Intracellular Biochemical Mechanisms Critical to the Control of Insulin Secretion

Dear Colleagues,

As the primary rapidly acting hormone-promoting anabolic process, insulin plays the key role in maintaining glucose homeostasis, and inadequate secretion is the major cause of diabetes. Accordingly, a focus has been placed on how pancreatic islet cells sense glucose levels and subsequently secrete the appropriate amounts of insulin. By studying isolated islets, a number of the components that comprise the biochemical and biophysical mechanisms mediating the stimulation of insulin secretion by fuels, hormones, and other extracellular signals have been conclusively identified. Of these, the most important is the absolute requirement for the activation of L-type calcium channels. The need for calcium influx has led to the commonly stated conclusion that a rise in cytosolic calcium can directly stimulate the secretion of exocytotic granules. However, at low glucose levels, increased cytosolic calcium induced by the L-type calcium channel activator BayK8644 has no effect on insulin secretion. Moreover, although KCl does increase calcium and insulin secretion at low glucose levels, KCl also increases metabolism in the islet so that KCl’s effects cannot be interpreted as evidence that calcium influx directly stimulates secretion. From this data, one could conclude that the influx of calcium through L-type calcium channels alone does not stimulate insulin secretion without co-factors that are generated by the metabolism of glucose (or other fuel). However, it is generally accepted that calcium directly triggers the initial events that enhance insulin secretion, and there needs to be a reconciliation of these diverse views on our understanding of these key regulatory steps. Factors that stimulate insulin secretion fall into 2 categories: ones that are required for the glucose- and fuel-induced stimulation of insulin secretion, and those that stimulate insulin secretion only when beta cells have been stimulated by fuel. The latter include pathways associated with PKA and PKC (that mediate important effects via GLP-1 and acetylcholine) as well as fatty acids and arginine, which only potentiate insulin secretion when glucose is elevated above the threshold levels needed for insulin secretion. The co-factors that, along with calcium, mediate glucose-stimulated insulin secretion are still not well established, and this is the major focus of this Special Issue. Some factors that are thought to mediate increased insulin secretion include cAMP, ATP, diacylglycerol, signals associated with pyruvate metabolism, glucagon, GABA, glutamate, SUMOylation, fatty acid signaling, reactive oxygen species, H₂S, and cytochrome c as well as the increased sensitivity of secretory granules. It is important to work out which of these can mediate glucose’s primary effect on insulin secretion, and which will only enhance insulin secretion in the presence of glucose. Those investigators that proscribe to the notion that calcium can directly enhance exocytosis in the absence of metabolic co-factors need to show this without the use of potassium as a tool. Authors are encouraged to submit papers on intracellular factors regulating insulin secretion and may in particular want to consider submitting papers that focus on:

1. demonstrating the direct effects of calcium on insulin secretion in the absence of additional metabolically generated factors;
2. metabolically generated factors that, along with calcium, mediate the stimulation of insulin secretion via glucose or fuels;
3. factors that stimulate (potentiate) glucose-stimulated insulin secretion, but do not increase insulin secretion at low glucose levels.

The issue of calcium’s unique or shared role in triggering insulin secretion is of fundamental importance to our understanding of the regulation of insulin secretion and diabetes. A collection of papers that leads to a consensus on key biochemical regulatory steps will be highly impactful to the field. Feel free to email the Guest Editor at [email protected] for questions on content or the focus of your article prior to submission.

Dr. Ian R. Sweet
Guest Editor

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• diabetes
• pancreatic islets
• diabetes drug development