Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy

Abstract

Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia. Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting glucose (from 205 ؎ 19 to 126 ؎ 11 mg/dl; P < 0.001), HbA 1c (from 9 ؎ 0.4 to 7.1 ؎ 0.5%; P < 0.001), triglycerides (from 1,380 ؎ 500 to 516 ؎ 236 mg/dl; P < 0.001), LDL (from 139 ؎ 16 to 85 ؎ 7 mg/dl; P < 0.01), and total cholesterol (from 284 ؎ 40 to 167 ؎ 21 mg/dl; P < 0.01). HDL was unchanged (from 31 ؎ 3 to 29 ؎ 2 mg/dl; P ‫؍‬ 0.9). Liver volumes were significantly reduced (from 3,663 ؎ 326 to 2,190 ؎ 159 cm 3 ; P < 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 ؎ 3.6 to 57.4 ؎ 3.4 kg; P ‫؍‬ 0.02) and resting energy expenditure (from 1,929 ؎ 86 to 1,611 ؎ 101 kcal/24 h; P < 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin represents the first novel, effective, long-term treatment for severe forms of lipodystrophy. Diabetes 54: 1994 -2002, 2005 T he lipodystrophies represent a group of clinical syndromes characterized by various degrees of adipocyte loss. In the generalized forms, adipocyte loss is the most severe. The discovery of leptin introduced a new concept in energy regulation (1). This formed the basis for understanding that adipose tissue is an endocrine organ and that generalized lipodystrophy in rodents and patients constituted a severe hypoleptinemic state (2,3). The metabolic phenotype is characterized by extreme dyslipidemia, insulin resistance, and diabetes (4).The production of recombinant leptin provided the opportunity to determine whether leptin replacement therapy in a leptin-sensitive state would improve this extreme metabolic phenotype. First in rodent models (5) and then in preliminary short-term studies in humans (6), it was shown that recombinant leptin administration could ameliorate dyslipidemia, insulin resistance, and diab...

Efficacy of leptin therapy in the different forms of human lipodystrophy

“…We have presented early evidence to show that this effect of leptin is also true in patients with lipodystrophy [4]. Further studies by our group and others have confirmed this finding [5][6][7][8][9][10].…”

“…Although Amgen and then later Amylin provided the recombinant leptin, the data were held and analysed by the academic investigators. r-metHuLeptin therapy was given as a self-administered once-or twice-daily s.c. injection as previously described [4,8,10]. In the earlier years of the protocol, the dose was escalated to the full dose over the first 2 months of treatment.…”

Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: a prospective cohort study

“…In this study, leptin levels in the lowest tertile were negatively and independently associated with cardiovascular mortality in both univariate and multivariate analyses [17], including age, serum insulin levels, BMI and monocyte chemoattracting protein, but not other traditional risk factors for CVD. The suggestion of a protective effect of elevated serum leptin levels, in that a preliminary small study (n=17 cases only), together with results from two recent human interventional studies in individuals with relative leptin deficiency and congenital lipoatrophy [26,27], as well as HIV lipoatrophy and the metabolic syndrome [28], showing that leptin-deficient subjects have reduced insulin sensitivity that is improved with leptin administration, prompted us to examine more closely the risk of CVD in women by stratifying for leptin levels below the previously used clinical cut-off levels for hypoleptinaemia [4]. We observed no significantly increased risk of CVD in women with leptin levels <4 ng/ml or <5 ng/ml before and/or after adjustment for confounders.…”

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints

“…Thirty-eight articles were eligible for full-text review. Of those, 26 were excluded mainly due to not being population-based data (case reports) or review articles and two of these studies were excluded as they represented data sets based on duplicated results from previous studies (20,21). Overall, 12 studies were included for data analysis (14,16,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”