="left">3 (3)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">Psychiatric</td>
<td align="left">5 (5)</td>
<td align="left">6 (6)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">Hematologic/neoplasm</td>
<td align="left">2 (2)</td>
<td align="left">2 (2)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">Cardiovascular</td>
<td align="left">2 (2)</td>
<td align="left">3 (3)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">GI</td>
<td align="left">3 (3)</td>
<td align="left">3 (3)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">GU</td>
<td align="left">2 (2)</td>
<td align="left">2 (2)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">Metabolic</td>
<td align="left">1 (1)</td>
<td align="left">6 (6)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">Miscellaneous</td>
<td align="left">0 (0)</td>
<td align="left">3 (3)</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left">Ocular</td>
<td align="left">16 (15)</td>
<td align="left">10 (10)</td>
<td align="left">0.2654</td>
</tr>
<tr>
<td align="left" colspan="4">Ocular details</td>
</tr>
<tr>
<td align="left"> Retinal</td>
<td align="left">3</td>
<td align="left">3</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left"> Lens</td>
<td align="left">4</td>
<td align="left">2</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left"> Vision</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left"> Infectious</td>
<td align="left">2</td>
<td align="left">0</td>
<td align="left">–</td>
</tr>
<tr>
<td align="left"> Glaucoma</td>
<td align="left">2</td>
<td align="left">2</td>
<td align="left">–</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Parentheses denote %</p>
<p>P values determined using contingency tables</p>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
</sec>
<sec id="Sec17">
<title>Discussion</title>
<p id="Par66">We tested the hypothesis that the anti-malarial drug chloroquine, which activates the kinase ATM, improves insulin sensitivity and decreases atherosclerosis in humans with metabolic syndrome. In mice, low dose chloroquine improves insulin sensitivity, decreases atherosclerosis, and suppresses activation of JNK in macrophages through pathways that require the presence of ATM [
<xref ref-type="bibr" rid="CR6">6</xref>
]. The absence of ATM in mice affects hepatic insulin sensitivity and promotes atherosclerosis, suggesting the involvement of processes that link hepatic insulin resistance and vascular disease. Accordingly, we translated these findings to humans by conducting two trials, the first to determine if chloroquine improves insulin sensitivity in the liver, and the second to determine if chloroquine decreases CIMT.</p>
<p id="Par67">The overall results were disappointing. Hyperinsulinemic euglycemic clamp studies demonstrated a dose response relationship between chloroquine administration and hepatic insulin sensitization but the effect was modest. Treatment with chloroquine for 1 year (using the lowest dose found to increase hepatic insulin sensitivity) had no effect on the primary endpoint of CIMT and no beneficial effects on MRI imaging. One limitation of the study is that it may have been underpowered to detect a difference in CIMT. Sample size estimates at the time of initiation of these studies were based on reports showing that insulin sensitizers had effects on CIMT with groups of 31–57 subjects [
<xref ref-type="bibr" rid="CR27">27</xref>
–
<xref ref-type="bibr" rid="CR30">30</xref>
], but subsequent work indicated the need for larger sample sizes [
<xref ref-type="bibr" rid="CR31">31</xref>
]. Taken together, our findings suggest that chloroquine will not be clinically useful for the treatment of metabolic syndrome.</p>
<p id="Par68">There were positive results from our studies. Chronic administration of chloroquine lowered blood pressure, decreased activation of JNK in circulating monocytes, and decreased concentration of a cholesterol oxidation product that reflects oxidative stress. These findings suggest that chloroquine decreases systemic inflammation and improves some components of the metabolic syndrome. The inhibition of JNK is known to enhance insulin sensitivity and decrease atherosclerosis in animals [
<xref ref-type="bibr" rid="CR32">32</xref>
,
<xref ref-type="bibr" rid="CR33">33</xref>
]. Oxidative stress activates JNK, and recent studies implicate ATM, which is activated by chloroquine, in modulation of reactive oxygen species generation [
<xref ref-type="bibr" rid="CR34">34</xref>
]. Metformin, the most widely used insulin sensitizer, appears to work through redox-dependent mechanisms in liver [
<xref ref-type="bibr" rid="CR35">35</xref>
]. Variants in the ATM gene alter the glycemic response to metformin in humans [
<xref ref-type="bibr" rid="CR36">36</xref>
]. These findings raise the possibility that chloroquine induction of ATM activity modifies redox signaling to decrease insulin resistance, but in humans these effects are small.</p>
<p id="Par69">Hydroxychloroquine, closely related to chloroquine, improves glycemic control in poorly controlled type 2 diabetes in humans [
<xref ref-type="bibr" rid="CR37">37</xref>
] and may improve glucose metabolism in human prediabetes [
<xref ref-type="bibr" rid="CR38">38</xref>
]. Its use in rheumatoid arthritis is associated with a reduced risk for developing diabetes in large observational studies [
<xref ref-type="bibr" rid="CR39">39</xref>
