The Pathobiology of Diabetes Mellitus

Diabetes mellitus is an increasingly common condition characterized by hyperglycemia caused by varying degrees of destruction and/or dysfunction of the pancreatic islets causing complete or near-complete loss (as in type 1 diabetes) or insufficient (as in type 2 diabetes) insulin secretion. The hyperglycemia, with the related disturbances of carbohydrate, protein and lipid metabolism, contributes to extrapancreatic tissue damage, including poor wound healing and the long-term complications of diabetic retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. While diabetes has been known since 2500 BC, the survival and long-term prognosis of people with type 1 diabetes have only started to improve recently. Key developments have been the availability of exogenous insulin injections (since 1922), self-blood glucose monitoring and improved insulin preparations and delivery methods (over the last 30 years) and, for a very small minority, pancreas or islet transplantation. While the pathophysiology of the hyperglycemia of type 2 diabetes and gestational diabetes is complex, failure of insulin secretion to fully compensate for insulin resistance underscores the importance of pancreatic islet dysfunction in this heterogeneous condition. In this chapter, we describe normal pancreas function and how it is disturbed and treated in the common forms of diabetes. We also describe the short-and long-term consequences of diabetes that stem from pancreatic islet failure. Current and emerging glucose control treatments, most of which are closely related to and derived from normal islet function, are also reviewed. We hope this chapter, complemented by others in this volume, will increase the reader’s interest in and understanding of pancreatic islet biology and the clinical and research challenges, and assist them in diabetes-related research to provide better clinical outcomes for those with or at risk of diabetes.