Interaction of GLP-I and Leptin at Rat Pancreatic B-Cells: Effects on Insulin Secretion and Signal Transduction

Fehmann, Hans-Christoph; Bode, Hans-Peter; Ebert, Thomas; Karl, Annalena; Göke, Burkhard

doi:10.1055/s-2007-979103

Cited by 31 publications

(30 citation statements)

References 14 publications

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“…We also find that leptin inhibits the stimulation of proinsulin mRNA levels in human islets mediated by the insulinotropic hormone glucagon-like peptide-1 (GLP-1). These findings support further the existence of an antagonism between leptin and GLP-1 signaling on β-cells as indicated by the reported studies in mouse and rat islets (18,21,29). Based on these findings, we propose that in obese individuals leptin reception on β-cells is desensitized, similar to what is proposed to occur at the level of the hypothalamus.…”

Section: Introductionsupporting

confidence: 90%

“…Germane to the studies undertaken and described herein is that leptin also acts directly on receptors in pancreatic β-cells to suppress insulin secretion in rodents (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Leptin suppresses insulin secretion, insulin messenger ribonucleic acid (mRNA) levels, and transcription from the rat insulin promoter (30a) in isolated islets, perfused pancreata of mice and rats, and rats studied in vivo.…”

mentioning

confidence: 89%

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

Seufert¹

1999

Journal of Clinical Endocrinology & Metabolism

182

178

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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...

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Section: Introductionsupporting

confidence: 90%

mentioning

confidence: 89%

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

Seufert¹

1999

Journal of Clinical Endocrinology & Metabolism

182

178

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“…Furthermore, in ob/ob mice, insulin secretion was markedly inhibited by leptin treatment. Previous studies have demonstrated that leptin has a direct effect on the pancreatic B cell to reduce both basal and GLP-1-stimulated insulin secretion (29,50,51). Thus, the observation that leptin increases GLP-1 release at the same time as it decreases insulin secretion appears contradictory.…”

Section: Discussionmentioning

confidence: 99%

Role of Leptin in the Regulation of Glucagon-Like Peptide-1 Secretion

2003

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T he hormone glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine L cells, which are localized in the distal ileum and colon (1), after nutrient ingestion (2-5). GLP-1 acts through a specific G-protein-coupled receptor to potently stimulate glucose-dependent insulin secretion (6 -8). GLP-1 further reduces glycemia through inhibition of both glucagon secretion (9) and gastric emptying (10) and by stimulation of pancreatic ␤-cell proliferation and neogenesis (11,12). The GLP-1 receptor is also expressed in hypothalamic nuclei that are responsible for modulating feeding behavior (13,14), and central GLP-1 administration reduces food intake in rodents, whereas peripheral administration of GLP-1 promotes satiety and decreases body weight in humans (13,15). These pleiotropic actions of GLP-1 therefore offer great potential for the treatment of hyperglycemia in patients with type 2 diabetes (1,15).It has recently been shown that plasma GLP-1 levels are reduced in obesity (16 -19), a condition that is highly correlated to type 2 diabetes (20). The mechanisms leading to decreased GLP-1 secretion in obesity have not been elucidated. However, because plasma leptin levels are proportional to fat mass, we postulated the existence of an adipo-enteroendocrine interaction between leptin and GLP-1. Leptin, a product of the ob gene in white adipose tissue, activates hypothalamic circuits, leading to the inhibition of food intake (21,22). The leptin receptor gene encodes five alternatively spliced forms of mRNA (23,24). However, only the long form of the leptin receptor (ObRb) contains an intracellular JAK-STAT signaling motif, and Ob-Rb appears to be responsible for the physiological actions of leptin (25-27). Although Ob-Rb is predominantly distributed in the ventral medial hypothalamic region known to be important in determining feeding behavior (21,28), it is now recognized that Ob-Rb is also expressed in several peripheral tissues, including the gut and the pancreas (29 -31).It has been shown that ob/ob mice, which are homozygous for a mutation of the ob gene, and db/db mice, which have a mutation in the leptin receptor, both exhibit hyperphagia and morbid obesity, leading to hyperinsulinemia and hyperglycemia (22,23). Although ob/ob and db/db mice serve as models of type 2 diabetes, human ob or db gene mutations are extremely rare, and no linkages with diabetes have been found (32,33). Nonetheless, most obese humans exhibit hyperleptinemia, and increased adiposity is believed to occur in association with the development of leptin resistance (21,32,33). One model of leptin resistance is the C57BL/6 mouse submitted to a high-fat diet (34). In contrast to the ob/ob and db/db mice, these mice develop impaired glucose tolerance but seldom progress to frank diabetes. We now demonstrate that leptin stimulates GLP-1 secretion from enteroendocrine L cells in vitro and in vivo and, furthermore, that leptin resistance in obese C57BL/6 mice is associated with impaired secretion of GLP-1. RESEARCH DESIGN AND METHODSCell cultu...

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“…The different functional, molecular, and gene regulatory effects of leptin involving insulin secretion (8,18 -28, 30,31,33-40,42-44,51-61), pancreatic ␤-cell gene expression (19,20,31,38,62,63), and signal transduction (21,22,27,38,51,54,64) are summarized in Table 1.…”

Section: Multiple Molecular Effects Of Leptin In Pancreatic ␤-Cellsmentioning

confidence: 99%

Leptin Effects on Pancreatic β-Cell Gene Expression and Function

2004

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Interaction of GLP-I and Leptin at Rat Pancreatic B-Cells: Effects on Insulin Secretion and Signal Transduction

Cited by 31 publications

References 14 publications

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

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

Role of Leptin in the Regulation of Glucagon-Like Peptide-1 Secretion

Leptin Effects on Pancreatic β-Cell Gene Expression and Function

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