RT Journal Article SR Electronic T1 Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations JF Diabetes JO Diabetes FD American Diabetes Association SP 2318 OP 2323 DO 10.2337/db06-0080 VO 55 IS 8 A1 Salehi, Albert A1 Vieira, Elaine A1 Gylfe, Erik YR 2006 UL http://diabetes.diabetesjournals.org/content/55/8/2318.abstract AB 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.