Journal
JOURNAL OF DIABETES INVESTIGATION
Volume 4, Issue 6, Pages 511-516Publisher
WILEY-BLACKWELL
DOI: 10.1111/jdi.12094
Keywords
Adenosine triphosphate-sensitive K+ channel; Modulatory signals; Physiological insulin secretion
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Funding
- Grants-in-Aid for Scientific Research [21591128, 25461383] Funding Source: KAKEN
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Existing concepts and models for glucose-stimulated insulin secretion (GSIS) are overviewed and a newer perspective has been formulated toward the physiological understanding of GSIS. A conventional model has been created on the basis of in vitro data on application of a square wave high glucose in the absence of any other stimulatory inputs. Glucose elicits rapid insulin release through an adenosine triphosphate-sensitive K+ channel (K-ATP channel)-dependent mechanism, which is gradually augmented in a K-ATP channel-independent manner. Biphasic GSIS thus occurs. In the body, the -cells are constantly exposed to stimulatory signals, such as glucagon-like peptide 1 (GLP-1), parasympathetic inputs, free fatty acid (FFA), amino acids and slightly suprathreshold levels of glucose, even at fasting. GLP-1 increases cellular cyclic adenosine monophosphate, parasympathetic stimulation activates protein kinaseC, and FFA, amino acids and glucose generate metabolic amplification factors. Plasma glucose concentration gradually rises postprandially under such tonic stimulation. We hypothesize that these stimulatory inputs together make the -cells responsive to glucose independently from its action on K-ATP channels. Robust GSIS in patients with a loss of function mutation of the sulfonylurea receptor, a subunit of K-ATP channels, is compatible with this hypothesis. Furthermore, pre-exposure of the islets to an activator of protein kinaseA and/or C makes -cells responsive to glucose in a K-ATP channel- and Ca2+-independent manner. We hypothesize that GSIS occurs in islet -cells without glucose regulation of K-ATP channels in vivo, for which priming with cyclic adenosine monophosphate, protein kinaseC and non-glucose nutrients are required. To understand the physiology of GSIS, comprehensive integration of accumulated knowledge is required.
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