Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance

Abstract

OBJECTIVEMetreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes.RESEARCH DESIGN AND METHODSWe studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.RESULTSIn obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally (8.01 ± 0.93–7.96 ± 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ∼50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling.CONCLUSIONSIn obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes.

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

“…Furthermore, sub-chronic administration of [D-Leu-4]-OB3 could potentially lead to the generation of leptin antibodies, although this seems unlikely given the minor structural differences between [D-Leu-4]-OB3 and the native leptin fragment. Moreover, previous clinical studies with leptin have noted non-neutralising effects of antibodies generated against leptin [36,37], in parallel with other observations using similar regulatory peptides [38]. In addition, the prominent beneficial effects of (pGlu-Gln)-CCK-8 on glucose tolerance, insulin sensitivity and triacylglycerol content of adipose and liver tissue were not enhanced by concurrent administration of [D-Leu-4]-OB3.…”

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

“…Metreleptin, an analogue of human leptin, improved insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy 102 . In obese patients with T2DM, however, metreleptin did not alter body weight or circulating inflammatory markers and reduced HbA1c only marginally 103 . New approaches in the development of anti-obesity and anti-diabetes pharmacophores are now focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptinrelated synthetic peptide analogues or mimetics 104 .…”

The effect of leptin, caffeine/ephedrine, and their combination upon visceral fat mass and weight loss

“…However, in 2011, phase II clinical trials were halted and the program was discontinued after patients reportedly developed antibodies to metreleptin. A separate trial investigating the effects of metreleptin in obese patients with type 2 diabetes reported significant increases in leptinbinding protein and antileptin antibodies in the majority of subjects treated with metreleptin (16). At this time, there are no ongoing combination leptin therapies for weight loss reported in the public domain.…”

“…Leptin is still used to treat individuals with congenital leptin deficiency (6,7). A few studies have investigated leptin's potential for improving insulin sensitivity, but results thus far have been null or marginal (15,16). There has also been interest in combining leptin with other therapeutic drugs to induce weight loss.…”

“…Participants were seen at weeks 0, 1, 2, 3,4,8,12,16,20, and 24 at which time weight, vital signs, adverse events (including injection site inspection), and medication dispensing was done. At baseline, subjects were instructed in lifestyle modification principles, a walking program with a goal of 30 min five times per week and a balanced calorie-restricted diet, 1200 kcal/day for women and 1500 kcal/day for men.…”