The Effects of Recombinant Human Leptin on Visceral Fat, Dyslipidemia, and Insulin Resistance in Patients with Human Immunodeficiency Virus-Associated Lipoatrophy and Hypoleptinemia

Department of Medicine, University of California, San Francisco, USA.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 02/2009; 94(4):1137-44. DOI: 10.1210/jc.2008-1588
Source: PubMed


Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities.
The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia.
This was a 6-month, open-label, proof-of-principle pilot study.
Metabolic ward studies were performed before and 3 and 6 months after leptin treatment.
Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml.
Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods).
Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety.
Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass.
Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.

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Available from: Giorgos K. Sakkas, Oct 09, 2015
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    • "Blood glucose is tightly controlled by two key processes:-insulin secretion by pancreatic β-cells in response to a nutrient and insulin action on major target organs, i.e., skeletal muscle, liver, and adipose tissue. T2DM, is often associated with obesity and results from insufficient insulin production/secretion and IR (Paz et al. 2006).There is much evidence supporting the statement that changes in insulin secretion and glucose metabolism are the major mediators of leptin production by adipose tissue (Havel 2000).The endogenous glucose production decreased significantly during leptin treatment , an effect that can be attributed primarily to a reduction in glycogenolysis , leptin treatment improved the ability of insulin to suppress endogenous glucose production, with significant decreases in both glycogenolysis and gluconeogenesis(Kathleen et al.2009) . The metabolic effects of leptin participate in the regulation of hepatic glucose metabolism under physiological conditions (Abdelgadir et al.2002). "
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    ABSTRACT: This study was performed in the Diabetes and Endocrine Center at Al-Husain Teaching Hospital. The patients and control groups were with age ranged between (40-83) years. Study was carried out on 60 patient with type 2 diabetes mellitus (28male and 32 female) and 20 apparently healthy subjects male and 20 female how dealt with as control group. Leptin and thyroid hormones(T3,T4, AND TSH) measurements were carried out using ELISA technique. Both patient and control groups were classified according to obesity, age, and gender. Results of the present study show that leptin hormone was significantly high in serum of type 2 diabetic patients group compared with control group (P < 0.001).also there was a significant gender difference (female more than male) and significant positive correlation with body mass index and body fat. Results also show that TSH hormone and FBS were significantly high(P < 0.000), while T3and T4 decrease significant(P < 0.000) in type 2 diabetic patients group and compared with control group.
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    • "In addition to its role in metabolism, treatment with r-metHuLeptin causes changes in the neurocognitive domains, suggesting that leptin might play a cognitive-enhancing role in the developing CNS (Paz-Filho et al., 2008b). The reported indications for r-metHuLeptin therapy include leptin deficiency syndrome and lipodystrophic syndrome linked to inactivating mutations in the leptin gene, hypothalamic amenorrhea , lipodystrophic syndrome (genetic, acquired, or linked to HIV infection) and highly active antiretroviral therapy-induced lipoatrophy (Lee et al., 2006; Brennan et al., 2009; Mulligan et al., 2009). There are few clinical reports on the effect of leptin therapy on diabetes. "
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    ABSTRACT: Obesity and diabetes mellitus are great public health concerns throughout the world because of their increasing incidence and prevalence. Leptin, the adipocyte hormone, is well known for its role in the regulation of food intake and energy expenditure. In addition to the regulation of appetite and satiety that recently has attracted much attentions, insight has also been gained into the critical role of leptin in the control of the insulin-glucose axis, peripheral glucose and insulin responsiveness. Since the discovery of leptin, leptin has been taken for its therapeutic potential to obesity and diabetes. Recently, the therapeutic effects of central leptin gene therapy have been reported in insulin-deficient diabetes in obesity animal models such as ob/ob mise, diet-induced obese mice, and insulin-deficient type 1 diabetes mice, and also in patients with inactivating mutations in the leptin gene. Herein, we review the role of leptin in regulating feeding behavior and glucose metabolism and also the therapeutic potential of leptin in obesity and diabetes mellitus.
    Frontiers in Neuroscience 04/2013; 7(7):51. DOI:10.3389/fnins.2013.00051 · 3.66 Impact Factor
    • "twice daily for 3 months, followed by 0.03 mg/kg s.c. twice daily for 6 months) among eight hypoleptinemic male patients with HALS.[54] Leptin treatment was associated with around 32% decrease in visceral fat, improvement in insulin sensitivity, fasting insulin and glucose levels, and HDL cholesterol, and 15–20% decrease in low density lipoprotein (LDL) cholesterol, with considerable decrease in triglyceride, whole body lipolysis, and free fatty acid levels. "
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    ABSTRACT: Leptin therapy in human recombinant form has recently been used in HIV-associated lipodystrophy syndrome on experimental basis in some small short-term clinical trials. It has shown its beneficial effects only in hypoleptinemic HIV-infected patients by causing definite improvement in their insulin sensitivity, glucose tolerance, lipid status, and truncal obesity. Leptin prevents lipotoxicity and activates insulin signaling pathways through several postulated mechanisms. Central leptin insufficiency with peripheral hyperleptinemia has come out to be a significant contributor to the development of obesity and metabolic syndrome. In this article, we will review the basis of leptin therapy in HIV patients, with its promises. However, further larger clinical trials are needed to prove its long-term efficacy in the control of metabolic complications related to HIV therapy.
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