The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene. We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but 1 were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor: of the 8 patients studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndromes and leprechaunism. The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor. The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed that the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age. Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance.
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...
Glycated hemoglobin is currently the gold standard for assessment of long-term glycemic control and response to medical treatment in patients with diabetes. Glycated hemoglobin, however, does not address fluctuations in blood glucose. Glycemic variability (GV) refers to fluctuations in blood glucose levels. Recent clinical data indicate that GV is associated with increased risk of hypoglycemia, microvascular and macrovascular complications, and mortality in patients with diabetes, independently of glycated hemoglobin level. The use of continuous glucose monitoring devices has markedly improved the assessment of GV in clinical practice and facilitated the assessment of GV as well as hypoglycemia and hyperglycemia events in patients with diabetes. We review current concepts on the definition and assessment of GV and its association with cardiovascular complications in patients with type 2 diabetes.
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