Editorial Toward a Systems Biology of Insulin Secretion and Type 2 Diabetes Donald F. Steiner,1 Christian Boitard,2 Erol Cerasi,3 Suad Efendic,4 Jean-Claude Henquin,5 and Ele Ferrannini6 storage, and utilization of nutrients for either energy production or growth. lthough it is clear that ␤-cell pathology, in Appropriately, the symposium opened with an introduc- particular disordered insulin secretion, is a key tory lecture by Leopold, reviewing our current knowledge underlying pathogenetic feature of most forms of the control of metabolism and growth in the fruit fly, A of diabetes, complex interactions of the islets Drosophila melanogaster, by insulin-like peptides and an with other organs, such as brain, liver, gut, and several insulin signaling pathway that is remarkably similar in peripheral tissues, are also essential for the normal inte- many of its components to that of man. No less than seven gration of metabolism. It is this area that has been Drosophila insulin-like peptides have been found. Three of explored in the Seventh Annual Servier-IGIS Meeting, these are expressed in specialized neurones in the insect which was held last Spring in St. Jean Cap Ferrat in brain, while others are expressed in larval tissues during Southern France. The focus of these meetings, since their development. Insulin-like peptides released from the brain inception in 2000, has been the ␤-cell and the mechanisms cells downregulate hemolymph sugar levels, while a glu- underlying its development and function as the source of cagon-like peptide, the adipokinetic hormone, from other insulin, the most essential regulator of the blood glucose neuroendocrine structures opposes it by raising sugar level. levels. Interestingly, these adipokinetic hormone-produc- The familiar pathways of glucose, lipid, and amino acid ing cells, unlike the insulin-producing cells, express an metabolism in humans and other mammals are, of course, ϩ ATP-sensitive K channel (KATP channel) that responds to fundamental to almost all organisms, except perhaps for tolbutamide to increase their secretory activity, resulting the most highly specialized bacteria, so it is not surprising in hyperglycemia. Moreover, mutations that influence that insulin-like molecules and the insulin/IGF receptor components of the insulin receptor pathway result in signaling system are well conserved features of all meta- reduced growth, reflected in smaller cells in smaller zoans that have been studied. With the rise of multicellular adults. Impaired insulin signaling also results in increased organisms in evolution came the need to regulate and longevity, decreased reproduction, and increased stress coordinate metabolism and growth in order to maintain resistance. Complex interactions with other endocrine both the constancy of the internal environment (ho- (ecdysone, juvenile hormone) and metabolic (TOR, etc.) meostasis) and also to respond to the external environ- pathways integrate nutrition and metabolism and eventual ment. One of the most prominent environmental stimuli organismal size. The powerful genetic tools available for had to be the availability of nutrients and fuels for survival Drosophila make it a rich experimental source for identi- and growth. The insulin-like hormones, insulin and IGF, fication of new components of these important conserved appear to have evolved, along with a panoply of other pathways. regulatory substances, to fine-tune the efficient uptake, Much recent work has focused on the role of lipids as modulators of insulin action and as important factors in the pathogenesis of type 2 diabetes via induction of insulin From the 1Departments of Biochemistry and Medicine, University of Chicago, resistance. Shulman and coworkers have used magnetic Chicago, Illinois; 2Institut National de la Sante´ et de la Recherche Me´dicale resonance spectroscopy to explore the molecular mecha- U561, St. Vincent de Paul Hospital, Paris, France; the 3Department of nisms underlying defective glucose transport and glycogen Endocrinology and Metabolism, Hebrew University Hadassah Medical Center, Jerusalem, Israel; the 4Department of Molecular Medicine, Division of Endo- metabolism in muscle. Increased lipid metabolites such as crinology & Diabetes, Karolinska Hospital, Stockholm, Sweden; the 5Unit of fatty acyl-CoAs and diacylglycerol activate kinase cas- Endocrinology and Metabolism, University of Louvain, Brussels, Belgium; and cades that impair insulin signaling due to Ser/Thr phos- the 6Metabolism Unit, CNR Institute of Clinical Physiology, University of Pisa, Pisa, Italy. phorylation of IRS-1. Similar mechanisms may operate to Address correspondence and reprint requests to Donald F. Steiner. E-mail: impair hepatic