Editorial Novel Factors in the Regulation of -Cell Function

Insulin secretion and -cell biology are the focus of the Servier-IGIS Symposia that have been held yearly since 2000 in St. Jean Cap Ferrat in southern France (1). This volume, the fourth of a series published in Diabetes (1–3), collects the proceedings of the fourth Servier-IGIS Symposium, which focused on novel factors involved in islet biology and -cell function. Special emphasis was placed on nuclear receptors, new genes that are associated with type 2 diabetes, and the role of mitochondria and lipid modulators in islet function. This symposium offers a striking example of how better knowledge of -cell biology and the introduction of genetic tools to explore the pathophysiology of type 2 diabetes complement each other to improve our understanding of glucose homeostasis. Section I details the role of nuclear receptors in islet function, with special emphasis on peroxisome proliferator–activated receptors (PPARs). PPAR was cloned in 1990; related receptors were subsequently cloned, namely PPAR (or ) and PPAR . They form heterodimers with retinoid X receptor (RXR); their natural ligands are fatty acids and lipid-derived substrates. These receptors are major regulators of lipid metabolism, linking availability of glucose and lipids and long-term metabolic adaptation. Most importantly, they are targeted by key drugs used in treatment of hyperlipidemias and diabetes, namely fibrates and thiazolidinediones. Thiazolidinediones are synthetic PPAR agonists developed to improve glucose tolerance by enhancing insulin sensitivity and restoring -cell function. Patients with dominant-negative PPAR mutations develop severe hyperglycemia, and PPAR gene variants have been associated with type 2 diabetes. Besides the many actions of PPAR agonists on the transcription of genes controlling insulin sensitivity in adipose tissue, they increase glucose sensing in liver and in -cells. In the latter, PPAR also enhances growth and prevents apoptosis. PPAR (the target of fibrates) controls lipid uptake and oxidation and directs lipid flux predominantly to the liver. PPAR is expressed in a wide range of tissues, especially those with free fatty acid (FFA) oxidation. In addition to indirect actions on -cells via effects on insulin sensitivity, PPAR agonists have direct effects on islets. Exposure of -cells to high FFA levels along with high glucose may result in depressed insulin secretion and, possibly, -cell death. The influence of PPAR on insulin secretion includes long-term adaptation to prolonged starvation, as best exemplified in PPAR -null mice. Defective signaling via PPAR enhances insulin secretion at basal glucose concentrations, i.e., during fasting. Multiple lines of evidence suggest that PPAR activation depresses glucosestimulated insulin release. A third focus of section I was on glucocorticoid receptors in -cells. Glucocorticoids have long been known to exert their diabetogenic effect through decreased glucose uptake by peripheral tissues and increased hepatic glucose production but also direct inhibition of insulin release. The development of transgenic mice overexpressing glucocorticoid receptor in -cells under the control of the rat insulin I promoter has provided a unique model to study the long-term effects of enhanced glucocorticoid sensitivity in -cells. Interestingly, hyperglycemia in this model is related to enhanced inhibition of insulin secretion through 2-adrenergic receptors, without evidence for increased -cell apoptosis. Finally, new approaches have made it possible to delineate novel activation pathways in the -cell. Insulin release is only one facet of -cell function; other signaling pathways are involved to integrate insulin synthesis and storage, cell proliferation, apoptosis, and differentiation. Recent findings point to receptors for novel extracellular messengers and new location of ion channels. In -cells, the stimulus-secretion coupling is regulated by global as well as localized Ca signals in the vicinity of a primed pool of secretory granules beneath the plasma membrane. Novel digital imaging methods and spot confocal microscopy have made it possible to define distinct secretory granule pools and relate them to localized Ca signals. While spatial restriction of Ca signals close to the From INSERM U342, St. Vincent de Paul Hospital, Paris, France; the Department of Endocrinology & Metabolism, Hebrew University Hadassah Medical Center, Jerusalem, Israel; the Department of Molecular Medicine, Division of Endocrinology & Diabetes, Karolinska Hospital, Stockholm, Sweden; the Department of Physiology, Endocrinology-Metabolism, Université Catholique de Louvain, Brussels, Belgium; the Department of Biochemistry and Molecular Biology, and Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois; and the Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa, Pisa, Italy. Address correspondence and reprint requests to E. Ferrannini, MD, Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy. E-mail: [email protected]. Received and accepted for publication 13 October 2003. 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 Les Laboratoires Servier. ASP, acylation-stimulating protein; FFA, free fatty acid; mtD, mitochondrial diabetes; PKG, protein kinase G; PLA2, phospholipase A2; PPAR, peroxisome proliferator–activated receptor; QTL, quantitative trait locus; ROS, reactive oxygen species; RXR, retinoid X receptor; SNP, single nucleotide polymorphism; UCP, uncoupling protein. © 2004 by the American Diabetes Association.