,
<xref ref-type="bibr" rid="CR40">40</xref>
], and its administration to healthy obese subjects without the metabolic syndrome increases the Matsuda index of insulin sensitivity [
<xref ref-type="bibr" rid="CR41">41</xref>
].</p>
<p id="Par70">Chloroquine was well tolerated. Subjects in the dose escalation study received 7.2 g and those in the yearlong study 29.2 g. Retinopathy is a serious but rare adverse effect of chloroquine; our subjects had regular eye exams and retinopathy was not detected.</p>
</sec>
<sec id="Sec18">
<title>Conclusions</title>
<p id="Par71">Low dose chloroquine modestly enhanced hepatic insulin sensitivity but did not affect CIMT. Despite some positive effects on secondary endpoints including the demonstration of suppression of the stress kinase JNK, overall results suggest that chloroquine will not be useful for the treatment of metabolic syndrome in humans.</p>
</sec>
</body>
<back>
<glossary>
<title>Abbreviations</title>
<def-list>
<def-item>
<term>ALT</term>
<def>
<p id="Par6">alanine aminotransferase</p>
</def>
</def-item>
<def-item>
<term>ANOVA</term>
<def>
<p id="Par7">analysis of variance</p>
</def>
</def-item>
<def-item>
<term>AUC</term>
<def>
<p id="Par8">area under the curve</p>
</def>
</def-item>
<def-item>
<term>ATM</term>
<def>
<p id="Par9">ataxia telangiectasia mutated</p>
</def>
</def-item>
<def-item>
<term>BMI</term>
<def>
<p id="Par10">body mass index</p>
</def>
</def-item>
<def-item>
<term>CIMT</term>
<def>
<p id="Par11">carotid intima-media thickness</p>
</def>
</def-item>
<def-item>
<term>CLIA</term>
<def>
<p id="Par12">Clinical Laboratory Improvement Amendments</p>
</def>
</def-item>
<def-item>
<term>COPD</term>
<def>
<p id="Par13">chronic obstructive pulmonary disease</p>
</def>
</def-item>
<def-item>
<term>CRP</term>
<def>
<p id="Par14">C-reactive protein</p>
</def>
</def-item>
<def-item>
<term>DBP</term>
<def>
<p id="Par15">diastolic blood pressure</p>
</def>
</def-item>
<def-item>
<term>DNA</term>
<def>
<p id="Par16">deoxyribonucleic acid</p>
</def>
</def-item>
<def-item>
<term>G6PD</term>
<def>
<p id="Par17">glucose-6-phosphate dehydrogenase</p>
</def>
</def-item>
<def-item>
<term>HDL</term>
<def>
<p id="Par18">high density lipoprotein</p>
</def>
</def-item>
<def-item>
<term>HIV</term>
<def>
<p id="Par19">human immunodeficiency virus</p>
</def>
</def-item>
<def-item>
<term>HOMA-IR</term>
<def>
<p id="Par20">homeostasis model assessment-insulin resistance</p>
</def>
</def-item>
<def-item>
<term>IL-6</term>
<def>
<p id="Par21">interleukin 6</p>
</def>
</def-item>
<def-item>
<term>IL-17A</term>
<def>
<p id="Par22">interleukin 17A</p>
</def>
</def-item>
<def-item>
<term>IV</term>
<def>
<p id="Par23">intravenous</p>
</def>
</def-item>
<def-item>
<term>JNK</term>
<def>
<p id="Par24">c-Jun-N-terminal kinase</p>
</def>
</def-item>
<def-item>
<term>LDL</term>
<def>
<p id="Par25">low density lipoprotein</p>
</def>
</def-item>
<def-item>
<term>LDL-C</term>
<def>
<p id="Par26">low density lipoprotein cholesterol</p>
</def>
</def-item>
<def-item>
<term>MAP</term>
<def>
<p id="Par27">mean arterial pressure</p>
</def>
</def-item>
<def-item>
<term>MRI</term>
<def>
<p id="Par28">magnetic resonance imaging</p>
</def>
</def-item>
<def-item>
<term>NEFA</term>
<def>
<p id="Par29">non-esterified fatty acid</p>
</def>
</def-item>
<def-item>
<term>NHLBI</term>
<def>
<p id="Par30">National Heart, Lung, and Blood Institute</p>
</def>
</def-item>
<def-item>
<term>OGTT</term>
<def>
<p id="Par31">oral glucose tolerance test</p>
</def>
</def-item>
<def-item>
<term>SBP</term>
<def>
<p id="Par32">systolic blood pressure</p>
</def>
</def-item>
<def-item>
<term>SD</term>
<def>
<p id="Par33">standard deviation</p>
</def>
</def-item>
<def-item>
<term>SE</term>
<def>
<p id="Par34">standard error</p>
</def>
</def-item>
<def-item>
<term>TNFα</term>
<def>
<p id="Par35">tumor necrosis factor alpha</p>
</def>
</def-item>
<def-item>
<term>VEGF</term>
<def>
<p id="Par36">vascular endothelial growth factor</p>
</def>
</def-item>
</def-list>
</glossary>
<fn-group>
<fn>
<p>
<bold>Publisher's Note</bold>
</p>
<p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p>
</fn>
<fn>
<p>Janet B. McGill and Mariko Johnson contributed equally to this work</p>
</fn>
</fn-group>
<ack>
<title>Acknowledgements</title>
<p>We appreciate the efforts of the dedicated volunteers who devoted considerable time to participate in these trials, and the suggestions of the members of the data safety and monitoring board.</p>
</ack>
<notes notes-type="author-contribution">
<title>Authors’ contributions</title>
<p>CFS obtained the funding; JBM, MJ, SH, WTC and CFS conducted the clinical trial; WTC, KEY, REO, BR, MBK, DAM, DSO and CFS analyzed samples; LLF and VGD conducted the CIMT studies; SAW conducted the MRI studies, CFS and KBS analyzed the data. CFS wrote the manuscript; JBM edited the manuscript. All authors read and approved the final manuscript.</p>
</notes>
<notes notes-type="funding-information">
<title>Funding</title>
<p>This work was supported by NIH Grants HL083762, DK020579, DK076729, DK056341, GM103422, UL1RR024992, KL2RR024994.</p>
</notes>
<notes notes-type="data-availability">
<title>Availability of data and materials</title>
<p>The datasets used and analyzed in the current study are available from the corresponding authors on reasonable request. All data generated during this study are included in this published article.</p>
