Inhibitory Effects of Leptin on Pancreatic α-Cell Function

Abstract

OBJECTIVELeptin released from adipocytes plays a key role in the control of food intake, energy balance, and glucose homeostasis. In addition to its central action, leptin directly affects pancreatic β-cells, inhibiting insulin secretion, and, thus, modulating glucose homeostasis. However, despite the importance of glucagon secretion in glucose homeostasis, the role of leptin in α-cell function has not been studied in detail. In the present study, we have investigated this functional interaction.RESEARCH DESIGN AND METHODSThe presence of leptin receptors (ObR) was demonstrated by RT-PCR analysis, Western blot, and immunocytochemistry. Electrical activity was analyzed by patch-clamp and Ca2+ signals by confocal microscopy. Exocytosis and glucagon secretion were assessed using fluorescence methods and radioimmunoassay, respectively.RESULTSThe expression of several ObR isoforms (a–e) was detected in glucagon-secreting αTC1-9 cells. ObRb, the main isoform involved in leptin signaling, was identified at the protein level in αTC1-9 cells as well as in mouse and human α-cells. The application of leptin (6.25 nmol/l) hyperpolarized the α-cell membrane potential, suppressing the electrical activity induced by 0.5 mmol/l glucose. Additionally, leptin inhibited Ca2+ signaling in αTC1-9 cells and in mouse and human α-cells within intact islets. A similar result occurred with 0.625 nmol/l leptin. These effects were accompanied by a decrease in glucagon secretion from mouse islets and were counteracted by the phosphatidylinositol 3-kinase inhibitor, wortmannin, suggesting the involvement of this pathway in leptin action.CONCLUSIONSThese results demonstrate that leptin inhibits α-cell function, and, thus, these cells are involved in the adipoinsular communication.

Serum Leptin, Adiponectin and Tumor Necrosis Factor-α in Hyperlipidemic Rats with/without Concomitant Diabetes Mellitus

“…The antidiabetic effects of leptin may be mediated by glucagon suppression (30,31). Verification of these results in humans holds implications for future use of leptin as an antidiabetic agent.…”

Leptin therapy in insulin-deficient type I diabetes

“…To determine if the antidiabetic effects of leptin might be mediated by glucagon suppression, which was suggested by Tuduri et al (17), we compared plasma glucagon in the four groups of diabetic mice. Plasma glucagon averaged 392 ± 42 pg/ mL and 463 ± 112 pg/mL, respectively, in ad libitum fed and pair-fed PBS-treated diabetic controls, and it was suppressed to 79 ± 40 pg/mL by leptin therapy and 54 ± 18 pg/mL by insulin treatment (Fig.…”

Leptin promotes K ATP channel trafficking by AMPK signaling in pancreatic β-cells

“…In addition to its central action, leptin regulates the release of insulin and glucagon, the key hormones regulating glucose homeostasis, by direct actions on β-and α-cells of pancreatic islets, respectively (10)(11)(12). It thus was proposed that the adipoinsular axis is crucial for maintaining nutrient balance and that dysregulation of this axis contributes to obesity and diabetes (12).…”