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Diabetes Mellitus is a complex illness caused by genetic and environmental factors that control either energy and nutrient metabolism, or the susceptibility to the development of an autoimmune process that destroys the insulin-secreting beta cells of the pancreatic islets, described further below. Morbidity and mortality are due primarily to microvascular complications in the retina, kidney and peripheral nervous system, and to atherosclerosis. Current therapies are now evolving at rapid rate, however the burden of this illness continues to increase. The research programs serviced by the Boston Area Diabetes and Endocrinology Research Center (BADERC) in aggregate, address most of major problems arising from Diabetes Mellitus and its complications, across the spectrum from laboratory-based cellular and molecular biology relevant to metabolic regulation and the function of the immune system, to animal models of autoimmunity, metabolic dysfunction and vascular disease, to translational research on human subjects. Overview: Diabetes Mellitus is a highly prevalent ailment, characterized by chronic hyperglycemia and premature deterioration of the vascular system due to accelerated atherogenesis as well as a characteristic microangiopathy, most importantly in the retina, that places diabetes as the leading cause of blindness under age 60. The microangiopathy is now recognized to be the consequence of the sustained hyperglycemia, and affects all patients with diabetes, regardless of pathogenesis of the hyperglycemia. All forms of diabetes are also accompanied by degeneration of the peripheral nervous system, another metabolic insult caused by sustained hyperglycemia, occasionally complicated by intercurrent microinfarction. Diabetes is the most prevalent cause of renal failure requiring chronic renal replacement therapy. Although occurring in only a subset of hyperglycemic patients diabetic nephropathy is also attributable to the sustained hyperglycemia, acting through hemodynamic and metabolic factors to damage the renal glomerulus in susceptible individuals. The atherogenic complications of diabetes result from sustained hyperglycemia, which in the Type 2 syndrome is compounded by a coexistent proatherogenic state now best known as the ?Metabolic Syndrome?. It has been estimated that the total costs of Diabetes in the U.S. in 1992 approached $105 billion, roughly 15% of all expenditures for health care and the prevalence and costs of this illness continue to increase. The causes of diabetes and its complications are diverse and as yet incompletely understood; cures are not yet at hand. The research programs of the participating scientists seek to address these problems. TYPE I DIABETES Two clinical forms of Diabetes Mellitus are recognized that differ in pathogenesis, but ultimately lead to relative or absolute insulin deficiency and sustained hyperglycemia. Type 1 diabetes is an autoimmune disease wherein the beta cells of the pancreatic islet are destroyed during an asymptomatic interval of years by a cell-mediated immune process, whose activity can be detected by the measurement of circulating antibodies to islet polypeptides e.g., insulin, glutamic acid decarboxylase, etc. Hyperglycemia develops when the loss of beta cell mass has progressed to well over 90% of initial levels. This syndrome, previously called juvenile diabetes, has a peak incidence in early adolescence, but occurs throughout life and accounts for perhaps ten percent for all diabetes. Prior to the discovery of insulin, Type 1 diabetes was uniformly fatal within days to months from the onset of hyperglycemia; patients expired in a state of skeletal emaciation, drifting into coma from ketoacidosis or succumbing to overwhelming intercurrent infections. Insulin, discovered by Banting and Best in 1921, provided an apparently miraculous cure, restoring nutrient metabolism to near normal, and enabling heretofore doomed subjects to resume nearly normal lives. By the 1950's, the advent of intermediate-acting insulins, an increasing sophistication in the treatment of diabetic ketoacidosis, the arrival of antibiotics and improvements in obstetric and surgical care led to a public perception that the excessive mortality of Type 1 diabetes had been brought under control. A very different reality, however, confronted patients and physicians as the realization dawned the insulin had not "cured" Type 1 diabetes. Thus, after the passage of 10-15 years, otherwise well-appearing, relatively young Type 1 diabetics experienced an accelerating accumulation of complicating conditions such as ischemic retinopathy leading to blindness, renal failure, myocardial infarction, stroke and the remarkably frequent occurrence of lower limb amputation required for control of neuropathic ulcers complicated by infection and vascular insufficiency. The abrogation of early mortality was now seen to have uncovered the existence of a set of late complications whose impact in suffering was considerable, whose lethality, although delayed still occurred prematurely, and whose burden of medical care in terms of cost was radically greater than that engendered by the rapidly fatal illness of the preinsulin era. Insulin, miraculous as its discovery was, can now in retrospect be seen as the original "halfway" technology; a partial therapy that postpones but does not eliminate disease-specific adverse outcomes, and thereby introduces large new costs. The Diabetes Control and Complications Trial provided the first indisputable evidence in man that control of glycemia will ameliorate the prevalence and progression of the microvascular and neuropathic complications, and perhaps the excessive atherogenesis of the Type 1 diabetic as well. The challenge now is to 1) apply the methods that are already available in the broadest, most efficacious and cost effective way. 2) Generate the knowledge base that will enable the development of new therapies that can cure the metabolic and vasculopathic lesions that prevail in diabetes. 