</notes>
<notes>
<title>Ethics approval and consent to participate</title>
<p id="Par72">Ethics approval was granted by the Washington University Human Research Protection Office, Washington University in St. Louis, St. Louis, Missouri. All patients provided written informed consent.</p>
</notes>
<notes>
<title>Consent for publication</title>
<p id="Par73">Not applicable.</p>
</notes>
<notes notes-type="COI-statement">
<title>Competing interests</title>
<p id="Par74">The authors declare that they have no competing interests.</p>
</notes>
<ref-list id="Bib1">
<title>References</title>
<ref id="CR1">
<label>1.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Eckel</surname>
<given-names>RH</given-names>
</name>
<name>
<surname>Alberti</surname>
<given-names>KG</given-names>
</name>
<name>
<surname>Grundy</surname>
<given-names>SM</given-names>
</name>
<name>
<surname>Zimmet</surname>
<given-names>PZ</given-names>
</name>
</person-group>
<article-title>The metabolic syndrome</article-title>
<source>Lancet</source>
<year>2010</year>
<volume>375</volume>
<issue>9710</issue>
<fpage>181</fpage>
<lpage>183</lpage>
<pub-id pub-id-type="doi">10.1016/S0140-6736(09)61794-3</pub-id>
<pub-id pub-id-type="pmid">20109902</pub-id>
</element-citation>
</ref>
<ref id="CR2">
<label>2.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mottillo</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Filion</surname>
<given-names>KB</given-names>
</name>
<name>
<surname>Genest</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Joseph</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Pilote</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Poirier</surname>
<given-names>P</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis</article-title>
<source>JACC.</source>
<year>2010</year>
<volume>56</volume>
<issue>14</issue>
<fpage>1113</fpage>
<lpage>1132</lpage>
<pub-id pub-id-type="doi">10.1016/j.jacc.2010.05.034</pub-id>
<pub-id pub-id-type="pmid">20863953</pub-id>
</element-citation>
</ref>
<ref id="CR3">
<label>3.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Solinas</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Becattini</surname>
<given-names>B</given-names>
</name>
</person-group>
<article-title>JNK at the crossroad of obesity, insulin resistance, and cell stress response</article-title>
<source>Mol Metab.</source>
<year>2017</year>
<volume>6</volume>
<issue>2</issue>
<fpage>174</fpage>
<lpage>184</lpage>
<pub-id pub-id-type="doi">10.1016/j.molmet.2016.12.001</pub-id>
<pub-id pub-id-type="pmid">28180059</pub-id>
</element-citation>
</ref>
<ref id="CR4">
<label>4.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Look</surname>
<given-names>ARG</given-names>
</name>
<name>
<surname>Gregg</surname>
<given-names>EW</given-names>
</name>
<name>
<surname>Jakicic</surname>
<given-names>JM</given-names>
</name>
<name>
<surname>Blackburn</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Bloomquist</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Bray</surname>
<given-names>GA</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post hoc analysis of the Look AHEAD randomised clinical trial</article-title>
<source>Lancet Diabetes Endocrinol.</source>
<year>2016</year>
<volume>4</volume>
<issue>11</issue>
<fpage>913</fpage>
<lpage>921</lpage>
<pub-id pub-id-type="doi">10.1016/S2213-8587(16)30162-0</pub-id>
<pub-id pub-id-type="pmid">27595918</pub-id>
</element-citation>
</ref>
<ref id="CR5">
<label>5.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Semenkovich</surname>
<given-names>CF</given-names>
</name>
</person-group>
<article-title>Insulin resistance and atherosclerosis</article-title>
<source>J Clin Invest.</source>
<year>2006</year>
<volume>116</volume>
<issue>7</issue>
<fpage>1813</fpage>
<lpage>1822</lpage>
<pub-id pub-id-type="doi">10.1172/JCI29024</pub-id>
<pub-id pub-id-type="pmid">16823479</pub-id>
</element-citation>
</ref>
<ref id="CR6">
<label>6.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Schneider</surname>
<given-names>JG</given-names>
</name>
<name>
<surname>Finck</surname>
<given-names>BN</given-names>
</name>
<name>
<surname>Ren</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Standley</surname>
<given-names>KN</given-names>
</name>
<name>
<surname>Takagi</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Maclean</surname>
<given-names>KH</given-names>
</name>
<etal></etal>
</person-group>
<article-title>ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome</article-title>
<source>Cell Metab</source>
<year>2006</year>
<volume>4</volume>
<issue>5</issue>
<fpage>377</fpage>
<lpage>389</lpage>
<pub-id pub-id-type="doi">10.1016/j.cmet.2006.10.002</pub-id>
<pub-id pub-id-type="pmid">17084711</pub-id>
</element-citation>
</ref>
<ref id="CR7">
<label>7.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mercer</surname>
<given-names>JR</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>KK</given-names>
</name>
<name>
<surname>Figg</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Gorenne</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Mahmoudi</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Griffin</surname>
<given-names>J</given-names>
</name>
<etal></etal>
</person-group>
<article-title>DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome</article-title>
<source>Circ Res.</source>
<year>2010</year>
<volume>107</volume>
<issue>8</issue>
<fpage>1021</fpage>
