Whether insulin acutely regulates plasma leptin in humans is controversial. We examined the dosage-response and time-course characteristics of the effect of insulin on leptin in 10 men (age 42+/-2 years [mean+/-SE]; BMI 29.3+/-2.0 kg/m2). Each individual underwent four 9-h euglycemic clamps (insulin at 20, 40, 80, and 400 mU x m[-2] x min[-1) and a control saline infusion. Although plasma glucose and insulin levels remained constant, leptin diminished from 9.1+/-3.0 to 5.9+/-2.1 ng/ml (P < 0.001) by the end of the control experiment. Conversely, plasma leptin showed a dosage-dependent increase during the insulin infusions that was evident within 30-60 min. The insulin-induced increase in leptin was proportionately lower in obese insulin-resistant men. Free fatty acids (FFAs) decreased during insulin and did not change during saline infusions. ED50 (the dose producing half-maximal effect) for insulin's effect on leptin and FFA was similar (138+/-36 vs. 102+/-24 pmol/l, respectively; P=0.11). To further define the role of physiological insulinemia, we compared the effect of a very low dosage insulin infusion (10 mU x m[-2] x min[-1]) with that of a control saline infusion in another group of 10 men (mean age 39+/-3 years; BMI 27.1+/-1.0 kg/m2). Plasma leptin remained stable during that insulin infusion, but fell by 37+/-2% in the control experiment. Thus physiological insulinemia can acutely regulate plasma leptin. Insulin could mediate the effect of caloric intake on leptin and could be a determinant of its plasma concentration. Inadequate insulin-induced leptin production in obese and insulin-resistant subjects may contribute to the development or worsening of obesity.

Recent studies have demonstrated that the normal human testes, colon, and liver contain a substance that resembles hCG. To extend these findings, we examined aqueous extracts of a variety of normal human tissues for the presence of this material. The beta-hCG RIA, rat Leydig cell radioreceptor assay, and a newly developed, highly specific hCG RIA were used to measure hCG activity in a serial dilutions of the extracts. Detectable concentrations of the hCG-like material were found in 146 of the 149 individual tissue samples studied. Parallelism was noted between the hCG standard and serial dilutions of extracts of testis, ovary, pituitary, lung, liver, kidney, spleen, stomach, placenta, and some small intestinal tissue samples in the beta-hCG RIA, radioreceptor assay, and the highly specific hCG RIA. An absence of parallelism was found between extracts of nonpituitary tissues and LH in the beta-LH RIA. Pancreatic extracts altered the [125I]hCG used as the labeled ligand in these assays, which led to spurious results. Chromatography of the extracts on Concanavalin A-Sepharose columns revealed that the hCG-like materials from different tissues varied widely in their adsorbtion to Concanavalin A, possibly reflecting differences in their carbohydrate contents. These results indicate that an hCG-like substance is widely distributed throughout normal human tissues and further supports the concept that the fetal genome responsible for hCG production is not completely suppressed in adult tissues.

Leptin, the obese (ob) gene product, is thought to be a lipostatic hormone that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure. The determinants of plasma leptin concentration were evaluated in 267 subjects (106 with normal glucose tolerance, 102 with impaired glucose tolerance, and 59 with noninsulin-dependent diabetes). Fasting plasma leptin levels ranged from 1.8-79.6 ng/mL (geometric mean, 12.4), were higher in the obese subjects, and were not related to glucose tolerance. Women had approximately 40% higher leptin levels than men at any level of adiposity. After controlling for body fat, postmenopausal women had still higher leptin levels than men of similar age, and their levels were not different from those in younger women. Multiple regression analysis showed that adiposity, gender, and insulinemia were significant determinants of leptin concentration, explaining 42%, 28%, and 2% of its variance, respectively. Neither age nor the waist/hip ratio was significantly related to leptin concentration. Thus, our data indicate that gender is a major determinant of the plasma leptin concentration. This sex difference is not apparently explained by sex hormones or body fat distribution. Leptin's sexual dimorphism suggests that women may be resistant to its putative lipostatic actions and that it may have a reproductive function.

Obstetricians and Gynecologists, Family Physicians Learning Objectives: After completing this CME activity, physicians should be better able to state an ethnic difference in reproductive dysfunction between South Asian and white women with polycystic ovary syndrome (PCOS), state an ethnic difference in metabolic dysfunction between South Asian and white women with PCOS, identify a genetic abnormality found in South Asian women with PCOS, and list 2 environmental factors that predispose South Asian women to metabolic dysfunction.

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