3) Develop from this knowledge base ameliorative and especially, curative treatments for diabetes and its concomitant vascular diseases. These are the overall goals of the Boston Area Diabetes and Endocrinology Research Center (BADERC) A specific long term goal of this center is to promote work aimed at the cure of anti-beta cell autoimmunity and the restoration of beta cell function through beta cell replacement therapies. Despite recent improvements in the efficacy of human islet transplants for the treatment of Type 1 diabetes, as first reported by investigators in Edmonton, it appears inescapable that, even if autoimmunity and transplant rejection were overcome, shortfalls in the availability of donor tissue will prevent islet transplant from becoming a practical therapy for a significant fraction of insulin-requiring diabetics. Thus the support of work on beta cell regeneration in vivo and development in vitro is a major priority of the BADERC. TYPE 2 DIABETES The vast majority, perhaps 90% of patients with diabetes can be classified as Type 2, or non-insulin dependent diabetes (NIDDM). This is a disease of late-middle and older age, affecting 1/15 individuals of Caucasian ancestry over age 40, perhaps 1/8 individuals of African-American or Hispanic origin, and nearly 1/3 native Americans. The pathogenesis and ontogeny of the Type 2 syndrome has been extensively studied and is now well described; what remains obscure are the specific genetic contributions, the linkage of the metabolic abnormalities to the accelerated atherogenesis, and the identity of practical and effective therapies. Despite the late onset, considerable evidence from identical twin sets and other genetically restricted populations leaves no doubt that susceptibility is profoundly determined by genes, and inputs from multiple genetic loci are probably contributory in most patients. Nevertheless, equally compelling evidence demonstrates that the environment (specifically, the easy availability of calories leading to the development of obesity) operates with equal potency to determine whether this genetic susceptibility will be manifest clinically as hyperglycemia. It is now clear that both impaired insulin secretion and action are detectable when any degree of abnormal glucose tolerance is present, and the development of frank fasting hyperglycemia almost always requires considerable impairment of both insulin secretion and action. In the hyperglycemic Type 2 diabetic, the hyperglycemia itself contributes substantially both to faulty beta cell function and impaired insulin action, but correction of the hyperglycemia leaves behind unmistakable defects in both limbs, as is true in individuals who have only impaired glucose tolerance. Studies of genetically susceptible populations prior to the development of abnormal glucose tolerance has shown evidence for impaired insulin action as the consistent, unequivocal precursor abnormality; evidence for impaired insulin secretion in the prehyperglycemic interval is much less compelling, but certainly available in the form of subnormal beta cell responses to low-dose glucose challenge, or altered periodicity in basal insulin release. Thus the most widely held model for the pathogenesis of Type 2 diabetes envisions a person who is deficient in his/her ability to clear glucose from the circulation under the stimulus of postprandial insulin. i.e., is "insulin resistant". Such an individual maintains normal glucose tolerance during early life by hypersecreting insulin in response to minimal hyperglycemia, within the "normal" range. With time, insulin resistance worsens, due to an excessive caloric intake with the development of obesity, and the deconditioning of skeletal muscle metabolism that accompanies a progressively sedentary existence. Beta cell responsiveness declines, due to the development of minimal hyperglycemia per se, or due to some toxic concomitant of chronic insulin hypersecretion such as a amylin deposition, or perhaps due to factors that are genetically determined e.g., an intrinsic secretory defect, an initially small beta cell mass, or a limited beta cell replicative capacity, etc. The development of hyperglycemia itself then leads to further impairments in insulin secretion and action, in a positively reinforcing, feedforward manner. In this scenario, amelioration of the hyperglycemia can be accomplished by decreasing the carbohydrate-derived caloric load, by reducing overall calories so as to cause weight loss, thereby reducing the component of insulin resistance attributable to obesity, or by supplementing insulin action through