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

Publication ,  Journal Article
McGill, JB; Johnson, M; Hurst, S; Cade, WT; Yarasheski, KE; Ostlund, RE; Schechtman, KB; Razani, B; Kastan, MB; McClain, DA; de Las Fuentes, L ...
Published in: Diabetol Metab Syndr
2019

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.

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Published In

Diabetol Metab Syndr

DOI

ISSN

1758-5996

Publication Date

2019

Volume

11

Start / End Page

61

Location

England

Related Subject Headings

  • 4206 Public health
  • 3205 Medical biochemistry and metabolomics
  • 1103 Clinical Sciences
  • 1101 Medical Biochemistry and Metabolomics
 

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McGill, J. B., Johnson, M., Hurst, S., Cade, W. T., Yarasheski, K. E., Ostlund, R. E., … Semenkovich, C. F. (2019). Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness. Diabetol Metab Syndr, 11, 61. https://doi.org/10.1186/s13098-019-0456-4
McGill, Janet B., Mariko Johnson, Stacy Hurst, William T. Cade, Kevin E. Yarasheski, Richard E. Ostlund, Kenneth B. Schechtman, et al. “Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.Diabetol Metab Syndr 11 (2019): 61. https://doi.org/10.1186/s13098-019-0456-4.
McGill JB, Johnson M, Hurst S, Cade WT, Yarasheski KE, Ostlund RE, et al. Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness. Diabetol Metab Syndr. 2019;11:61.
McGill, Janet B., et al. “Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.Diabetol Metab Syndr, vol. 11, 2019, p. 61. Pubmed, doi:10.1186/s13098-019-0456-4.
McGill JB, Johnson M, Hurst S, Cade WT, Yarasheski KE, Ostlund RE, Schechtman KB, Razani B, Kastan MB, McClain DA, de Las Fuentes L, Davila-Roman VG, Ory DS, Wickline SA, Semenkovich CF. Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness. Diabetol Metab Syndr. 2019;11:61.
Journal cover image

Published In

Diabetol Metab Syndr

DOI

ISSN

1758-5996

Publication Date

2019

Volume

11

Start / End Page

61

Location

England

Related Subject Headings

  • 4206 Public health
  • 3205 Medical biochemistry and metabolomics
  • 1103 Clinical Sciences
  • 1101 Medical Biochemistry and Metabolomics