Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations

• DOI: 10.2337/db06-0080
• Publication Date: 2006-07-27T20:07:45Z
• Authors: Albert Salehi; Elaine Vieira; Erik Gylfe
• Keywords: Cytoplasm; ATP-sensitive K+ channel; Fysiologi; Physiology; Cell- och molekylärbiologi; Endocrinology and Diabetes; Cell Line; Islets of Langerhans; Mice; 03 medical and health sciences; Cricetinae; Insulin Secretion; Animals; Insulin; Fysiologi och anatomi; Cells, Cultured; 0303 health sciences; KATP channel; Dose-Response Relationship, Drug; Physiology and Anatomy; Glucagon; Clone Cells; Mice, Inbred C57BL; Glucose; cytoplasmic Ca2+ concentration; Endokrinologi och diabetes; [Ca2+]i; Calcium; Cell and Molecular Biology

Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25–30 mmol/l and In-R1-G9 cells at 12–20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the α-cells. Studies of isolated mouse α-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia.