Editorial Insulin Secretion: Movement at All Levels Jean-Claude Henquin,1 Christian Boitard,2 Suad Efendic,3 Ele Ferrannini,4 Donald F
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Editorial Insulin Secretion: Movement at All Levels Jean-Claude Henquin,1 Christian Boitard,2 Suad Efendic,3 Ele Ferrannini,4 Donald F. Steiner,5 and Erol Cerasi6 the clinician eventually measures in a brachial vein; there- fore, several articles deal with the cellular and molecular ith this Second SERVIER-IGIS Symposium events that control the release phenomenon. The effector Diabetes Supplement, we, the members of proteins involved in this extremely complex process are the International Group on Insulin Secretion discussed in detail, as are the respective roles of several W(IGIS), happily realize that we have been able regulatory signals: Ca2ϩ, the triggering signal, whose cyto- to keep the promise made in the First SERVIER-IGIS solic concentration in -cells increases upon closure of Symposium (Diabetes 50 [Suppl. 1], 2001): we are indeed ϩ K ATP channels, and various messengers potentially in- initiating a tradition, with a yearly series of state-of-the-art ϩ volved in the “amplification pathway” or “K ATP channel- collections on various aspects of islet biology, with the independent” component of insulin release. It is suggested emphasis on type 2 diabetes. Without the logistics and the ϩ that even sulfonylureas, K ATP channel-active drugs par generous unrestricted educational grant put at our dis- excellence, may have such “distal” actions. posal by SERVIER, Paris, it is doubtful that we would ever In Section 2 an “old-timer”—biphasic insulin release—is embark on this project, let alone succeed in producing tackled, again from several angles. The phenomenon was these high-quality publications. described more than 30 years ago but its mechanism The Second SERVIER-IGIS Symposium dealt with the seems to resist full clarification. Several articles discuss “Kinetics of Insulin Release in Health and Type 2 Diabe- this aspect of -cell behavior in terms of the macrophysi- tes.” To optimally fulfill its preeminent role in glucose ology of the event, whereas others try to identify the homeostasis, insulin secretion must not only be quantita- molecular characteristics of first- versus second-phase tively appropriate, it must also follow a precise time release. There seems to emerge some degree of consensus, course. It has indeed been known since the 1960s that suggesting that the first phase is triggered by a rapid, insulin secretion is phasic; later work refined the definition depolarization-mediated elevation of cytosolic Ca2ϩ, while of phasicity by the discovery of superimposed oscillations the second phase is more under the influence of metabolic of varying frequencies. Many of these features are absent factors and kinase isoforms of the PKA and PKC families, or disturbed in type 2 diabetic patients, sometimes before all amplifying the effects of the rise of Ca2ϩ on the overt hyperglycemia is established. These convincing find- exocytotic machinery. Also, it seems clear that simple ings notwithstanding, the conditions required to demon- compartmental models (two pools of granules, or pools of strate certain aspects of phasic insulin release are -cells with different glucose sensitivities) are inadequate sometimes unphysiological. Just to mention the often used to fully account for the phasicity of insulin release under hyperglycemic clamp, in nature the -cell is never exposed different experimental set-ups. In terms of quantitative to a “jump” of the extracellular glucose concentration data, it has been calculated that first-phase insulin release, from 5 to 15–20 mmol/l within 2–3 min. It is therefore a which has attracted so much interest, corresponds to the legitimate question whether phasic insulin release is a discharge of only 50–100 of the more than 10,000 granules bona fide biological characteristic of the -cell. This contained in a -cell. supplement examines the question from several angles, at This tiny first-phase insulin release indeed affects the different levels of “magnification.” glucose metabolism of the whole organism, as analyzed in Section 1 serves as a general introduction. The charac- Section 3. Studies in animals and humans have shown that teristics of the exocytotic events in -cells determine what the liver’s sensitivity to insulin makes it a prime candidate as a biological target for first-phase insulin release, allow- From the 1Department of Physiology, Endocrinology-Metabolism, Universite´ ing the closure of glucose production, a factor of para- Catholique de Louvain, Brussels, Belgium; 2INSERM U342, St. Vincent de Paul mount importance for the postprandial hyperglycemia of Hospital, Paris, France; the 3Department of Molecular Medicine, Division of the type 2 diabetic patient. Also discussed in Section 3 is Endocrinology & Diabetes, Karolinska Hospital, Stockholm, Sweden; the 4Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa, the evolution of phasic insulin secretion throughout the Pisa, Italy; the 