Editorial Impact of Treatment on Islet Function in Type 2 Diabetes

Five years already! We, the members of the International Group on Insulin Secretion (IGIS), are very happy that the Servier-IGIS Symposium on insulin secretion and islet pathophysiology, which we first organized in 2000, has, beyond our expectations, become a traditional, awaited, and much appraised event. The pleasant venue and climate of the French Riviera in early spring undoubtedly contribute to the attractiveness of the symposium. However, we trust that the major reason for its success is the high quality of the presentations and scientific exchanges. These standards extend to the rapid publication of most contributions as refereed and edited review or original articles in a series of supplements to Diabetes (1–4). Both the symposium and the publication are made possible by a generous, unrestricted educational grant from Les Laboratoires Servier (Paris). This fifth edition focused on therapeutic approaches of type 2 diabetes and their impact on islet function. Although their hypoglycemic properties had already been recognized in 1942, sulfonamides (carbutamide) started to be used in the treatment of type 2 diabetes in 1955 (5). If millions of diabetic patients have successfully been treated with sulfonylureas for 50 years, it is because these compounds luckily hit a key regulatory site of insulin secretion, the ATP-sensitive K channel (KATP channel) that was to be discovered about 30 years later (6,7) and whose structure was identified only 10 years ago (8,9). Several sessions of the symposium were dedicated to this target, its role in various tissues, and the perspective of designing novel drugs with high selectivity. Alternative ways to stimulate deficient insulin secretion were discussed as well as the impact that treatment, whether directly targeting -cells or not, may have on islet function and progression of diabetes. Whenever possible and relevant, the contributors bridged our increasingly sophisticated knowledge of -cell pathophysiology to more clinical aspects of diabetes. Section I emphasizes that type 2 diabetes is a major manifestation of the metabolic syndrome. Since this syndrome is a systemic disease, affecting multiple organs, a systems-level analysis is important both for understanding the pathophysiology of the disease and for optimization of its treatment. In patients with the metabolic syndrome, the body’s inherent dynamics that ensure robustness against unstable food supply are disturbed. The metabolic and hormonal perturbations leading to diabetes develop slowly. Thus, a model is proposed that defines five stages of evolving -cell dysfunction during the progression to diabetes. In stage 1, insulin secretion is increased to maintain normoglycemia in the face of insulin resistance. In stage 2, glucose levels start to rise, due to reduction in the -cell mass and disruption of function. Stage 3 is a transient unstable period of early decompensation, while stage 4 is characterized by a significant reduction in -cell mass, eventually leading to the severe decompensation of stage 5. Some morphometric studies on postmortem pancreata from patients with type 2 diabetes have measured a 50% reduction in the -cell mass, but it should be pointed out that the extent of decrease is clearly smaller in other series. Although it is often assumed that apoptosis is responsible for -cell loss in type 2 diabetes, limitations in -cell replication and/or neogenesis could be just as important. Whatever the magnitude of the changes in -cell mass, there is little doubt that a major -cell dysfunction contributes to the insufficient secretion of insulin in type 2 diabetes. For example, fasting and stimulated proinsulin levels are disproportionately elevated relative to insulin levels. It is reported that reducing -cell secretory load with somatostatin decreased (but did not normalize) the proinsulin-to-insulin ratio in type 2 diabetes. These findings suggest that an intrinsic -cell abnormality could increase the proinsulin-to-insulin ratio and that the anomaly is exacerbated when the demand of From the Unit of Endocrinology and Metabolism, University of Louvain, Faculty of Medicine, Brussels, Belgium; the Institut National de la Santé et de la Recherche Médicale U342, St. Vincent de Paul Hospital, Paris, France; the Department of Endocrinology and Metabolism, Hebrew University Hadassah Medical Center, Jerusalem, Israel; the Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa, Pisa, Italy; the Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois; and the Department of Molecular Medicine, Division of Endocrinology & Diabetes, Karolinska Hospital, Stockholm, Sweden. Address correspondence to Jean-Claude Henquin, MD, PhD, Université Catholique de Louvain, Endocrinology & Metabolism Unit, UCL 55 30 Faculty of Medicine, Avenue Hippocrate 55, Brussels 1200, Belgium. E-mail: henquin@ endo.ucl.ac.be. Or Suad Efendic, MD, PhD, Department of Molecular Medicine, Karolinska Institute, SE-17176 Stockholm, Sweden. E-mail: suad.efendic@ molmed.ki.se. Received and accepted for publication 14 September 2004. This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier. AMPK, AMP-activated protein kinase; [Ca ]i, cytosolic Ca 2 ; DPP-IV, dipeptidyl-peptidase IV; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; IGIS, International Group on Insulin Secretion; KATP channel, ATP-sensitive K channel; LXR, liver X receptor; NBD, nucleotide-binding domain; PPAR, peroxisome proliferator–activated receptor; SOCS, suppressors of cytokine signaling; SREBP, sterol regulatory binding protein; SUR1, sulfonylurea receptor 1. © 2004 by the American Diabetes Association.