<lpage>1031</lpage>
<pub-id pub-id-type="doi">10.1161/CIRCRESAHA.110.218966</pub-id>
<pub-id pub-id-type="pmid">20705925</pub-id>
</element-citation>
</ref>
<ref id="CR8">
<label>8.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Le Guezennec</surname>
<given-names>X</given-names>
</name>
<name>
<surname>Brichkina</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>YF</given-names>
</name>
<name>
<surname>Kostromina</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Han</surname>
<given-names>W</given-names>
</name>
<name>
<surname>Bulavin</surname>
<given-names>DV</given-names>
</name>
</person-group>
<article-title>Wip1-dependent regulation of autophagy, obesity, and atherosclerosis</article-title>
<source>Cell Metab</source>
<year>2012</year>
<volume>16</volume>
<issue>1</issue>
<fpage>68</fpage>
<lpage>80</lpage>
<pub-id pub-id-type="doi">10.1016/j.cmet.2012.06.003</pub-id>
<pub-id pub-id-type="pmid">22768840</pub-id>
</element-citation>
</ref>
<ref id="CR9">
<label>9.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Razani</surname>
<given-names>B</given-names>
</name>
<name>
<surname>Feng</surname>
<given-names>C</given-names>
</name>
<name>
<surname>Semenkovich</surname>
<given-names>CF</given-names>
</name>
</person-group>
<article-title>p53 is required for chloroquine-induced atheroprotection but not insulin sensitization</article-title>
<source>J Lipid Res</source>
<year>2010</year>
<volume>51</volume>
<issue>7</issue>
<fpage>1738</fpage>
<lpage>1746</lpage>
<pub-id pub-id-type="doi">10.1194/jlr.M003681</pub-id>
<pub-id pub-id-type="pmid">20208057</pub-id>
</element-citation>
</ref>
<ref id="CR10">
<label>10.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Geisel</surname>
<given-names>MH</given-names>
</name>
<name>
<surname>Bauer</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Hennig</surname>
<given-names>F</given-names>
</name>
<name>
<surname>Hoffmann</surname>
<given-names>B</given-names>
</name>
<name>
<surname>Lehmann</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Mohlenkamp</surname>
<given-names>S</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Comparison of coronary artery calcification, carotid intima-media thickness and ankle-brachial index for predicting 10-year incident cardiovascular events in the general population</article-title>
<source>Eur Heart J</source>
<year>2017</year>
<volume>38</volume>
<issue>23</issue>
<fpage>1815</fpage>
<lpage>1822</lpage>
<pub-id pub-id-type="doi">10.1093/eurheartj/ehx120</pub-id>
<pub-id pub-id-type="pmid">28379333</pub-id>
</element-citation>
</ref>
<ref id="CR11">
<label>11.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Subramanian</surname>
<given-names>S</given-names>
</name>
<name>
<surname>DeRosa</surname>
<given-names>MA</given-names>
</name>
<name>
<surname>Bernal-Mizrachi</surname>
<given-names>C</given-names>
</name>
<name>
<surname>Laffely</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Cade</surname>
<given-names>WT</given-names>
</name>
<name>
<surname>Yarasheski</surname>
<given-names>KE</given-names>
</name>
<etal></etal>
</person-group>
<article-title>PPARalpha activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans</article-title>
<source>Am J Physiol Endocrinol Metab</source>
<year>2006</year>
<volume>291</volume>
<issue>6</issue>
<fpage>E1365</fpage>
<lpage>E1371</lpage>
<pub-id pub-id-type="doi">10.1152/ajpendo.00230.2006</pub-id>
<pub-id pub-id-type="pmid">16868225</pub-id>
</element-citation>
</ref>
<ref id="CR12">
<label>12.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Derosa</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Fogari</surname>
<given-names>E</given-names>
</name>
<name>
<surname>D’Angelo</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Bianchi</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Bonaventura</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Romano</surname>
<given-names>D</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Adipocytokine levels in obese and non-obese subjects: an observational study</article-title>
<source>Inflammation.</source>
<year>2013</year>
<volume>36</volume>
<issue>4</issue>
<fpage>914</fpage>
<lpage>920</lpage>
<pub-id pub-id-type="doi">10.1007/s10753-013-9620-4</pub-id>
<pub-id pub-id-type="pmid">23467997</pub-id>
</element-citation>
</ref>
<ref id="CR13">
<label>13.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Derosa</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Bonaventura</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Bianchi</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Romano</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Fogari</surname>
<given-names>E</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Effects of
<italic>Berberis aristata</italic>
/
<italic>Silybum marianum</italic>
association on metabolic parameters and adipocytokines in overweight dyslipidemic patients</article-title>
<source>J Biol Regul Homeost Agents.</source>
<year>2013</year>
<volume>27</volume>
<issue>3</issue>
<fpage>717</fpage>
<lpage>728</lpage>
<pub-id pub-id-type="pmid">24152839</pub-id>
</element-citation>
</ref>
<ref id="CR14">
<label>14.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Azimi-Nezhad</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Mirhafez</surname>
<given-names>SR</given-names>
</name>
<name>
<surname>Stathopoulou</surname>
<given-names>MG</given-names>
</name>
<name>
