Clinical, endocrine and metabolic studies in the kindred of familial partial lipodystrophy--a syndrome of insulin resistance.

OBJECTIVE: To study clinical, endocrine and metabolic profiles in the kindred of subjects with familial partial lipodystrophy (FPLD, Dunnigan type). MATERIAL AND METHODS: Twenty two relatives (10 males, 12 females), from an extended family with FPLD, were assessed for the phenotypic features, impaired glucose tolerance (IGT)/diabetes mellitus (DM), dyslipidemia and the presence of insulin resistance. Plasma glucose and serum lipids were measured using glucose oxidase and standard colorimetric methods. Serum insulin was estimated by radioimmunoassay. RESULTS: The age was 12 to 67 years, two being adolescents. Two of the 20 adults were overweight and eight were underweight; BMI (adults) was 15.5 to 28.5. Features of FPLD were evident among eight out of 12 women. This typical phenotype was not obvious in all 10 male members. Varying degree of Hirsuitism was observed in four of 12 women, acanthosis nigricans in 11 out of 22 members and skin tags were present in only eight of 22; hypertension in six members and diabetes in four. Eleven members had either impaired glucose tolerance (IGT) (n=7), or DM (n=4). Ten of 20 members showed hyperinsulinemic response on oral glucose tolerance test (OGTT). Dyslipidemia was present in 13 family members. CONCLUSION: The majority (2/3rd) of female members showed typical phenotypic features of FPLD, with a clustering of cardiovascular risk factors and insulin resistance syndrome. More than half the men without phenotypic features of FPLD had either IGT/DM, dyslipidemia, hypertension or cardiovascular disease.

Physiological insulinemia acutely modulates plasma leptin.

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.

Sexual dimorphism in plasma leptin concentration.

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.

Anterior pituitary hormone levels in the cerebrospinal fluid of patients with pituitary and parasellar tumors.

Cerebrospinal fluid (CSF) concentrations of growth hormone, prolactin (PRL), adrenocorticotropin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and the glycoprotein hormone alpha subunit were determined in 30 patients with pituitary and parasellar tumors. Although many of the patients had elevated hormone levels, no differentiation between patients with intrasellar tumors and those with pituitary tumors with suprasellar extension or primary suprasellar tumors could be made based upon the absolute CSF hormone concentration. A highly significant correlation between serum and CSF PRL concentrations was found (r = 0.87; P less than 0.001), suggesting that CSF PRL is derived from the serum. No correlation was found between the serum and CSF concentrations of the other anterior pituitary hormones.

Widespread distribution of a chorionic gonadotropin-like substance in normal human tissues.

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.

Properties of human chorionic gonadotropin produced in vitro by ovarian carcinoma cells.

The present study was designed to compare the immunological, physical, and biological properties of native hCG with an hCG molecule secreted ectopically in vitro by an ovarian adenocarcinoma cell line maintained in long term tissue culture. The hCG produced by the cell line was concentrated by ultrafiltration of the tissue culture medium. The inhibition curves generated by serial dilutions of the culture medium concentrates were parallel to those obtained with purified urinary hCG in the beta-hCG RIA and the rat Leydig cell radioreceptor assay (RRA). The ectopic hCG also reacted with an antibody generated against the carboxyl-terminal peptide (109-145) of beta-hCG. The immunoreactive material cochromatographed with urinary hCG on a Sephadex G-100 column, as determined by the beta-hCG RIA and RRA. Neither free alpha nor free beta subunits were found in the tissue culture medium. The tissue culture gonadotropin was adsorbed onto a Concanavalin A-Sepharose column and could be eluted with alpha-D-methylglucoside. The biological activity of the ectopic hCG was 9289 IU/mg, as determined by the ventral prostate weight (VPW) method in hypophysectomized immature male rats. The biological to immunological ratios by the ventral prostate weight method and RRA were 1.79 and 2.17, respectively. The in vivo disappearance rate of ectopic hCG after injection into immature female rats was significantly faster than that of placental or urinary hCG, but was considerably slower than the disappearance rate of human LH. These studies demonstrate that the immunoreactive and biologically active portions of the hCG produced by the ovarian adenocarcinoma cell line and native hCG are similar or identical. The faster disappearance rate of the ectopic hCG in the rat model may be due to incomplete sialylation of the oligosaccharide moiety of the hCG molecule.