Phillip Görden

BACKGROUND: The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition. METHODS: Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin. RESULTS: During treatment with recombinant leptin, the serum leptin level increased from a mean (+/- SE) of 1.3 +/- 0.3 ng per milliliter to 11.1 +/- 2.5 ng per milliliter (0.1 +/- 0.02 to 0.9 +/- 0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the 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. CONCLUSIONS: Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.

In six patients with acanthosis nigricans variable degrees of glucose intolerance, hyperinsulinemia and marked resistance to exogenous insulin were found. Studies of insulin receptors on circulating monocytes suggest that the insulin resistance in these patients was due to a marked decrease in insulin binding to its membrane receptors. When these patients were fasted, there was a fall in plasma insulin but no increase in insulin binding, suggesting that the receptor defect was not secondary to the hyperinsulinemia. The clinical features shared by these cases and several similar ones previously reported may be divided into two unique clinical syndromes: Type A, a syndrome in younger females with signs of virilization or accelerated growth, in whom the receptor defect may be primary, and Type B, a syndrome in older females with signs of an immunologic disease, in whom circulating antibodies to the insulin receptor are found.

Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

The National Institutes of Health Consensus Development Conference on<i>Helicobacter pylori</i>in Peptic Ulcer Disease brought together specialists in gastroenterology, surgery, infectious diseases, epidemiology, and pathology, as well as the public to address the following questions: (1) What is the causal relationship of<i>H pylori</i>to upper gastrointestinal disease? (2) How does one diagnose and eradicate<i>H pylori</i>infection? (3) Does eradication of<i>H pylori</i>infection benefit the patient with peptic ulcer disease? (4) What is the relationship between<i>H pylori</i>infection and gastric malignancy? (5) Which<i>H pylori</i>—infected patients should be treated? (6) What are the most important questions that must be addressed by future research in<i>H pylori</i>infections? Following 1½ days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared their consensus statement. Among their findings, the consensus panel concluded that (1) ulcer patients with<i>H pylori</i>infection require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation with the illness or on recurrence; (2) the value of treating of nonulcerative dyspepsia patients with<i>H pylori</i>infection remains to be determined; and (3) the interesting relationship between<i>H pylori</i>infection and gastric cancers requires further exploration. (<i>JAMA</i>. 1994;272:65-69)