<surname>Murray</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Ndiaye</surname>
<given-names>NC</given-names>
</name>
<name>
<surname>Bahrami</surname>
<given-names>A</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The relationship between vascular endothelial growth factor cis- and trans-acting genetic variants and metabolic syndrome</article-title>
<source>Am J Med Sci</source>
<year>2018</year>
<volume>355</volume>
<issue>6</issue>
<fpage>559</fpage>
<lpage>565</lpage>
<pub-id pub-id-type="doi">10.1016/j.amjms.2018.03.009</pub-id>
<pub-id pub-id-type="pmid">29891039</pub-id>
</element-citation>
</ref>
<ref id="CR15">
<label>15.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Suarez-Ortegon</surname>
<given-names>MF</given-names>
</name>
<name>
<surname>Blanco</surname>
<given-names>E</given-names>
</name>
<name>
<surname>McLachlan</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Fernandez-Real</surname>
<given-names>JM</given-names>
</name>
<name>
<surname>Burrows</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Wild</surname>
<given-names>SH</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Ferritin levels throughout childhood and metabolic syndrome in adolescent stage</article-title>
<source>Nutr Metab Cardiovasc Dis.</source>
<year>2019</year>
<volume>29</volume>
<issue>3</issue>
<fpage>268</fpage>
<lpage>278</lpage>
<pub-id pub-id-type="doi">10.1016/j.numecd.2018.11.008</pub-id>
<pub-id pub-id-type="pmid">30648600</pub-id>
</element-citation>
</ref>
<ref id="CR16">
<label>16.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Demir</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Harmankaya</surname>
<given-names>NO</given-names>
</name>
<name>
<surname>Kirac Utku</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Aciksari</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Uygun</surname>
<given-names>T</given-names>
</name>
<name>
<surname>Ozkan</surname>
<given-names>H</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The relationship between epicardial adipose tissue thickness and serum interleukin-17a level in patients with isolated metabolic syndrome</article-title>
<source>Biomolecules.</source>
<year>2019</year>
<volume>9</volume>
<issue>3</issue>
<fpage>97</fpage>
<pub-id pub-id-type="doi">10.3390/biom9030097</pub-id>
</element-citation>
</ref>
<ref id="CR17">
<label>17.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Gabrielsen</surname>
<given-names>JS</given-names>
</name>
<name>
<surname>Gao</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>Simcox</surname>
<given-names>JA</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Thorup</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Jones</surname>
<given-names>D</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Adipocyte iron regulates adiponectin and insulin sensitivity</article-title>
<source>J Clin Invest.</source>
<year>2012</year>
<volume>122</volume>
<issue>10</issue>
<fpage>3529</fpage>
<lpage>3540</lpage>
<pub-id pub-id-type="doi">10.1172/JCI44421</pub-id>
<pub-id pub-id-type="pmid">22996660</pub-id>
</element-citation>
</ref>
<ref id="CR18">
<label>18.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Stein</surname>
<given-names>JH</given-names>
</name>
<name>
<surname>Korcarz</surname>
<given-names>CE</given-names>
</name>
<name>
<surname>Hurst</surname>
<given-names>RT</given-names>
</name>
<name>
<surname>Lonn</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Kendall</surname>
<given-names>CB</given-names>
</name>
<name>
<surname>Mohler</surname>
<given-names>ER</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force</article-title>
<source>J Am Soc Echocardiography.</source>
<year>2008</year>
<volume>21</volume>
<issue>2</issue>
<fpage>93</fpage>
<lpage>111</lpage>
<pub-id pub-id-type="doi">10.1016/j.echo.2007.11.011</pub-id>
</element-citation>
</ref>
<ref id="CR19">
<label>19.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>de Fuentes</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Waggoner</surname>
<given-names>AD</given-names>
</name>
<name>
<surname>Mohammed</surname>
<given-names>BS</given-names>
</name>
<name>
<surname>Stein</surname>
<given-names>RI</given-names>
</name>
<name>
<surname>Miller</surname>
<given-names>BV</given-names>
<suffix>3rd</suffix>
</name>
<name>
<surname>Foster</surname>
<given-names>GD</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function</article-title>
<source>JACC.</source>
<year>2009</year>
<volume>54</volume>
<issue>25</issue>
<fpage>2376</fpage>
<lpage>2381</lpage>
<pub-id pub-id-type="doi">10.1016/j.jacc.2009.07.054</pub-id>
<pub-id pub-id-type="pmid">20082927</pub-id>
</element-citation>
</ref>
<ref id="CR20">
<label>20.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Porter</surname>
<given-names>FD</given-names>
</name>
<name>
<surname>Scherrer</surname>
<given-names>DE</given-names>
</name>
<name>
<surname>Lanier</surname>
<given-names>MH</given-names>
</name>
<name>
<surname>Langmade</surname>
<given-names>SJ</given-names>
</name>
<name>
<surname>Molugu</surname>
<given-names>V</given-names>
</name>
<name>
<surname>Gale</surname>
<given-names>SE</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease</article-title>
<source>Sci Transl Med.</source>
<year>2010</year>
<volume>2</volume>
<issue>56</issue>
<fpage>5681</fpage>
<pub-id pub-id-type="doi">10.1126/scitranslmed.3001417</pub-id>
</element-citation>
