New perspectives in diabetes research and treatment.

Diabetes mellitus affects millions of people worldwide, and its chronic complications are a leading cause of death in many countries. In the USA, for example, there are >15 million diabetics, and diabetes is the seventh leading cause of death. Indeed, these figures probably underestimate the true prevalence of the condition and its complications. In a minority of patients, diabetes is brought about by the autoimmune destruction of insulin-producing pancreatic β cells [type 1 diabetes mellitus (T1DM)]. In the vast majority of patients, diabetes is brought about by a combination of genetic and environmental factors that affect the organism's ability to respond to insulin [type 2 diabetes mellitus (T2DM)]. T2DM is due to a complex abnormality of insulin action in peripheral tissues such as muscle, adipose tissue and liver, and to impaired insulin production in β cells. In the past few years, research on the genetics, epidemiology, pathophysiology and treatment of both forms of diabetes has made great advances. In this special issue of Trends in Endocrinology and Metabolism, leading diabetologists have been asked to review selected areas of investigation.Exciting advances have been made in understanding how insulin affects cellular functions and how insulin ‘inaction’ brings about complex metabolic changes that eventuate in hyperglycemia and chronic complications. The causes of insulin resistance in humans with T2DM are probably diverse. In this issue, R. Bergman and M. Ader make a powerful case for the role of free fatty acids (FAA) in the pathogenesis of T2DM. This idea reflects back to the pioneering work of Randle1xThe glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Randle, P.J. Lancet. 1963; I: 785–789AbstractSee all References1, and was revived by the provocative observations of McGarry2xWhat if Minkowski had been ageusic? An alternative angle on diabetes. McGarry, J.D. Science. 1992; 258: 766–770CrossRef | PubMedSee all References2, suggesting that diabetes is indeed a disease of lipid metabolism. This hypothesis has gained increasing experimental support. Nevertheless, as Bergman points out, the mechanism(s) by which lipids, and FAAs in particular, affect insulin action is quite complex and requires further investigation.Over the years, Trends in Endocrinology and Metabolism has provided timely updates on the painstaking process of unravelling the mechanism of insulin action. This issue is no exception. B. Cheatham reviews key signaling mechanisms coupling insulin-receptor activation to membrane translocation of the insulin-sensitive glucose transporter GLUT4. It is humbling to realize that, 50 years after the seminal observations of Levine3xAction of insulin on the permeability of cells to free hexoses, as studied by its effect on the distribution of galactose. Levine, R. Am. J. Physiol. 1950; 164: 70–76See all References3, we still do not understand the mechanics of this basic effect of insulin. A wealth of data in different experimental models indicates that the lipid kinase activity of the enzyme phosphoinositol 3 (PI 3) kinase is necessary to mediate some of the actions of insulin on glucose transport. However, the distal components of this pathway, as well as the contribution of PI 3-kinase-independent pathways to insulin action, remain to be dissected, as do the various insulin-independent mechanisms that lead to similar biological effects. Several groups are now closing in on molecules required for GLUT4 translocation, and my prediction is that, before long, they should be able to unravel the complete chain of events that leads to glucose uptake in response to insulin. This area of research has direct implications for the development of novel therapeutic approaches to diabetes.As a result of recent developments in our understanding of insulin signaling, both the classical approach and alternatives to insulin treatment have been greatly expanded, for example, through the introduction of novel types of drugs that act to sensitize the body to insulin. A. Saltiel and J. Olefsky review the mechanisms of action of one of the most intriguing classes of compounds for use in T2DM, the thiazolidinediones or TZDs. The advent of these new agents has been marred by controversy about their side effects, and for this reason it was thought most appropriate that some basic information on this important issue be reviewed. With the introduction of new and apparently less toxic compounds, TZDs are now firmly entrenched in the therapeutic armamentarium of T2DM.Among the vast literature on diabetic complications, the biology of advanced glycation end products (AGE) is reviewed. AGEs have long been implicated in the control of vascular and inflammatory cellular responses to a variety of stimuli, and have been regarded as a potential trigger in the onset of diabetic complications. Although only in the first stages of clinical experimentation, compounds to block receptors of AGE (RAGE) represent a provocative new approach to treating diabetic complications. A-M. Schmidt and D. Stern review the RAGE story, evaluate the significance of this receptor in biology and assess the potential that their blockade will prove useful in the treatment of diabetic complications.Pancreatic β-cell biology has also seen substantial progress in the past decade, and promises to yield important insight into the generation of b cells for replacement therapy in T1DM patients, and to improve graft survival and function in the burgeoning field of islet transplantation. Two aspects of the extensive research on the pancreatic b cell are highlighted in this issue. S. Bonner-Weir takes on the topic of β-cell function and the role of programmed cell death in maintaining adequate β-cell mass. It is now clear that β-cell growth is a dynamically regulated process, and that β-cell neogenesis and regeneration play important roles in both forms of diabetes. Understanding factors and signaling pathways that underlie these important physiologic processes is a key issue if we are to prevent b-cell failure in patients with insulin resistance and improve β-cell function in patients with overt diabetes.The recent report on the results of the Edmonton trial on islets cell transplantation4xIslet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. Shapiro, A.M. et al. New Engl. J. Med. 2000; 343: 230–238CrossRef | PubMed | Scopus (3281)See all References4 has rekindled interest in this approach as a way of restoring β-cell function. These encouraging preliminary findings have inspired a larger North American clinical trial to seize upon this preliminary experience and move islet transplantation from the realm of research into that of clinical care. E. Liu and K.C. Herold review this topic and provide background information on the methodology of islet transplantation, its indications and what improvements can be brought to bear on the technique.No comprehensive diabetes review could afford to ignore research in the field of genetics of diabetes. Genetic factors play a key role in the development of both T1DM and T2DM. The article by M.A. Permutt and A.T. Hattersley reviews the findings of a number of genome-wide scans in patients with T2DM and puts them in the context of the ‘post genome’ era. There are great expectations in the scientific community for the results of such genome-wide scans for genes encoding diabetes. Candidate gene studies have mostly been a source of disappointment and disillusion, and in recent years have come to a virtual standstill in their ability to provide new genes countering susceptibility to diabetes. However, the preliminary results of the genome scans should be taken with a grain of salt for a number of reasons. First, the chromosomal regions of interest are still quite broad. As Permutt points out, our ability to identify genes within these critical regions will be enormously enhanced by the completion of the human genome sequence and single nucleotide polymorphisms (SNP) maps. Second, a considerable degree of healthy controversy has surrounded the findings, largely because investigators are charting a new course, and a real consensus on ways and means in the search for traits contributing to diabetes has yet to emerge.In assembling contributors for this issue of Trends in Endocrinology and Metabolism, I have tried to highlight topics that have seen substantial developments in the recent past, in the hope of providing a reference tool for the physician-scientist for a few years to come. I wish to thank Kevin Catt, Editor-in-Chief, for providing inspiration and suggestions for the realization of this endeavor, Nick Halmi for his punctilious editing, as well as Helen Gannon and Linsey Stapley for their unflagging efforts to remedy scientists’ chronic aversion to deadlines.