administration of additional insulin or by using sulfonylureas, which readjust the threshold for glucose-stimulated insulin secretion. ATHEROSCLEROSIS AND DIABETES-THE METABOLIC SYNDROME Far and away the most important cause of morbidity and mortality for the Type 2 diabetic patient results from the excessive and premature occurrence of atherosclerotic cardiovascular disease. It is widely appreciated that the risk for atherosclerosis is attributable to a number of factors that act in a multiplicative way; in addition to hyperglycemia, the classical atherogenic risk factors include smoking, hypertension and hypercholesterolemia. It is now well established that a low value of HDL cholesterol confers an independent and powerful risk in addition to that conferred by high LDL cholesterol. Much evidence indicates that obesity also confers an independent risk, even when corrected statistically for the impact of these known intermediates. Given the high prevalence of the risk factors for atherosclerosis in the population at large, it would not be surprising that the superimposition of marked hyperglycemia, especially when combined with obesity as is common in the Type 2 syndrome, would be associated with excessive atherogenesis. This formulation however, significantly understates the unusually high susceptibility to atherosclerosis experienced by the Type 2 diabetic, especially the female diabetic; the relative protection from atherosclerotic cardiovascular disease seen in women is abolished by diabetes. The atherosclerosis of the diabetic is still largely "explained by" or statistically attributable to the known risk factors enumerated above; the crucial point however is that it is now appreciated that these risk factors actually cluster in the diabetic population. In other words, something about the Type 2 diabetic state results in an excess prevalence of hypertension, high LDL cholesterol, low HDL cholesterol, obesity, etc. What are the crucial elements that initiate this clustering? It is clear from epidemiologic observations that hyperglycemia per se is an independent risk factor for atherogenesis, and experimental studies provide evidence for multiple sites at which hyperglycemia, acting through non-enzymatic glycosylation and perhaps other mechanisms, can affect adversely lipid metabolism, the cellular constituents of the vessel wall, as well as the function of platelets and the clotting and fibrolytic system. Nevertheless, several kinds of evidence indicate that hyperglycemia itself is a relatively modest contributor to overall atherogenic risk. Many long term studies of populations who exhibit impaired glucose tolerance (IGT), the large majority of whom (60-70%) never progress to exhibit a degree of hyperglycemia sufficient to merit a diagnosis of Type 2 diabetes, have shown that the prevalence of atherosclerosis in such IGT subjects is at least half of, and often approaches that of populations with frank Type 2 diabetes. Reciprocally, if one begins with populations selected for the occurrence of atherosclerosis a commonly occurring phenotype emerges, that includes impaired glucose tolerance (IGT), hypertension, obesity, low HDL cholesterol, elevated triglycerides and LDL cholesterol. It is now clear that this metabolic syndrome reflects a pathogenetically linked set abnormalities, and is actually the precursor state for atherogenesis is a large segment of the nondiabetic population; the Type 2 diabetics appear to be the subset of these subjects who are unable to sustain a level of insulin secretion adequate to prevent the progression of "impaired glucose tolerance" to frank hyperglycemia. As to the initiating stimulus for this atherogenic-metabolic syndrome, an early hypothesis proposed that resistance to the hypoglycemic action of insulin is the culprit; the resulting sustained hyperinsulinemia, although relatively ineffective in promoting postprandial activation of glucose transport, phosphorylation and deposition as glycogen in skeletal muscle can nevertheless, perhaps acting together with excess caloric intake, alter the metabolism of the hepatocyte, vascular smooth muscle and endothelial cells, and the adipocyte, so as to result in hypertension, abnormal lipoprotein metabolism and excessive adiposity. Recent evidence however emphasizes the importance of central obesity in the initiation of the metabolic syndrome. It is now recognized that the adipose organ, in addition to its function in the storage and release of triglyceride-fatty acids, is also a source of a wide array of secretory products that affect metabolism, vascular function and the inflammatory response. Overfilling of the central adipose depots results not only in the excess delivery into the circulation of free fatty acids, but altered secretion of a variety of adipocyte derived factors, cytokines as well as hormones, that contribute to the insulin resistant and proatherogenic, prothrombotic state that is the ?metabolic syndrome?. The tight linkage of diabetes and atherosclerosis and the importance of atherosclerosis as a determinant of outcome for the diabetic patient requires that an intellectual alliance be forged between investigators working these two disciplines, and the development and maturation of such an interaction is a major goal of the BADERC. |
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