</ref>
<ref id="CR21">
<label>21.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yaghootkar</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Lamina</surname>
<given-names>C</given-names>
</name>
<name>
<surname>Scott</surname>
<given-names>RA</given-names>
</name>
<name>
<surname>Dastani</surname>
<given-names>Z</given-names>
</name>
<name>
<surname>Hivert</surname>
<given-names>MF</given-names>
</name>
<name>
<surname>Warren</surname>
<given-names>LL</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes</article-title>
<source>Diabetes</source>
<year>2013</year>
<volume>62</volume>
<issue>10</issue>
<fpage>3589</fpage>
<lpage>3598</lpage>
<pub-id pub-id-type="doi">10.2337/db13-0128</pub-id>
<pub-id pub-id-type="pmid">23835345</pub-id>
</element-citation>
</ref>
<ref id="CR22">
<label>22.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Simcox</surname>
<given-names>JA</given-names>
</name>
<name>
<surname>McClain</surname>
<given-names>DA</given-names>
</name>
</person-group>
<article-title>Iron and diabetes risk</article-title>
<source>Cell Metab</source>
<year>2013</year>
<volume>17</volume>
<issue>3</issue>
<fpage>329</fpage>
<lpage>341</lpage>
<pub-id pub-id-type="doi">10.1016/j.cmet.2013.02.007</pub-id>
<pub-id pub-id-type="pmid">23473030</pub-id>
</element-citation>
</ref>
<ref id="CR23">
<label>23.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ramm</surname>
<given-names>GA</given-names>
</name>
<name>
<surname>Powell</surname>
<given-names>LW</given-names>
</name>
<name>
<surname>Halliday</surname>
<given-names>JW</given-names>
</name>
</person-group>
<article-title>Pathways of intracellular trafficking and release of ferritin by the liver in vivo: the effect of chloroquine and cytochalasin D</article-title>
<source>Hepatology</source>
<year>1994</year>
<volume>19</volume>
<issue>2</issue>
<fpage>504</fpage>
<lpage>513</lpage>
<pub-id pub-id-type="doi">10.1002/hep.1840190232</pub-id>
<pub-id pub-id-type="pmid">8294107</pub-id>
</element-citation>
</ref>
<ref id="CR24">
<label>24.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Matsuda</surname>
<given-names>M</given-names>
</name>
<name>
<surname>DeFronzo</surname>
<given-names>RA</given-names>
</name>
</person-group>
<article-title>Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp</article-title>
<source>Diabetes Care</source>
<year>1999</year>
<volume>22</volume>
<issue>9</issue>
<fpage>1462</fpage>
<lpage>1470</lpage>
<pub-id pub-id-type="doi">10.2337/diacare.22.9.1462</pub-id>
<pub-id pub-id-type="pmid">10480510</pub-id>
</element-citation>
</ref>
<ref id="CR25">
<label>25.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Han</surname>
<given-names>MS</given-names>
</name>
<name>
<surname>Jung</surname>
<given-names>DY</given-names>
</name>
<name>
<surname>Morel</surname>
<given-names>C</given-names>
</name>
<name>
<surname>Lakhani</surname>
<given-names>SA</given-names>
</name>
<name>
<surname>Kim</surname>
<given-names>JK</given-names>
</name>
<name>
<surname>Flavell</surname>
<given-names>RA</given-names>
</name>
<etal></etal>
</person-group>
<article-title>JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation</article-title>
<source>Science</source>
<year>2013</year>
<volume>339</volume>
<issue>6116</issue>
<fpage>218</fpage>
<lpage>222</lpage>
<pub-id pub-id-type="doi">10.1126/science.1227568</pub-id>
<pub-id pub-id-type="pmid">23223452</pub-id>
</element-citation>
</ref>
<ref id="CR26">
<label>26.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Houstis</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Rosen</surname>
<given-names>ED</given-names>
</name>
<name>
<surname>Lander</surname>
<given-names>ES</given-names>
</name>
</person-group>
<article-title>Reactive oxygen species have a causal role in multiple forms of insulin resistance</article-title>
<source>Nature</source>
<year>2006</year>
<volume>440</volume>
<issue>7086</issue>
<fpage>944</fpage>
<lpage>948</lpage>
<pub-id pub-id-type="doi">10.1038/nature04634</pub-id>
<pub-id pub-id-type="pmid">16612386</pub-id>
</element-citation>
</ref>
<ref id="CR27">
<label>27.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Minamikawa</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Tanaka</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Yamauchi</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Inoue</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Koshiyama</surname>
<given-names>H</given-names>
</name>
</person-group>
<article-title>Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes</article-title>
<source>J Clin Endocrinol Metab</source>
<year>1998</year>
<volume>83</volume>
<issue>5</issue>
<fpage>1818</fpage>
<lpage>1820</lpage>
<pub-id pub-id-type="doi">10.1210/jcem.83.5.4932</pub-id>
<pub-id pub-id-type="pmid">9589700</pub-id>
</element-citation>
</ref>
<ref id="CR28">
<label>28.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Koshiyama</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Shimono</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Kuwamura</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Minamikawa</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Nakamura</surname>
<given-names>Y</given-names>
</name>
</person-group>
<article-title>Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes</article-title>
<source>J Clin Endocrinol Metab</source>
<year>2001</year>
<volume>86</volume>
<issue>7</issue>
