As has already been demonstrated for autoimmune patients, HCQ demonstrated great anti-diabetic properties. The first proofs of the role of HCQ in glucose and insulin homeostasis date back to 1999, when Emami, Gerstein, Pasutto, and Jamali [105] demonstrated that diabetic rats treated with oral doses of 80, 120, and 160 mg/kg/day of HCQ exhibited a dose-dependent increase in insulin blood levels, with a consequent reduction of glucose concentration. Higher doses of HCQ (200 mg/kg/day) were tested by Abdel-Hamid, A.A. and El-Firgany Ael, D. [106] on diabetic rats, finding an HCQ-mediated decrease in the pancreas, as the mechanism underlying the improvement of the metabolic profile in diabetic rats. The same authors associated the beneficial impact of HCQ on insulin resistance in diabetic rats with its ability to restore adipokine balance and reduce endothelial stress markers [113]. Given the positive outcomes deriving from preclinical studies, the therapeutic potential of HCQ was also assessed in several clinical trials. Included in a randomized, double-blinded study of 18 months with 300 mg of HCQ twice a day were 135 diabetic obese patients. HCQ treatment improved glycemic control, as demonstrated by the decrease of glycated hemoglobin by up to 1% respect to the placebo, without any side effects [107]. An open-label longitudinal study engaging 13 obese non-diabetic individuals examined the effects of a dose of 6.5 mg/kg/day of HCQ for six weeks, demonstrating a significant reduction in insulin resistance, assessed by HOMA index [108]. In a randomized, double-blinded, controlled trial on 39 prediabetic subjects, the effect of 12-week treatment with 6.5 mg/kg/day of HCQ on glycemic status and lipidic profile was evaluated. Results reported a significant increase in insulin levels, demonstrating the potential use of HCQ to counteract the risk of developing diabetes [109]. A randomized double-blind study involving 267 type-2 diabetic patients compared the efficacy of HCQ (400 mg/day) and pioglitazone, a common anti-diabetic drug, in the control of glycemic and lipidic profiles. No statistically significant differences emerged between the two medicines in terms of glycated hemoglobin and glucose levels, although both drugs produced an improvement in glycemic parameters. Regarding lipidic status, total cholesterol and LDL levels were reduced more by HCQ than pioglitazone. Given the good tolerability of the treatment, HCQ may arise as a therapeutic alternative in diabetes management [110].