Insulin occludes leptin activation of ATP-sensitive K+ channels in rat CRI-G1 insulin secreting cells

• Published in: The Journal of physiology Vol. 511; no. 3; pp. 695 - 706
• Main Authors: Harvey, J., Ashford, M. L. J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15.09.1998; Blackwell Science Ltd; Blackwell Science Inc
• Subjects: Adenosine Triphosphate - physiology; Androstadienes - pharmacology; Animals; Binding, Competitive - physiology; Chromones - pharmacology; Diabetes Mellitus, Type 2 - metabolism; Diazoxide - pharmacology; Drug Interactions; Electric Conductivity; Enzyme Inhibitors - pharmacology; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin - pharmacology; Insulin Antagonists - pharmacology; Insulin Secretion; Insulin-Like Growth Factor I - physiology; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; Leptin; Membrane Potentials - drug effects; Membrane Potentials - physiology; Morpholines - pharmacology; Original; Patch-Clamp Techniques; Potassium Channels - physiology; Proteins - pharmacology; Rats; Tolbutamide - pharmacology; Vasodilator Agents - pharmacology; Wortmannin
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1111/j.1469-7793.1998.695bg.x

Using whole-cell and cell-attached recording configurations, the effects of insulin on leptin activation of ATP-sensitive K + (K ATP ) channels were examined in the CRI-G1 insulinoma cell line. Whole-cell recordings demonstrated that the leptin-induced hyperpolarization and increased potassium conductance are completely occluded by prior exposure to insulin (1-50 nM). In cell-attached recordings, insulin prevented leptin activation of tolbutamide-sensitive K ATP channels. Furthermore, insulin (50 nM) slowly and completely reversed the effects of leptin (10 nM), an action not attributable to direct inhibition of K ATP channels per se. Low concentrations of insulin-like growth factor-1 (IGF-1; 10–100 nM) failed to prevent leptin activation of K ATP channels, although higher concentrations (1 μ m ) did inhibit leptin actions. The action of insulin was specific for leptin, as the hyperglycaemic agent diazoxide activated K ATP channels following prior exposure to insulin. Wortmannin (1-10 nM) and LY 294002 (10 μ m ) prevented leptin activation of K ATP channels, indicating an involvement of phosphoinositide 3-kinase (PI 3-kinase). In conclusion, leptin activation of K ATP channels is counter-regulated by insulin in the CRI-G1 insulinoma cell line. This feedback mechanism may be important in the local integration of hormonal signals which regulate insulin secretion and in alterations of metabolic homeostasis associated with obesity and non-insulin dependent diabetes mellitus (NIDDM).