<fpage>3452</fpage>
<lpage>3456</lpage>
<pub-id pub-id-type="doi">10.1210/jcem.86.7.7810</pub-id>
<pub-id pub-id-type="pmid">11443224</pub-id>
</element-citation>
</ref>
<ref id="CR29">
<label>29.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Stocker</surname>
<given-names>DJ</given-names>
</name>
<name>
<surname>Taylor</surname>
<given-names>AJ</given-names>
</name>
<name>
<surname>Langley</surname>
<given-names>RW</given-names>
</name>
<name>
<surname>Jezior</surname>
<given-names>MR</given-names>
</name>
<name>
<surname>Vigersky</surname>
<given-names>RA</given-names>
</name>
</person-group>
<article-title>A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes</article-title>
<source>Am Heart J.</source>
<year>2007</year>
<volume>153</volume>
<issue>3</issue>
<fpage>445</fpage>
<pub-id pub-id-type="doi">10.1016/j.ahj.2006.11.005</pub-id>
</element-citation>
</ref>
<ref id="CR30">
<label>30.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Xiang</surname>
<given-names>AH</given-names>
</name>
<name>
<surname>Hodis</surname>
<given-names>HN</given-names>
</name>
<name>
<surname>Kawakubo</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Peters</surname>
<given-names>RK</given-names>
</name>
<name>
<surname>Kjos</surname>
<given-names>SL</given-names>
</name>
<name>
<surname>Marroquin</surname>
<given-names>A</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Effect of pioglitazone on progression of subclinical atherosclerosis in non-diabetic premenopausal Hispanic women with prior gestational diabetes</article-title>
<source>Atherosclerosis.</source>
<year>2008</year>
<volume>199</volume>
<issue>1</issue>
<fpage>207</fpage>
<lpage>214</lpage>
<pub-id pub-id-type="doi">10.1016/j.atherosclerosis.2007.10.016</pub-id>
<pub-id pub-id-type="pmid">18054942</pub-id>
</element-citation>
</ref>
<ref id="CR31">
<label>31.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Saremi</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Schwenke</surname>
<given-names>DC</given-names>
</name>
<name>
<surname>Buchanan</surname>
<given-names>TA</given-names>
</name>
<name>
<surname>Hodis</surname>
<given-names>HN</given-names>
</name>
<name>
<surname>Mack</surname>
<given-names>WJ</given-names>
</name>
<name>
<surname>Banerji</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors</article-title>
<source>ATVB.</source>
<year>2013</year>
<volume>33</volume>
<issue>2</issue>
<fpage>393</fpage>
<lpage>399</lpage>
<pub-id pub-id-type="doi">10.1161/ATVBAHA.112.300346</pub-id>
</element-citation>
</ref>
<ref id="CR32">
<label>32.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kaneto</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Nakatani</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>Miyatsuka</surname>
<given-names>T</given-names>
</name>
<name>
<surname>Kawamori</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Matsuoka</surname>
<given-names>TA</given-names>
</name>
<name>
<surname>Matsuhisa</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide</article-title>
<source>Nat Med.</source>
<year>2004</year>
<volume>10</volume>
<issue>10</issue>
<fpage>1128</fpage>
<lpage>1132</lpage>
<pub-id pub-id-type="doi">10.1038/nm1111</pub-id>
<pub-id pub-id-type="pmid">15448687</pub-id>
</element-citation>
</ref>
<ref id="CR33">
<label>33.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ricci</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Sumara</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Sumara</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Rozenberg</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Kurrer</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Akhmedov</surname>
<given-names>A</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis</article-title>
<source>Science</source>
<year>2004</year>
<volume>306</volume>
<issue>5701</issue>
<fpage>1558</fpage>
<lpage>1561</lpage>
<pub-id pub-id-type="doi">10.1126/science.1101909</pub-id>
<pub-id pub-id-type="pmid">15567863</pub-id>
</element-citation>
</ref>
<ref id="CR34">
<label>34.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Valentin-Vega</surname>
<given-names>YA</given-names>
</name>
<name>
<surname>Maclean</surname>
<given-names>KH</given-names>
</name>
<name>
<surname>Tait-Mulder</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Milasta</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Steeves</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Dorsey</surname>
<given-names>FC</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Mitochondrial dysfunction in ataxia-telangiectasia</article-title>
<source>Blood</source>
<year>2012</year>
<volume>119</volume>
<issue>6</issue>
<fpage>1490</fpage>
<lpage>1500</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2011-08-373639</pub-id>
<pub-id pub-id-type="pmid">22144182</pub-id>
</element-citation>
</ref>
<ref id="CR35">
<label>35.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Madiraju</surname>
<given-names>AK</given-names>
</name>
<name>
<surname>Qiu</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>Perry</surname>
<given-names>RJ</given-names>
</name>
<name>
<surname>Rahimi</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>XM</given-names>
</name>
<name>
<surname>Zhang</surname>
<given-names>D</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo</article-title>
<source>Nature Med.</source>
<year>2018</year>
<volume>24</volume>
<issue>9</issue>
