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Title: Severe Lipodystrophy Good Reason To Consider Leptin-Replacement Therapy

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N Engl J Med 2002;346:570-8.
02/21/2002 10:20:03 AM
By Anne MacLennan

Leptin deficiency may be a key factor in the insulin resistance and other metabolic abnormalities that characterise severe lipodystrophy. In this study, leptin-replacement therapy led to clear and dramatic metabolic benefits in a group of patients with lipodystrophy and leptin deficiency. Treatment with recombinant leptin resulted in an absolute reduction in the glycosylated haemoglobin value of 1.9 percent. Such a reduction is predicted to decrease relative risk of retinopathy by approximately 48 percent and nephropathy by approximately 22 percent in diabetics. Furthermore, triglyceride levels in fell by 60 percent, a reduction predicted to decrease relative risk of cardiovascular events in the general population by between 35 percent and 65 percent. To date, the insulin resistance and hypertriglyceridemia that characterise lipodystrophy have been refractory to treatment. Commonly, the condition is managed with a combination of medications. However, patients continue to have severe hypertriglyceridemia leading to recurrent attacks of acute pancreatitis; severe hyperglycemia posing risks of diabetic retinopathy and nephropathy; and non-alcoholic steatohepatitis, which can result in cirrhosis. Leptin-replacement therapy appears to have to the potential to prevent all of these complications, suggest these authors. Elif Arioglu Oral and colleagues from the Diabetes Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, and the Clinical Center, National Institutes of Health, Bethesda, Maryland; the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas and Amgen, Thousand Oaks, California, United States did this work. Study participants were nine female patients ranging in age from 15 years to 42 years. Eight had diabetes mellitus, and all had lipodystrophy and serum leptin levels of less than 4 ng per millilitre. All were given recombinant methionyl human leptin (recombinant leptin) subcutaneously twice a day for four months at escalating doses to achieve low, intermediate and high physiologic replacement levels of leptin. During treatment, the serum leptin level increased from a mean of 1.3 ą 0.3 ng per millilitre to 11.1 ą 2.5 ng per millilitre. Absolute decrease in the glycosylated haemoglobin value was 1.9 percent in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent and liver volume by an average of 28 percent in all nine patients and led to discontinuation of, or a large reduction in, antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated. Leptin-replacement therapy thus improved glycemic control and decreased triglyceride levels in these patients. Further, leptin deficiency contributes to the insulin resistance and other metabolic abnormalities linked with severe lipodystrophy, the authors conclude. Results of this study also demonstrate a novel action of leptin; it appears to provide a signal that regulates total-body sensitivity to insulin and triglyceride levels in addition to its known role in the control of energy homeostasis. The adipocyte hormone leptin has a central role in energy homeostasis; serum leptin levels are directly proportional to adipocyte mass. Normally, a low leptin level signals starvation and directs the body to adapt to this condition. One way to gain insight into the physiological important of leptin in humans is to study the conditions associated with its absence or deficiency. Patients with a complete deficiency of leptin as a result of mutations in the leptin gene are morbidly obese from infancy and have a number of hormonal abnormalities, including insulin resistance and hypogonadotropic hypogonadism. In one such patient, physiologic replacement with recombinant leptin for one year led to a substantial weight reduction and an improvement in the hormonal abnormalities. The concept that adipose tissue is an endocrine organ was strongly supported by the discovery of leptin. Leptin has direct or indirect effects on the key organs of metabolism, including the brain, liver, muscle, fat and pancreas but is certainly not the only circulating adipocyte signal. Lack of adipocytes should result in a deficiency of all fat-derived signals. On the basis of their findings, these authors suggest leptin deficiency appears to be the chief contributor to the metabolic abnormalities linked with lipodystrophy. Thus, severe lipodystrophy may be an important reason to consider leptin-replacement therapy. Remaining to be answered are questions relating to optimal dose, the role of leptin-replacement in other insulin resistance states and the degree of leptin deficiency that will respond to replacement therapy.

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