Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes

Cellular and Molecular Pathways Underlying Leptin Tolerance

Hyun-Seuk Moon; Giuseppe Matarese; Aoife M. Brennan; John P. Chamberland; Xiaowen Liu; Christina G. Fiorenza; Geetha H. Mylvaganam; Luisa Abanni; Fortunata Carbone; Catherine J. Williams; Alex M. De Paoli; Benjamin E. Schneider; Christos S. Mantzoros

Disclosures

Diabetes. 2011;60(6):1647-1656. 

In This Article

Abstract and Introduction

Abstract

Objective Metreleptin 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 Methods We 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.
Results In 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.
Conclusions In 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.

Introduction

Metreleptin has consistently been shown to dramatically improve insulin resistance and HbA1c in several clinical trials involving hypoleptinemic subjects with lipodystrophy, hypoleptinemia, insulin resistance, and the metabolic syndrome.[1] No prior study has evaluated in detail the effect of metreleptin in obese subjects, with garden variety diabetes, obesity, and high circulating leptin levels, who are presumably resistant or tolerant to the effects of leptin.[2] Furthermore, no prior study has evaluated mechanisms underlying such leptin tolerance.

In the context of a large, randomized, placebo–controlled trial, we examined for the first time the efficacy of metreleptin in regulating body weight, glycemic control, and immune function in hyperleptinemic obese subjects with type 2 diabetes. We subsequently examined whether the observed suboptimal efficacy of circulating leptin in regulating adiposity and immune function in obese diabetic individuals is attributable to specific, identifiable mechanisms at the cellular and molecular level. In this respect, we methodically explored mechanisms previously shown to underlie other hormone resistance syndromes, e.g., insulin resistance or underlying immunogenicity seen with use of other biologics. To further elucidate the role of leptin in regulating human adiposity and immune function and to study potential mechanisms underlying the development of leptin resistance or tolerance, we then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.

More specifically, we first discovered that levels of leptin-binding protein (LBP) and antibodies against metreleptin increased in response to metreleptin treatment, limiting circulating free leptin to ~50 ng/mL despite total leptin levels of ~982.7 ng/mL in obese diabetic subjects. We then proceeded to study whether mechanisms that have been described to affect leptin signaling and thus leptin resistance in mice, i.e., endoplasmic reticulum (ER) stress,[3–6] are also operative in humans. Subsequently, we investigated intracellular leptin signaling in vivo in response to metreleptin administration in lean and obese subjects by comparatively studying metreleptin signaling in human adipose tissue (hAT) and human peripheral blood mononuclear cells (hPBMCs) from both lean and obese humans in vivo. Finally, we extended these observations by studying leptin signaling in vitro and ex vivo in hAT and hPBMCs from lean and obese subjects to determine whether neuroendocrine changes induced by metreleptin in vivo or paracrine mechanisms ex vivo may differentially affect leptin signaling in humans in vivo versus ex vivo or in vitro.

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