<fpage>1384</fpage>
<lpage>1394</lpage>
<pub-id pub-id-type="doi">10.1038/s41591-018-0125-4</pub-id>
<pub-id pub-id-type="pmid">30038219</pub-id>
</element-citation>
</ref>
<ref id="CR36">
<label>36.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<collab>GoDarts</collab>
<collab>Group UDPS</collab>
<collab>Wellcome Trust Case Control C</collab>
<name>
<surname>Zhou</surname>
<given-names>K</given-names>
</name>
<name>
<surname>Bellenguez</surname>
<given-names>C</given-names>
</name>
<name>
<surname>Spencer</surname>
<given-names>CC</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes</article-title>
<source>Nat Genetics.</source>
<year>2011</year>
<volume>43</volume>
<issue>2</issue>
<fpage>117</fpage>
<lpage>120</lpage>
<pub-id pub-id-type="doi">10.1038/ng.735</pub-id>
<pub-id pub-id-type="pmid">21186350</pub-id>
</element-citation>
</ref>
<ref id="CR37">
<label>37.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Gerstein</surname>
<given-names>HC</given-names>
</name>
<name>
<surname>Thorpe</surname>
<given-names>KE</given-names>
</name>
<name>
<surname>Taylor</surname>
<given-names>DW</given-names>
</name>
<name>
<surname>Haynes</surname>
<given-names>RB</given-names>
</name>
</person-group>
<article-title>The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas–a randomized trial</article-title>
<source>Diabetes Res Clin Prac.</source>
<year>2002</year>
<volume>55</volume>
<issue>3</issue>
<fpage>209</fpage>
<lpage>219</lpage>
<pub-id pub-id-type="doi">10.1016/S0168-8227(01)00325-4</pub-id>
</element-citation>
</ref>
<ref id="CR38">
<label>38.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sheikhbahaie</surname>
<given-names>F</given-names>
</name>
<name>
<surname>Amini</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Gharipour</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Aminoroaya</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Taheri</surname>
<given-names>N</given-names>
</name>
</person-group>
<article-title>The effect of hydroxychloroquine on glucose control and insulin resistance in the prediabetes condition</article-title>
<source>Adv Biomed Res.</source>
<year>2016</year>
<volume>5</volume>
<fpage>145</fpage>
<pub-id pub-id-type="doi">10.4103/2277-9175.187401</pub-id>
<pub-id pub-id-type="pmid">27656614</pub-id>
</element-citation>
</ref>
<ref id="CR39">
<label>39.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wasko</surname>
<given-names>MC</given-names>
</name>
<name>
<surname>Hubert</surname>
<given-names>HB</given-names>
</name>
<name>
<surname>Lingala</surname>
<given-names>VB</given-names>
</name>
<name>
<surname>Elliott</surname>
<given-names>JR</given-names>
</name>
<name>
<surname>Luggen</surname>
<given-names>ME</given-names>
</name>
<name>
<surname>Fries</surname>
<given-names>JF</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis</article-title>
<source>JAMA</source>
<year>2007</year>
<volume>298</volume>
<issue>2</issue>
<fpage>187</fpage>
<lpage>193</lpage>
<pub-id pub-id-type="doi">10.1001/jama.298.2.187</pub-id>
<pub-id pub-id-type="pmid">17622600</pub-id>
</element-citation>
</ref>
<ref id="CR40">
<label>40.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Solomon</surname>
<given-names>DH</given-names>
</name>
<name>
<surname>Massarotti</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Garg</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Canning</surname>
<given-names>C</given-names>
</name>
<name>
<surname>Schneeweiss</surname>
<given-names>S</given-names>
</name>
</person-group>
<article-title>Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis</article-title>
<source>JAMA</source>
<year>2011</year>
<volume>305</volume>
<issue>24</issue>
<fpage>2525</fpage>
<lpage>2531</lpage>
<pub-id pub-id-type="doi">10.1001/jama.2011.878</pub-id>
<pub-id pub-id-type="pmid">21693740</pub-id>
</element-citation>
</ref>
<ref id="CR41">
<label>41.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mercer</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Rekedal</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Garg</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Lu</surname>
<given-names>B</given-names>
</name>
<name>
<surname>Massarotti</surname>
<given-names>EM</given-names>
</name>
<name>
<surname>Solomon</surname>
<given-names>DH</given-names>
</name>
</person-group>
<article-title>Hydroxychloroquine improves insulin sensitivity in obese non-diabetic individuals</article-title>
<source>Arthritis Res Ther.</source>
<year>2012</year>
<volume>14</volume>
<issue>3</issue>
<fpage>R135</fpage>
<pub-id pub-id-type="doi">10.1186/ar3868</pub-id>
<pub-id pub-id-type="pmid">22676348</pub-id>
</element-citation>
</ref>
</ref-list>
</back>
</pmc>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Pmc/Corpus

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000094 | SxmlIndent | more

Ou

HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000094 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Sante
   |area=    ChloroquineV1
   |flux=    Pmc
   |étape=   Corpus
   |type=    RBID
   |clé=     PMC:6664523
   |texte=   Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i   -Sk "pubmed:31384309" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd   \
       | NlmPubMed2Wicri -a ChloroquineV1
Wicri

This area was generated with Dilib version V0.6.33.
Data generation: Wed Mar 25 22:43:59 2020. Site generation: Sun Jan 31 12:44:45 2021