Diabetic microangiopathy, genetics, environment, and treatment

As the major cause of disability and death in insulin-dependent diabetes, microangiopathy is obviously of major concern to diabetologists. Unlike macroangiopathy, which can readily be prevented by means that are currently on hand, the origin and treatment of microangiopathy remain far more problematical. The complexity of this lesion is indicated by the findings in this laboratory that hyperglycemia induced by the rodenticide, vacor, can cause microangiopathy independent of genetic diabetes, yet significant microangiopathic lesions can be detected in genetic diabetic patients before the appearance of hyperglycemia. Further, there is now intriguing evidence based both on basement membrane measurements from our laboratory and on clinical studies showing that significantly microangiopathy only rarely occurs prior to the onset of puberty. The evidence that control or even normalization of blood glucose levels does not influence the course of established microangiopathy is becoming increasingly convincing. Five prospective, randomized studies over the past five years have shown that strict regulation of glucose has no consistent benefit on, and in some studies may, at least transiently, accelerate, the retinopathy of diabetes. Moreover, the first controlled study of successful pancreatic transplantation to achieve normalization of blood glucose levels has again demonstrated that established retinopathy is neither prevented nor even delayed by normal glucose levels. This review, therefore, emphasizes that, though hyperglycemia is required for clinically significant microangiopathy to occur, clearly other factors, genetic, environmental, or both, must play major roles in determining the course of microangiopathy. It is toward these nonglycemic factors in the development of diabetic microangiopathy that future research should increasingly be directed.