5Department of Biochemistry and Molecular Biology and development of type 2 diabetes, including studies on Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois; and the 6Department of Endocrinology & Metabolism, Hebrew University Hadas- so-called gluco- and lipotoxicity. Since the early 1960s, it sah Medical Center, Jerusalem, Israel. has become something of a dogma that it is first-phase Address correspondence and reprint requests to [email protected] or insulin secretion that is mostly affected in diabetes. There [email protected]. The symposium and the publication of this article have been made possible may be more heterogeneity also in this aspect, as shown by an unrestricted educational grant from Servier, Paris. by a genetic study included in this supplement. DIABETES, VOL. 51, SUPPLEMENT 1, FEBRUARY 2002 S1 EDITORIAL Oscillations characterize the functioning of most biolog- tration of the hormone in a time series of frequently drawn ical systems. -cells are no exception, as discussed in plasma samples, as shown in Section 6. Distinct oscilla- detail in Section 4. Insulin secretion is not only biphasic, it tions associated with or independent of glucose changes is also pulsatile at both the single islet and whole pancreas occur with different periods, the shortest ones being close levels. It has long been known that -cells are electrically to those of pulsatile insulin secretion in vitro. In addition excitable and that their membrane potential typically to the alteration of the two “classical” phases of insulin oscillates during glucose stimulation. These repetitive ϩ secretion, perturbations of insulin pulsatility have been depolarizations, in concert with other Ca2 entry path-  2ϩ identified as an early sign of -cell dysfunction in glucose ways, generate oscillations of cytoplasmic free Ca , intolerance and type 2 diabetes. We should, however, which trigger pulses of insulin secretion. Evidence is also realize that the exact “raison d’eˆtre” of the oscillatory presented that several metabolic events oscillate in glucose- behavior of -cells is not entirely clear. Some data suggest  stimulated -cells, but no consensus has yet been reached that it serves to produce insulin with a time course on their origin: whether they reflect intrinsic properties of ensuring the optimal response of target tissues. Alterna- glucose metabolism, or are generated by subtle positive or 2ϩ tively, oscillations of various signals could be advanta- negative feedback loops linked to Ca oscillations re- geous for the -cell itself (not necessarily for secretion), mains disputed. Another debated issue is whether these and the oscillations of secretion could simply be an metabolic oscillations only serve to entrain electrical and ϩ obligatory consequence thereof. Anyhow, the conclusions Ca2 oscillations, or directly contribute to the oscillations drawn from these clinical investigations amply justify the of insulin secretion via the amplification pathway. Identi- efforts of many basic researchers to elucidate the mecha- fication of the mechanisms by which all islets within the pancreas are synchronized to produce defined pulses of nisms controlling the kinetics of insulin secretion. insulin in the portal vein is also challenging. We are convinced that this supplement will provide the The confusion of plasma insulin concentration for pan- reader with an up-to-date overview of insulin secretion, creatic insulin secretion has led to many misconceptions examined at all levels, from the molecular to the physio- in diabetes research; hence, the importance of the devel- logical and clinical levels. Not only is insulin release opment, since the 1960s, of increasingly reliable means of dynamic, but so is its research, as witnessed by the extrapolating -cell function from peripheral hormone impressive amount of science presented in this Second levels, usually with the help of mathematical modeling. In SERVIER-IGIS Symposium. It is our conviction that diabe- Section 5 two original approaches are presented, both tes research, like research in other medical areas, must be based on the use of a more physiological stimulus (oral indivisible and span from molecular biology to clinical glucose or multiple meals). These will certainly be of great investigation. We believe the present supplement is an help in larger population and patient studies. Another excellent illustration of this philosophy. important message is that insulin secretion and insulin sensitivity (or resistance) are closely linked, and therefore -cell function cannot be studied isolated from insulin ACKNOWLEDGMENTS action. Several articles discuss the methodology for solv- We are grateful to Dr. Didier Halimi and his team (Servier, ing this problem and present concrete examples. Paris) for the extraordinary help provided for the organi- The pulsatility of insulin secretion can also be studied in zation of the symposium and the editorial management of vivo by monitoring and adequately analyzing the concen- this supplement. S2 DIABETES, VOL. 51, SUPPLEMENT 1, FEBRUARY 2002.