insulin signaling due to increased hepatic [email protected]. lipids in insulin-resistant subjects. These changes then CNS, central nervous system; FFA, free fatty acid; FFAR, free fatty acid receptor; GBS, gastric bypass surgery; GIP, gastric inhibitory polypeptide; lead to relative increases in gluconeogenesis and reduced GLP, glucagon-like peptide; HGP, hepatic glucose production; IL, interleukin; hepatic glucose uptake via lowered AKT2 and increased ϩ KATP channel, ATP-sensitive K channel. FOXO transcriptional effects on several key gluconeogenic The symposium and the publication of this editorial have been made rate-controlling enzymes. In related magnetic resonance possible by an unrestricted educational grant from Servier, Paris. DOI: 10.2337/db06-S000 spectroscopy studies, significant decreases in mitochon- © 2006 by the American Diabetes Association. drial oxidative phosphorylation activity in muscles and The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance liver have been found in elderly, lean, insulin-resistant with 18 U.S.C. Section 1734 solely to indicate this fact. volunteers, in association with increased muscle and he- DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006 S1 D.F. STEINER AND ASSOCIATES patic lipid content. Similar changes were found in young, actions, is released in large amounts during exercise. lean offspring of parents with type 2 diabetes associated Increases in IL-6 production and secretion are associated with reduced mitochondrial density, consistent with other with increases in AMPK activity in tissues such as muscle reported studies. The mechanisms underlying the reduc- and adipose tissue. AMPK enhances ATP generation while tion in mitochondrial biogenesis in these individuals is an inhibiting nonessential energy consuming processes via important area for further study that may lead to new phosphorylation of selected metabolic enzymes. Ruder- targets for therapeutic intervention. man and colleagues have demonstrated decreased AMPK While lipid overload can lead to insulin resistance and activity in muscle and adipose tissue in young IL-6–null impaired ␤-cell function, fatty acids and other lipids are mice and a diminished enzyme response to exercise in also important for normal ␤-cell function. It is well estab- these tissues. These animals later develop manifestations lished that fatty acids can augment glucose-stimulated of the metabolic syndrome with obesity, dyslipidemia, and insulin secretion, an effect that may be especially impor- impaired glucose tolerance. Key questions are whether tant in meeting the demands for increased insulin in these effects of IL-6 contribute to the reported benefits of compensated insulin resistance. Lipids can act both exercise in reducing the prevalence of type 2 diabetes, through their metabolism as well as via free fatty acid coronary atherosclerosis, and other concomitants of the (FFA) receptor (FFAR) activation. Prentki and associates metabolic syndrome in humans. have studied these mechanisms in detail and find that In liver, as in the ␤-cell, glucokinase plays a key role as increased cytosolic malonyl-CoA arising from glucose and a glucose sensor. However, the complex conformational lipid metabolism acts via AMPK/malonyl-CoA pathways to states and regulatory networks that control glucokinase limit fatty acid oxidation, thus increasing long-chain acyl- function differ significantly in these two tissues. As dis- CoA signaling molecules. Glucose can then enhance ester- cussed by Baltrusch and Tiedge, these range from the use ification and subsequent lipolysis of long-chain acyl-CoA of alternate promoters to regulate enzyme expression and to renew the FFA pool, which can then interact with the shuttling of a high-affinity regulatory protein between FFAR/GPR40, enhancing cytosolic Ca2ϩ and insulin secre- cytosol and nucleus in the liver to altered compartmental- tion. Glucose may also enhance release of arachidonic ization of glucokinase in ␤-cells and its activation by acid from phospholipids to activate yet other lipid-signal- binding of the bifunctional enzyme 6-phosphofructo-2- ing pathways in the ␤-cell. kinase/fructose-2,6-biphosphatase (PFK-2/FBPase-2) to in- Since many of the foregoing effects of lipids on insulin crease its Vmax. Some of these effects, and those of secretion depend on glucose-stimulated lipolytic activity, chemical glucokinase activators, are related to various efforts are currently underway to identify ␤-cell lipases. conformational states with altered catalytic activity, as Indeed, orlistat, a lipase inhibitor, abolishes lipolysis of tri- revealed in recent crystallographic studies. and diglycerides in islets, inhibiting insulin secretion with- This