The Effects of Hydroxychloroquine on Insulin Sensitivity, Insulin Clearance, and Inflammation in Insulin-Resistant Adults: a Randomized Trial.

Aims Hydroxychloroquine (HCQ) has anti-inflammatory effects often employed in the treatment of rheumatic diseases. Observational studies have shown that patients treated with HCQ have a lower incidence of diabetes mellitus, suggesting metabolic effects that could be repurposed for the prevention and/or treatment of diabetes. However, the mechanism of action of HCQ on glucose metabolism has not been established. We sought to determine the effect of HCQ on skeletal muscle and liver insulin sensitivity, insulin clearance, inflammation, and adipokines. Methods Insulin-resistant adults without rheumatic disease were randomized to 13 weeks of HCQ (400 mg/d PO) vs. placebo (double-blinded). Primary outcomes were changes in skeletal muscle and liver insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp and stable-isotope tracer methods. Secondary outcomes included insulin clearance, inflammation biomarkers, and adipokines. Results Compared to placebo, HCQ significantly improved skeletal muscle insulin sensitivity by 26% (P=0.019) and enhanced systemic glucose clearance (P=0.025). In contrast, HCQ had no effect on hepatic insulin sensitivity. HCQ did not affect insulin clearance but decreased circulating IL-6 (P=0.01) and increased adiponectin (P=0.045). There were no effects on leptin, RBP-4, FGF-21, or c-reactive protein. Conclusions HCQ selectively enhances insulin sensitivity and glucose disposal in skeletal muscle, without affecting hepatic insulin sensitivity or insulin clearance. These findings offer a mechanistic explanation for the anti-diabetic properties of HCQ and suggest that this medication might be useful in conditions linked to insulin resistance such as type 2 diabetes. This article is protected by copyright. All rights reserved.