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DOI: 10.2337/db06-0080
© 2006 by the American Diabetes Association
Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations
1 Department of Clinical Science, Clinical Research Center, Malmö University Hospital, Malmö, Sweden
2 Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Address correspondence and reprint requests to Prof. Erik Gylfe, Department of Medical Cell Biology, BMC Box 571, SE-751 23 Uppsala, Sweden. E-mail: erik.gylfe{at}mcb.uu.se
Abbreviations:
[Ca2+]i, cytoplasmic Ca2+ concentration; KATP channel, ATP-sensitive K+ channel
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 
-cells. Studies of isolated mouse -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.
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