EDITORIAL FOCUSThe right stuff: β-cell channels, cycles, and sensorsPhilippe A. HalbanPhilippe A. HalbanPublished Online:01 Dec 2008https://doi.org/10.1152/ajpendo.90692.2008This is the final version - click for previous versionMoreSectionsPDF (38 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat 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 β-cells to compensate for the prevailing insulin resistance. Indeed, it is the combination of impaired β-cell function and decreased β-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 β-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 β-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, genome-wide association studies are providing insight into the genetic basis of type 2 diabetes, placing the spotlight squarely on the β-cell (6).It has been known for many years that glucose stimulus-secretion 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 ATP-sensitive K+ (KATP) channels, triggering a cascade of electrophysiological events, increasing cytosolic Ca2+, 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 Ca2+ 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 β-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 β-cells from different species and primary and transformed β-cells from the same species. These differences are all too often overlooked with cavalier and misleading extrapolation from transformed rodent to primary human β-cells (that are only rarely used for direct study).Christopher Newgard is a leading expert in intermediary metabolism who has helped chart the complex and specific metabolic landscape of the β-cell and its role in disease (13). Jensen et al. (10) highlight the importance of metabolic flux and, most specifically, cycling of pyruvate intermediates in glucose stimulus-secretion coupling. Largely on the basis of their recent findings, these authors argue convincingly for a major involvement of byproducts of the pyruvate/isocitrate cycle (NADPH and α-ketoglutarate) as key amplifying signals in glucose stimulus-secretion coupling. Although more detailed than the other two review articles, this makes for compelling reading as each candidate cycle is systematically presented, documented, and its role then supported or refuted. Aside from providing new insight into glucose stimulus-secretion coupling, this review article offers an accessible yet impressive refresher course in carbohydrate metabolism. The search for the remaining elusive metabolic factors that potentiate glucose stimulus-secretion coupling continues, and the authors conclude with a challenging “to-do” list that rightly includes repeating some of the key experiments using human islets.Regardless of the proximal metabolic or ionic events discussed above, our understanding of glucose stimulus-secretion coupling would be incomplete without knowing how exocytosis is ultimately increased in response to a rise in cytosolic Ca2+. The exocytotic machinery of the β-cell is no longer a black box, thanks in major part to the realization that this cell shares many features in common with neuronal cells in which these events have already been better studied. Claes Wollheim has devoted his distinguished academic career to the study of the β-cell and was one of the early players in the “calcium game” (14). Showing his tenacity, Wollheim revisits this theme (7) by focusing on the β-cell calcium sensor. As mentioned repeatedly above, a rise in Ca2+ is a prerequisite for glucose-stimulated insulin secretion. But how does this work? How is this rise detected and translated into a signal for increased exocytosis? It would seem as though the elusive calcium sensor has now been identified: synaptotagmin. Gauthier and Wollheim provide a concise overview of the exocytotic machinery and home in on this family of proteins. They argue that two isoforms are of particular relevance to calcium sensing in the β-cell (synaptotagmin VII and IX) and they, too, stress the importance of studying primary β-cells rather than transformed cell lines that are typically less well differentiated and present a mixed endocrine cell phenotype.These three review articles offer a unique glimpse into the rarefied world of the β-cell. This cell continues to fascinate and has certainly not yet shared all its most intimate secrets with us. The research community has been galvanized by the attention the β-cell is receiving from clinicians, geneticists, and the pharmaceutical industry alike. Understanding how the β-cell works in health and how and why it fails or dies in diabetes (whether it be quasi-total autoimmune destruction in type 1 diabetes or decreased functional mass in type 2) may pave the way for new (hopefully improved) treatment and perhaps a cure for diabetes. The development of glucagon-like peptide-1-based therapy for type 2 diabetes is a case study in this regard (5).REFERENCES1 Aguilar-Bryan L, Bryan J, Nakazaki M. Of mice and men: K(ATP) channels and insulin secretion. Recent Prog Horm Res 56: 47–68, 2001.Crossref | PubMed | Google Scholar2 Ashcroft The Walter B FM. Cannon Physiology in Perspective Lecture, 2007. ATP-sensitive K+ channels and disease: from molecule to malady. Am J Physiol Endocrinol Metab 293: E880–E889, 2007.Link | ISI | Google Scholar3 Ashcroft FM, Harrison DE, Ashcroft SJ. Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312: 446–448, 1984.Crossref | PubMed | ISI | Google Scholar4 Bryan J, Vila-Carriles WH, Zhao G, Babenko AP, Aguilar-Bryan L. Toward linking structure with function in ATP-sensitive K+ channels. Diabetes 53, Suppl 3: S104–S112, 2004.Crossref | PubMed | ISI | Google Scholar5 Drucker DJ. The biology of incretin hormones. Cell Metab 3: 153–165, 2006.Crossref | PubMed | ISI | Google Scholar6 Frayling TM, McCarthy MI. Genetic studies of diabetes following the advent of the genome-wide association study: where do we go from here? Diabetologia 50: 2229–2233, 2007.Crossref | PubMed | ISI | Google Scholar7 Gauthier B, Wollheim CB. Synaptotagmins and insulin exocytosis. Am J Physiol Endocrinol Metab (August 19, 2008); doi: 10.1152/ajpendo.90568.2008.Link | Google Scholar8 Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49: 1751–1760, 2000.Crossref | PubMed | ISI | Google Scholar9 Hiriart M, Aguilar-Bryan L. Glucose sensing in the pancreatic β-cell: channel regulation. Am J Physiol Endocrinol Metab (October 21, 2008); doi:10.1152/ajpendo.90493.2008.Link | ISI | Google Scholar10 Jensen MV, Joseph JW, Ronnebaum SM, Burgess SC, Sherry AD, Newgard CB. Metabolic cycling in control of glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab (August 26, 2008); doi:10.1152/ajpendo.90604.2008.Link | ISI | Google Scholar11 Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46: 3–19, 2003.Crossref | PubMed | ISI | Google Scholar12 Lacy PE, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 16: 35–39, 1967.Crossref | PubMed | ISI | Google Scholar13 Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9: 193–205, 2008.Crossref | PubMed | ISI | Google Scholar14 Wollheim CB, Sharp GW. Regulation of insulin release by calcium. Physiol Rev 61: 914–973, 1981.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: P. A. Halban, Dept. of Genetic Medicine and Development, Univ. of Geneva Medical Center, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland (e-mail: [email protected]) Download PDF Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 295Issue 6December 2008Pages E1277-E1278 Copyright & PermissionsCopyright © 2008 by American Physiological Societyhttps://doi.org/10.1152/ajpendo.90692.2008PubMed18713957History Received 13 August 2008 Accepted 13 August 2008 Published online 1 December 2008 Published in print 1 December 2008 Metrics