Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Mellitus

Abstract

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic β-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 β-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 insulinproducing β-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 β-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by β-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.Obesity and associated diabetes are epidemic throughout the world. The prevalence of morbid obesity is between 20-40% in populations of developing countries and predisposes to the development of diabetes, so-called adipogenic diabetes (1,2). Moreover, obese individuals characteristically manifest insulin resistance and hyperinsulinemia, which predispose to glucose intolerance, diabetes, and cardiovascular disease (1). From 50-80% of subjects worldwide with diabetes are obese depending upon the ethnic background and the community (3-8). It has been estimated that for every kilogram of increase in weight, the risk for diabetes increases 4.5% (9). Remarkably, 97 million American adults (35% of the population) are overweight or obese (10). The marked increase in the prevalence of obesity is believed to be due in large part to a change in life-style favoring excessive caloric intake and a sedentary existence (11).A major advance in understanding the hormonal causation of morbid obesity is the discovery of a hormone, leptin, produced by adipose tissue that modifies feeding behavior in rodents as a potent suppressor of food intake and stimulator of energy expenditure (12,13). Leptin exerts its actions centrally on appetite and thermogenic control centers located in the hypothalamus. It is important to note that obesity in humans is believed to be due to a desensitization of leptin reception within the hypothalamus, resulting in hyperphagia (1,(12)(13)(14...

Long-term leptin treatment of ob/ob mice improves glucose-induced insulin secretion

“…This is important, since, based on the inhibitory effects of leptin on insulin secretion in vitro, it has been proposed that the failure of leptin to inhibit insulin secretion from the b-cells of obaob mice may explain in part the development of hyperinsulinemia, insulin resistance and the progression to diabetes. 10,26 In agreement with the present data, it has been suggested that the long-term normalization of glucose tolerance in leptin gene treated obaob mice was not solely related to increased insulin sensitivity, but also due to improved insulin secretion. 7 We also show that leptin treatment decreased islet G6Pase activity.…”

“…In accordance with this, leptin treatment in vitro has been shown to inhibit GSIS in islets from obaob and lean mice, 9,10 normal rats 24,25 and humans. 26,27 In other studies, leptin was without any effect on GSIS. 12,13 These differences are most probably due to different experimental conditions, the dose or source of leptin, the duration of the leptin treatment and the lack of bioactivity of some preparations of leptin that have been used.…”

Lack of Association Between Impaired Glucose Tolerance and Appetite Regulating Hormones in Patients with Obstructive Sleep Apnea

“…Previous studies have shown leptin to decrease basal insulin secretion from the pancreatic islets 34 and down-regulates insulin gene transcription. 35 Leptin receptors have been demonstrated on the β-pancreatic cell, 36 and in animal studies acute physiologic increases in leptin significantly inhibited glucose stimulated insulin secretion in a dose-dependent manner. 37 Plasma levels of leptin, adequate to significantly suppress insulin, are found in mild obesity 38 and patients with IGT.…”

TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells

“…Suppression of insulin secretion and gene transcription by leptin in the obese range has also been demonstrated in human pancreatic islets. 15,17 It should be noted, however, that not all studies have reported inhibitory effects of leptin on insulin secretion. Thus, Shimizu et al, 24 and Tanizawa et al, 25 have actually shown stimulation of insulin secretion by leptin at a physiological range of concentrations, in HIT-T15 and MIN-6 cells, respectively.…”

“…15 ± 18 Moreover, leptin suppressed glucose or GLP-1 induced proinsulin gene transcription in isolated islets and b pancreatic cells. 17,19,20 In obaob mice, the animal model of obesity showing metabolic abnormalities similar to those seen in obese type 2 diabetic humans, daily administration of leptin could lower serum insulin and glucose levels, independently of its weight reducing effect. 21,22 Other studies, however, have either failed to show any effect on insulin release from isolated rat pancreases, 23 or have shown a stimulatory effect of leptin on basal but not glucose-stimulated insulin secretion and biosynthesis in pancreatic b cells.…”