title: Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial.
abstract: OBJECTIVE
  Hydroxychloroquine (HCQ), an antimalarial drug with anti-inflammatory properties, is employed in rheumatic diseases. In observational studies, patients with rheumatic diseases treated with HCQ have a lower risk of developing diabetes. However, the physiological mechanisms remain unexplained. We hypothesised that HCQ may have favourable effects on insulin sensitivity and/or beta cell function.
  
  
  METHODS
  This was a randomised, double-blind, parallel-arm (placebo vs HCQ 400 mg/day) trial at the University of Pittsburgh. Randomisation was conducted by a computer system with concealment by sealed envelopes. Treatment duration was 13 ± 1 weeks. Randomised participants (HCQ n = 17; placebo n = 15) were non-diabetic volunteers, age >18, overweight or obese, with one or more markers of insulin resistance. All participants were included in intention-to-treat analysis. Outcomes were changes in insulin sensitivity and beta cell function measured by intravenous glucose tolerance tests and minimal model analysis.
  
  
  RESULTS
  There was a positive change in insulin sensitivity with HCQ but not placebo (mean ± SEM: +20.0% ± 7.1% vs -18.4% ± 7.9%, respectively; p < 0.01; difference: 38.3% ± 10.6%; 95% CI: 17%, 60%). Improvement in beta cell function was also observed with HCQ but not placebo (+45.4% ± 12.3% vs -19.7% ± 13.6%; p < 0.01; difference: 65% ± 19%; 95% CI: 27%, 103%). There were modest treatment effects on fasting plasma glucose and HbA(1c) (p < 0.05) but circulating markers of inflammation (IL-6, IL-1, TNF-α, soluble intercellular adhesion molecule) were not affected in either group. In contrast, adiponectin levels increased after HCQ treatment but not after placebo (+18.7% vs +0.7%, respectively; p < 0.001). Both low- and high-molecular-weight adiponectin forms accounted for the increase. There were no serious or unexpected adverse effects.
  
  
  CONCLUSIONS
  HCQ improves both beta cell function and insulin sensitivity in non-diabetic individuals. These metabolic effects may explain why HCQ treatment is associated with a lower risk of type 2 diabetes. An additional novel observation is that HCQ improves adiponectin levels, possibly being a mediator of the favourable effects on glucose metabolism. Our findings suggest that HCQ is a drug with considerable metabolic effects that warrant further exploration in disorders of glucose metabolism.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01326533 FUNDING: This study was funded by National Institutes of Health no. 5R21DK082878, UL1-RR024153 and UL-1TR000005.
authors.affiliation: Division of Rheumatology, Department of Medicine, Allegheny Health Network, 4800 Friendship Avenue, North Tower, Suite 2600, Pittsburgh, PA, 15224, USA. mcwasko@wpahs.org.
authors.forename: Mary Chester M
authors.initials: MC
authors.lastname: Wasko
authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Candace K
authors.initials: CK
authors.lastname: McClure
authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Sheryl F
authors.initials: SF
authors.lastname: Kelsey
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, 200 Lothrop Street BST-E1140, Pittsburgh, PA, 15261, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Huber
authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.|Department of Medicine, University of Pittsburgh Graduate School of Public Health and School of Medicine, Pittsburgh, PA, USA.|Department of Pediatrics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Orchard
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, 200 Lothrop Street BST-E1140, Pittsburgh, PA, 15261, USA. toledofs@upmc.edu.
authors.forename: Frederico G S
authors.initials: FG
authors.lastname: Toledo
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000378:metabolism; D050177:Overweight / Q000097:blood / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D018799:Intercellular Adhesion Molecule-1; D006886:Hydroxychloroquine
keywords: Beta cell function; Hydroxychloroquine; Insulin sensitivity