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McGill JB, Johnson M, Hurst S, et al. Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness. Diabetol Metab Syndr. 2019;11:61doi: 10.1186/s13098-019-0456-4.
McGill, J. B., Johnson, M., Hurst, S., Cade, W. T., Yarasheski, K. E., Ostlund, R. E., Schechtman, K. B., Razani, B., Kastan, M. B., McClain, D. A., de Las Fuentes, L., Davila-Roman, V. G., Ory, D. S., Wickline, S. A., & Semenkovich, C. F. (2019). Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness. Diabetology & metabolic syndrome, 1161. https://doi.org/10.1186/s13098-019-0456-4
McGill, Janet B, et al. "Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness." Diabetology & metabolic syndrome vol. 11 (2019): 61. doi: https://doi.org/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 Jul 29;11:61. doi: 10.1186/s13098-019-0456-4. eCollection 2019. PMID: 31384309; PMCID: PMC6664523.
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Diabetol Metab Syndr. 2019 Jul 29;11:61. doi: 10.1186/s13098-019-0456-4. eCollection 2019.

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

Diabetology & metabolic syndrome

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

Affiliations

  1. 1Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8127, St. Louis, MO 63110 USA.
  2. 2Program in Physical Therapy, Washington University, St. Louis, MO USA.
  3. 3Division of Biostatistics, Washington University, St. Louis, MO USA.
  4. 4Cardiovascular Division, Washington University, St. Louis, MO USA.
  5. 5Department of Pharmacology & Cancer Biology, Duke University, Durham, NC USA.
  6. 6Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC USA.
  7. 7Department of Cell Biology & Physiology, Washington University, St. Louis, MO USA.

PMID: 31384309 PMCID: PMC6664523 DOI: 10.1186/s13098-019-0456-4

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.

Keywords: Atheroma; Blood pressure; Carotid intima-media thickness; Chloroquine; Glucose disposal; Insulin sensitivity; JNK; Lipids; Metabolic syndrome

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

References

  1. Diabetes Care. 1999 Sep;22(9):1462-70 - PubMed
  2. J Clin Endocrinol Metab. 2001 Jul;86(7):3452-6 - PubMed
  3. Diabetes Res Clin Pract. 2002 Mar;55(3):209-19 - PubMed
  4. Nat Med. 2004 Oct;10(10):1128-32 - PubMed
  5. Science. 2004 Nov 26;306(5701):1558-61 - PubMed
  6. Nature. 2006 Apr 13;440(7086):944-8 - PubMed
  7. J Clin Invest. 2006 Jul;116(7):1813-22 - PubMed
  8. Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1365-71 - PubMed
  9. Cell Metab. 2006 Nov;4(5):377-89 - PubMed
  10. Am Heart J. 2007 Mar;153(3):445.e1-6 - PubMed
  11. JAMA. 2007 Jul 11;298(2):187-93 - PubMed
  12. Atherosclerosis. 2008 Jul;199(1):207-14 - PubMed
  13. J Am Soc Echocardiogr. 2008 Feb;21(2):93-111; quiz 189-90 - PubMed
  14. J Am Coll Cardiol. 2009 Dec 15;54(25):2376-81 - PubMed
  15. Lancet. 2010 Jan 16;375(9710):181-3 - PubMed
  16. J Lipid Res. 2010 Jul;51(7):1738-46 - PubMed
  17. Circ Res. 2010 Oct 15;107(8):1021-31 - PubMed
  18. J Am Coll Cardiol. 2010 Sep 28;56(14):1113-32 - PubMed
  19. Sci Transl Med. 2010 Nov 3;2(56):56ra81 - PubMed
  20. Nat Genet. 2011 Feb;43(2):117-20 - PubMed
  21. JAMA. 2011 Jun 22;305(24):2525-31 - PubMed
  22. Blood. 2012 Feb 9;119(6):1490-500 - PubMed
  23. Arthritis Res Ther. 2012 Jun 07;14(3):R135 - PubMed
  24. Cell Metab. 2012 Jul 3;16(1):68-80 - PubMed
  25. J Clin Invest. 2012 Oct;122(10):3529-40 - PubMed
  26. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):393-9 - PubMed
  27. Science. 2013 Jan 11;339(6116):218-22 - PubMed
  28. Inflammation. 2013 Aug;36(4):914-20 - PubMed
  29. Cell Metab. 2013 Mar 5;17(3):329-41 - PubMed
  30. Diabetes. 2013 Oct;62(10):3589-98 - PubMed
  31. J Biol Regul Homeost Agents. 2013 Jul-Sep;27(3):717-28 - PubMed
  32. Lancet Diabetes Endocrinol. 2016 Nov;4(11):913-921 - PubMed
  33. Adv Biomed Res. 2016 Aug 30;5:145 - PubMed
  34. Mol Metab. 2016 Dec 08;6(2):174-184 - PubMed
  35. Eur Heart J. 2017 Jun 14;38(23):1815-1822 - PubMed
  36. Am J Med Sci. 2018 Jun;355(6):559-565 - PubMed
  37. Nat Med. 2018 Sep;24(9):1384-1394 - PubMed
  38. Nutr Metab Cardiovasc Dis. 2019 Mar;29(3):268-278 - PubMed
  39. Biomolecules. 2019 Mar 11;9(3): - PubMed
  40. Hepatology. 1994 Feb;19(2):504-13 - PubMed
  41. J Clin Endocrinol Metab. 1998 May;83(5):1818-20 - PubMed

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