Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness
Identifieur interne : 000675 ( Main/Exploration ); précédent : 000674; suivant : 000676Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness
Auteurs : Janet B. Mcgill [États-Unis] ; Mariko Johnson [États-Unis] ; Stacy Hurst [États-Unis] ; William T. Cade [États-Unis] ; Kevin E. Yarasheski [États-Unis] ; Richard E. Ostlund [États-Unis] ; Kenneth B. Schechtman [États-Unis] ; Babak Razani [États-Unis] ; Michael B. Kastan [États-Unis] ; Donald A. Mcclain [États-Unis] ; Lisa De Las Fuentes [États-Unis] ; Victor G. Davila-Roman [États-Unis] ; Daniel S. Ory [États-Unis] ; Samuel A. Wickline [États-Unis] ; Clay F. Semenkovich [États-Unis]Source :
- Diabetology & Metabolic Syndrome [ 1758-5996 ] ; 2019.
Abstract
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.
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.
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.
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.
Url:
DOI: 10.1186/s13098-019-0456-4
PubMed: 31384309
PubMed Central: 6664523
Affiliations:
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Mcclain</name><affiliation wicri:level="2"><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><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Winston-Salem</wicri:cityArea></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 wicri:level="2"><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><country>États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>St. Louis</wicri:cityArea></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 wicri:level="2"><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><country>États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>St. Louis</wicri:cityArea></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 wicri:level="2"><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><country>États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>St. Louis</wicri:cityArea></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 wicri:level="2"><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><country>États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>St. Louis</wicri:cityArea></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 wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>660 South Euclid Avenue, Box 8127, St. Louis</wicri:cityArea></affiliation><affiliation wicri:level="2"><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><country>États-Unis</country><placeName><region type="state">Missouri (État)</region></placeName><wicri:cityArea>St. Louis</wicri:cityArea></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 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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><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li><li>Missouri (État)</li></region></list><tree><country name="États-Unis"><region name="Missouri (État)"><name sortKey="Mcgill, Janet B" sort="Mcgill, Janet B" uniqKey="Mcgill J" first="Janet B." last="Mcgill">Janet B. Mcgill</name></region><name sortKey="Cade, William T" sort="Cade, William T" uniqKey="Cade W" first="William T." last="Cade">William T. Cade</name><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><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><name sortKey="Hurst, Stacy" sort="Hurst, Stacy" uniqKey="Hurst S" first="Stacy" last="Hurst">Stacy Hurst</name><name sortKey="Johnson, Mariko" sort="Johnson, Mariko" uniqKey="Johnson M" first="Mariko" last="Johnson">Mariko Johnson</name><name sortKey="Kastan, Michael B" sort="Kastan, Michael B" uniqKey="Kastan M" first="Michael B." last="Kastan">Michael B. Kastan</name><name sortKey="Mcclain, Donald A" sort="Mcclain, Donald A" uniqKey="Mcclain D" first="Donald A." last="Mcclain">Donald A. Mcclain</name><name sortKey="Ory, Daniel S" sort="Ory, Daniel S" uniqKey="Ory D" first="Daniel S." last="Ory">Daniel S. Ory</name><name sortKey="Ostlund, Richard E" sort="Ostlund, Richard E" uniqKey="Ostlund R" first="Richard E." last="Ostlund">Richard E. Ostlund</name><name sortKey="Razani, Babak" sort="Razani, Babak" uniqKey="Razani B" first="Babak" last="Razani">Babak Razani</name><name sortKey="Schechtman, Kenneth B" sort="Schechtman, Kenneth B" uniqKey="Schechtman K" first="Kenneth B." last="Schechtman">Kenneth B. Schechtman</name><name sortKey="Semenkovich, Clay F" sort="Semenkovich, Clay F" uniqKey="Semenkovich C" first="Clay F." last="Semenkovich">Clay F. Semenkovich</name><name sortKey="Semenkovich, Clay F" sort="Semenkovich, Clay F" uniqKey="Semenkovich C" first="Clay F." last="Semenkovich">Clay F. Semenkovich</name><name sortKey="Wickline, Samuel A" sort="Wickline, Samuel A" uniqKey="Wickline S" first="Samuel A." last="Wickline">Samuel A. Wickline</name><name sortKey="Yarasheski, Kevin E" sort="Yarasheski, Kevin E" uniqKey="Yarasheski K" first="Kevin E." last="Yarasheski">Kevin E. Yarasheski</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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