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Editorial—Advances Relevant to the Molecular Endocrinology of Diabetes

In keeping with the theme of this year’s annual meeting of The Endocrine Society, the editors of Molecular Endocrinology are pleased to present seven articles in this issue that address the molecular events underlying diabetes. Endo 2000 will begin with the opening Plenary Session, Diabetes: Then and Now, setting the tone for this year’s focus on diabetes. Another Plenary Session, Genetics and Physiology of Obesity in Mice and Man, will focus on the association between diabetes and obesity. The Presidential Lecture, an event that traditionally addresses an important emerging area of endocrinology, will be delivered by Dr. Francis Collins of the National Human Genome Research Institute. He will discuss initiatives in human genetics and their impact on diabetes.

Type I (insulin-dependent) and type II (non-insulin-dependent) are the two main forms of diabetes mellitus. The type I form is a slowly progressive autoimmune disease characterized by destruction of pancreatic ß-cells. In contrast, the type II form is associated with insulin resistance, as well as primary or secondary abnormalities of insulin secretion, caused by defects in the insulin signaling pathway. These defects include the insulin receptor as well as several cytosolic docking proteins (IRS proteins) that couple the receptor to various effector molecules such as phosphatidylinositol-3-OH kinase [PI(3)K], Grb2/SOS, SHP2, NCK, and CRK1. Both forms have a genetic basis. For type I, a major locus of susceptibility is linked to HLA-D on the short arm of chromosome 6, a region involved in the process of communication between cells that determine immune responses. The genetics underlying type II diabetes are also complex and probably involve several genes.

Approximately 90% of diabetics have the type II form; they represent about 10% of the population in the Western world. Given the magnitude of this disease and its pathological impact, there is a pressing need to uncover new and more effective therapies, a task that will be facilitated by coupling the molecular approaches currently in use with the explosion of functional genomics and its attendant methodologies.

In this issue, Itkin-Ansari and colleagues (pp. 814–822) report that PDX-1, a homeodomain transcription factor, acts in synergy with cell-to-cell contact to up-regulate the endogenous somatostatin promoter in an immortalized cell line from human fetal islets. This discovery unveils a new model for studying human islet cell development that may prove valuable for islet transplantation efforts used for treating type I diabetes.

Six other articles are more germane to type II diabetes. Two of these emphasize the importance of cross-talk between the insulin and other hormone signaling systems. As featured on the cover, Klein and colleagues (pp. 764–773) report that cross-talk between the adrenergic and insulin signaling systems impairs the regulation of uncoupling protein-1 (UCP-1) and may thereby contribute to reduced energy balance resulting in obesity and insulin resistance. In their article, Elbaz et al. (pp. 795–804) demonstrate functional trans-inactivation of insulin-receptor kinase by the G protein-coupled angiotensin II type 2 receptor, illustrating a novel negative form of communication by these two families of receptors.

Two other articles address issues further downstream in the insulin signaling pathway. Haruta and colleagues (pp. 783–794) demonstrate that insulin-induced serine/threonine phosphorylation and degradation of insulin receptor substrate-1 (IRS-1) are mediated by a rapamycin-sensitive pathway situated downstream of PI(3)-kinase and independent of ras/MAP kinase. This rapamycin-sensitive pathway targets IRS-1 to the proteosomes, suggesting that it may play a major role in down-regulation of insulin action after prolonged stimulation. Razzini et al. (pp. 823–836) focus on the pleckstrin homology domains of IRS-1, IRS-2, and IRS-3 and report that each binds with different specificities to the 3-phosphorylated phosphoinositide moieties. When these results are coupled with translocation effects, a novel positive feedback loop is uncovered, revealing that PI(3)-kinase functions as both an upstream regulator and downstream effector of IRS-1 and IRS-2 signaling.

Insulin-like growth factor (IGF-I) can also have important effects on insulin action. Our two remaining articles give this topic further consideration. Boney and colleagues (pp. 805–813) address how IGF-I can stimulate mitogenesis in proliferating preadipocytes and then trigger their differentiation into adipocytes when the cells become confluent. They conclude that signaling through the Shc to MAPK pathway plays a critical role in mediating IGF-I stimulation of mitogenesis in preadipocytes. In contrast, the trigger for differentiation into adipocytes appears to occur through down-regulation of MAPK caused by loss of proximal signaling through Shc. Moving even further downstream, Urban et al. (pp. 774–782) focus on an IGF-I responsive gene, porcine P-450 cholesterol side-chain cleavage enzyme (P450scc), and demonstrate that a single 30-bp response element (IGFRE) binds two factors with opposing activity. Previous studies indicated that Sp1 activates transcription when it occupies the IGFRE. Now they report that the PTB-associated splicing factor (PSF), an RNA binding component of spliceosomes, also binds to the IGFRE and thereby blocks the transcriptional effect of Sp1.

Together these seven articles contribute to our understanding of the insulin signaling pathway and to our understanding of genes that genetically define functional ß-cells in pancreatic islets. Their importance will become even greater as functional genomic and genetic studies of diabetes continue. Elaborate molecular and genetic networks will undoubtedly emerge. Each new participant will likely become a candidate for evaluation as a potential therapeutic target or agent. And so it is that molecular maps of diabetes may well become a pivotal example of the power and translational value of functional genomics.

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