The right stuff: β-cell channels, cycles, and sensors

Abstract

THE VAST MAJORITY of the 200 million or so individuals with diabetes worldwide suffer from type 2 diabetes, with relative insulin deficiency arising from the failure of -cells to compensate for the prevailing insulin resistance. Indeed, it is the combination of impaired -cell function and decreased -cell mass that underlies the progression from insulin resistance with normal glucose tolerance toward clinically manifested diabetes (11). Understanding the mechanism and regulation of insulin secretion in fine molecular detail may lead to the identification of new drug targets for type 2 diabetes. This is the focus of the three review articles in this issue of the American Journal of Physiology - Endocrinology and Metabolism. Written by acknowledged leaders in the field, they are not intended to be all embracing but rather to update us on today’s understanding of the molecules and events underlying three specific facets of the regulation of insulin secretion by glucose. As we learn more about neuroendocrine cells in general and the -cell in particular, the more obvious it becomes that characterizing the “right stuff” that underlies their exquisitely well-differentiated state will be one of the great challenges of contemporary cell biology. Forty years after publication of the method for isolating pancreatic islets that allowed for the in vitro study of -cells and insulin secretion (12), we are still discovering major new molecular players as we continue to unravel the mysteries of this enigmatic cell. At the same time, genomewide association studies are providing insight into the genetic basis of type 2 diabetes, placing the spotlight squarely on the -cell (6). It has been known for many years that glucose stimulussecretion coupling depends on metabolism of the sugar. Historically, the resulting rise in the ATP/ADP ratio was considered the major if not the only metabolic signal, closing ATPsensitive K (KATP) channels, triggering a cascade of electrophysiological events, increasing cytosolic Ca 2 , and ultimately stimulating exocytosis. But this is by no means the whole story. The (often lonesome) work of pioneers such as Jean-Claude Henquin indicated the profound effect of other metabolic messengers that amplify the glucose signal once cytosolic Ca 2 is elevated, acting largely independently of the KATP channel pathway (8). Identifying these other messengers remains a work in progress as is apparent from the review by Jensen et al. (10). Lydia Aguilar-Bryan has contributed greatly to our understanding of KATP channel structure and function (4), along with Europeans including Frances Ashcroft, who deserves special mention for her original and sustained body of work from 1984 (3) to this day (2). Nobody contests the importance of the canonical KATP pathway, and obviously not Hiriart and Aguilar-Bryan (9). However, given the great attention paid to this channel in earlier reviews, it is legitimate of them to have reviewed in greater detail some of the other major players in the ionic events underlying glucose sensing in the -cell. The scholarly approach taken there (9) is to break down the cascade of electrophysiological events arising from a glucose stimulus with a detailed evaluation of the possible involvement of specific channels in each of these events. A particularly important caveat that is mentioned on several occasions, here, in the other two reviews, and previously by Aguilar-Bryan (1), is the great difference between -cells from different species and primary and transformed -cells from the same species. These differences are all too often overlooked with cavalier and misleading extrapolation from transformed rodent to primary human -cells (that are only rarely used for direct study).