The effects of hydroxychloroquine on insulin sensitivity, insulin clearance and inflammation in insulin‐resistant adults: A randomized trial

Abstract

Aim To determine the effect of hydroxychloroquine (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/day) versus placebo (double‐blinded). Primary outcomes were changes in skeletal muscle and liver insulin sensitivity assessed by hyperinsulinaemic‐euglycaemic clamp and stable‐isotope tracer methods. Secondary outcomes included insulin clearance, inflammation biomarkers and adipokines. Results Compared with placebo, HCQ significantly improved skeletal muscle insulin sensitivity by 26% (p = .019) and enhanced systemic glucose clearance (p = .025). By contrast, HCQ had no effect on hepatic insulin sensitivity. HCQ did not affect insulin clearance but decreased circulating IL‐6 (p = .01) and increased adiponectin (p = .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 antidiabetic properties of HCQ and suggest that this medication might be useful in conditions linked to insulin resistance such as type 2 diabetes.

Supplemental hydroxychloroquine therapy regulates adipokines in patients with systemic lupus erythematosus with stable disease

“…However, since no association was found between HCQ-induced changes in adipokine levels and changes in SLE disease activity in this study, we could not determine that SLE disease activity is related to changes in adipokine levels. It is also possible that improvement in insulin resistance decreases resistin, as reported for adiponectin in healthy subjects [13,14]. Ahmed et al…”

“…HCQ improves skin symptoms and arthritis as well as prevents SLE are-ups, organ damage and cardiovascular events and reduces the risk of developing neuropsychiatric lupus [2]. In addition, HCQ has a favorable effect on lipid levels [7][8][9][10][11][12] and reduces insulin resistance [13,14] and the risk of thrombosis [15,16]. It has also been shown to increase survival in patients with SLE [16][17][18].…”

Diabetes-Modifying Antirheumatic Drugs: The Roles of DMARDs as Glucose-Lowering Agents

“…In line with this hypothesis, 13-week anakinra treatment has been shown to significantly reduce HbA1c values as well as IL-6 and CRP levels in patients with T2D [ 164 ]. Similar remarks can apply to HCQ, which has been shown to improve skeletal muscle insulin sensitivity, enhance systemic glucose clearance, and concomitantly reduce circulating IL-6 levels in insulin-resistant adults [ 93 ]. Therefore, further studies are warranted to better elucidate the role of IL-6 and IL-6 inhibitors on glucose homeostasis in CIRD patients with and without T2D.…”

“…Some of the glucose-lowering properties of HCQ were initially inferred from studies on the parent drug CQ, which has been shown to increase insulin levels in patients with T2D by promoting insulin secretion and inhibiting insulin degradation [ 92 ]. On the one hand, a recent study conducted by Toledo et al [ 93 ] in nondiabetic insulin-resistant adults without rheumatic diseases demonstrated that HCQ administration for 13 weeks at a dose of 400 mg/day, as compared to placebo, significantly improved skeletal muscle insulin sensitivity (assessed by hyperinsulinemic-euglycemic clamp and stable-isotope tracer methods) and enhanced systemic glucose clearance. By contrast, HCQ did not affect hepatic insulin sensitivity and insulin clearance, but led to a significant reduction in circulating IL-6 levels along with a significant increase in adiponectin levels [ 93 ].…”

“…On the one hand, a recent study conducted by Toledo et al [ 93 ] in nondiabetic insulin-resistant adults without rheumatic diseases demonstrated that HCQ administration for 13 weeks at a dose of 400 mg/day, as compared to placebo, significantly improved skeletal muscle insulin sensitivity (assessed by hyperinsulinemic-euglycemic clamp and stable-isotope tracer methods) and enhanced systemic glucose clearance. By contrast, HCQ did not affect hepatic insulin sensitivity and insulin clearance, but led to a significant reduction in circulating IL-6 levels along with a significant increase in adiponectin levels [ 93 ]. On the other hand, the putative effect of HCQ on endogenous insulin secretion may be mediated by a direct stimulatory effect of HCQ on beta cells (insulinotropic effect) and/or by indirect effects involving a decrease in pancreatic islet inflammation and/or a reduction in glucotoxicity- and lipotoxicity-induced beta cell dysfunction as a consequence of the improvement in metabolic control after HCQ treatment initiation.…”