Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus.
Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic beta-cells and an inhibition of insulin secretion by leptin via activation of ATP-sensitive potassium channels. Here we examine pancreatic islets isolated from pancreata of human donors for their responses to leptin. The presence of leptin receptors on islet beta-cells was demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nM) suppressed insulin secretion of normal islets by 20% at 5.6 mM glucose. Intracellular calcium responses to 16.7 mM glucose were rapidly reduced by leptin. Proinsulin messenger ribonucleic acid expression in islets was inhibited by leptin at 11.1 mM, but not at 5.6 mM glucose. Leptin also reduced proinsulin messenger ribonucleic acid levels that were increased in islets by treatment with 10 nM glucagon-like peptide-1 in the presence of either 5.6 or 11.1 mM glucose. These findings demonstrate direct suppressive effects of leptin on insulin-producing beta-cells in human islets at the levels of both stimulus-secretion coupling and gene expression. The findings also further indicate the existence of an adipoinsular axis in humans in which insulin stimulates leptin production in adipocytes and leptin inhibits the production of insulin in beta-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by beta-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes. (+info)
Obstructive uropathy and hydronephrosis in male KK-Ay mice: a report of cases.
Uropathy associated with hydronephrosis was observed frequently in our male KK-Ay mouse colony during a long-term study of diabetes. The lesion occurred in 24 of the 31 KK-Ay male mice and accounted for the greatest number of spontaneous deaths among them. It was observed after 4 months of age and involved about hard plugs of altered seminal material resembling the seminal vesicle secretion. The plugs became impacted in the urethral bulb and the bladder. The penile anatomy, with its flexure, pressure on the urethra from the bulbocavernosus muscle, and the characteristic ability of the seminal fluid to easily coagulate to form the vaginal plug may have contributed to the lesion. Correlation between development of the uropathy and diabetes has not been established. (+info)
Role of glutamine in human carbohydrate metabolism in kidney and other tissues.
Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Until recently, the understanding of many aspects of glutamine metabolism was based on animal and in vitro data. However, recent studies using isotopic and balance techniques have greatly advanced the understanding of glutamine metabolism in humans and its role in glucose metabolism in the kidney and other tissues. There is now evidence that in postabsorptive humans, glutamine is an important glucose precursor and makes a significant contribution to the addition of new carbon to the glucose carbon pool. The importance of alanine for gluconeogenesis, viewed in terms of the addition of new carbons, is less than previously assumed. It appears that glutamine is predominantly a renal gluconeogenic substrate, whereas alanine gluconeogenesis is essentially confined to the liver. As shown recently, renal gluconeogenesis contributes 20 to 25% to whole-body glucose production. Moreover, glutamine has been shown not only to stimulate net muscle glycogen storage but also to stimulate gluconeogenesis in normal humans. Finally, in humans with type II diabetes, conversion of glutamine to glucose is increased (more so than that of alanine). The available evidence on the hormonal regulation of glutamine gluconeogenesis in kidney and liver and its alterations under pathological conditions are discussed. (+info)
Prevalence of hepatitis B surface antigen and antibody in white and black patients with diabetes mellitus.
The prevalence of hepatitis B surface antigen (HBSAg) and antibody (anti-HBS) was determined in 531 white and 519 black diabetic outpatients and in appropriate white and black control populations. There was no difference between the prevalence of either HBSAg or anti-HBS in either the white or black diabetics and that in the white and black controls. These findings make it unlikely that the vast majority of patients with diabetes mellitus have either an increased susceptibility to infection by the hepatitis B virus or an impaired ability to clear the virus once they are infected. (+info)
An audit of the care of diabetics in a group practice.
The diabetics in a general practice of 20,175 patients were identified during one year and 119 were found-a prevalence of 5.9 per thousand.The age and sex distribution, method of treatment, criteria of diabetic control, complications, and present method of care were analysed from the medical records to examine the process of medical care of a chronic disease in general practice. (+info)
Regulation of fatty acid homeostasis in cells: novel role of leptin.
It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes, thus protecting them from lipotoxicity. The fact that TG content in nonadipocytes normally remains within a narrow range, while that of adipocytes varies enormously with food intake, is consistent with a system of TG homeostasis in normal nonadipocytes. The facts that when leptin receptors are dysfunctional, TG content in nonadipocytes such as islets can increase 100-fold, and that constitutively expressed ectopic hyperleptinemia depletes TG, suggest that leptin controls the homeostatic system for intracellular TG. The fact that the function and viability of nonadipocytes is compromised when their TG content rises above or falls below the normal range suggests that normal homeostasis of their intracellular TG is critical for optimal function and to prevent lipoapoptosis. Thus far, lipotoxic diabetes of fa/fa Zucker diabetic fatty rats is the only proven lipodegenerative disease, but the possibility of lipotoxic disease of skeletal and/or cardiac muscle may require investigation, as does the possible influence of the intracellular TG content on autoimmune and neoplastic processes. (+info)
Reversing adipocyte differentiation: implications for treatment of obesity.
Conventional treatment of obesity reduces fat in mature adipocytes but leaves them with lipogenic enzymes capable of rapid resynthesis of fat, a likely factor in treatment failure. Adenovirus-induced hyperleptinemia in normal rats results in rapid nonketotic fat loss that persists after hyperleptinemia disappears, whereas pair-fed controls regain their weight in 2 weeks. We report here that the hyperleptinemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma in epididymal fat; enzymes of fatty acid oxidation and their transcription factor, PPARalpha, normally low in adipocytes, are up-regulated, as are uncoupling proteins 1 and 2. This transformation of adipocytes from cells that store triglycerides to fatty acid-oxidizing cells is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, tumor necrosis factor alpha, and leptin, and by the appearance of the preadipocyte marker Pref-1. These findings suggest a strategy for the treatment of obesity by alteration of the adipocyte phenotype. (+info)
Screening of Korean forest plants for rat lens aldose reductase inhibition.
Naturally occurring substances which can prevent and treat diabetic complications were sought by examining ethanol extracts prepared from Korean forest plants for their inhibitory effects on rat lens aldose reductase activity in vitro. Among the plants examined, Acer ginnala, Illicium religiosum and Cornus macrophylla exerted the most strong inhibitory activity on aldose reductase. (+info)