The Pathophysiology of Diabetic Complications: How Much Does the Glucose Hypothesis Explain?

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia and alterations in fat and protein metabolism and by the occurrence of a specific set of long-term microvascular and neurologic complications. The clinical features and hyperglycemia of insulin-dependent diabetes mellitus (IDDM) are sufficiently characteristic so as not to require the occurrence of long-term complications to define it as a nosologic entity. However, the hyperglycemia of noninsulin-dependent diabetes mellitus (NIDDM) is part of a continuum. The glucose cutoffs that define NIDDM were selected on the basis of their association with diabetic complications, especially retinopathy [1]. Patients with modest levels of glucose intolerance not associated with long-term diabetes-specific complications are classified as having impaired glucose tolerance. On the other hand, patients with the more marked hyperglycemia associated with retinopathy are categorized as having diabetes. Thus, the currently accepted definition of diabetes mellitus tacitly recognizes the link between hyperglycemia and diabetic complications. Despite the close phenomenologic linkage of hyperglycemia with complications, which has given rise to the glucose hypothesis, the causal mechanism of diabetic complications is not established. Is hyperglycemia the cause of diabetic complications? If so, what is the mechanism of its effect? In addition, do all long-term complications share similar pathogenetic mechanisms? This article reviews the animal model, epidemiologic, and clinical data that support the glucose hypothesis; the observations that support a common cause of diabetic complications and those that suggest diverse causes; and the potential pathogenetic mechanisms by which hyperglycemia may mediate the development or progression, or both, of long-term complications. The Glucose Hypothesis The potential connection between the level of glycemia and the development of long-term complications was suggested many years ago and supported by some but not all early epidemiologic studies [2, 3]. The glucose hypothesis that evolved proposed that hyperglycemia was either directly or indirectly related to the development or progression, or both, of diabetes-specific complications, including retinopathy, nephropathy, and neuropathy. The consensus was that hyperglycemia was a necessary but insufficient element in the pathogenesis of the complications and that interventions decreasing glycemic levels would ameliorate complications. In the absence of reliable measures of long-term glycemia or complications or of animal models of diabetes, the glucose hypothesis could not be tested. The advent of glycosylated protein assays [4] and quantitative, precise measures of long-term complications led to more reliable epidemiologic studies and further support of the relation between glucose levels and retinopathy in both NIDDM [5, 6] and IDDM [7]. It has been more difficult to establish an association between nephropathy and neuropathy and objective, reliably measured levels of chronic glycemia [8]. Finally, the association between glycemic levels and the nonspecific macrovascular complications that often accompany diabetes has been particularly difficult to establish, not an unexpected finding considering the multifactorial pathogenesis of macrovascular disease [9]. A recent study has shown an association between prevalent cardiovascular disease and glycosylated hemoglobin level across the entire spectrum of HbA1c levels [10]. In addition to the human epidemiologic data, interventional studies in animal models of diabetes have shown that more stringent measures to obtain near-normal glycemia invariably result in improved outcome [11, 12]. The combined epidemiologic and animal model studies, spanning a diverse range of diabetes and its complications, vigorously support the glucose hypothesis. The recent demonstration of a beneficial effect of intensive therapy designed to lower glycemia on long-term complications in IDDM [13, 14] has boosted confidence in the glucose hypothesis, providing a final leg to the fulfillment of a variation of Koch's postulates for chronic diseases. Moreover, the relatively uniform salutary effects of intensive therapy on retinopathy, nephropathy, and neuropathy suggest that hyperglycemia may play a similar role in the pathogenesis of all three major diabetic complications. In the Diabetes Control and Complications Trial, intensive therapy reduced the development and progression of all complications by approximately 50% [14]. Shared and Unshared Characteristics of Long-Term Complications If hyperglycemia causes long-term complications, does it cause all of the complications? In addition, are all phases of complicationsfor example, initiation of nonproliferative versus progression to proliferative retinopathyrelated to hyperglycemia? The most obvious shared features of retinopathy, nephropathy, and neuropathy include their dependence on duration of disease [2]; the occurrence of complications in tissues in which glucose or its metabolites accumulate based on their plasma concentration and relatively independent of insulin [15-17]; and the involvement of relatively small caliber vessels with abnormal basement membranes (the retinal capillaries, vascular elements of the glomeruli, and vasa nervorum). Moreover, the abnormalities in retinal vessels, including early loss of the supportive pericytes, and in basement membrane [18] may be homologous to the mesangial accumulation and basement membrane thickening of the glomerulus [19, 20]. Finally, the association between glucose levels and the development of complications has been established for the complications, and, as noted above, the development and progression of all three diabetes-specific complications decrease with treatments that lower glucose levels. Despite the shared elements, many features are not shared. For example, although the retinal and glomerular lesions are in the microvasculature, the most common neuropathic complicationperipheral somatosensory neuropathyis more likely to be secondary to a metabolic derangement in neurons rather than a focal vascular problem [21]. Other forms of neuropathy (for example, the focal mononeuropathies) are probably secondary to obstruction of the vasa nervorum with ischemia [22, 23]. Although most patients with IDDM develop retinopathy over time, only 30% to 50% of patients with IDDM and no more than 15% of patients with NIDDM develop nephropathy to any degree [24, 25]. Similarly, many experimental animal models of diabetes develop retinopathy, but few develop renal disease. The development and progression of some complications, including nephropathy [26, 27] and perhaps retinopathy [28], are clearly influenced by other variables such as blood pressure, whereas neuropathy is not. Finally, different stages of complications may have different pathogenetic mechanisms. The more advanced stage of retinopathy is characterized by the development of new vessels, so-called proliferative retinopathy, which appears to develop in the setting of widespread vascular obstruction or dropout with resultant ischemia [29]. The proliferative changes, but not the earlier background retinopathy, are associated with angiogenic factors that probably have no direct relation to glycemia [30]. Potential Glucose-Related Mechanisms of Long-Term Complications Assuming that glucose levels are directly related to the development of some if not all diabetes-specific complications, what are the mechanisms? The two putative pathogenetic mechanisms that have received the most attention are the aldose reductase-sorbitol and the glycation models. Each of these, but especially the former, has been advanced through the availability of pharmacologic probes. Aldose reductase inhibitors have been available for more than two decades and have been tested in animal models and in human diabetes [31]. Glycation inhibitors such as aminoguanidine have been tested in animal models, and studies in humans are under way [32]. The role of aldose reductase in catalyzing the intracellular accumulation of sugar alcohols such as sorbitol in tissues that develop complications has been recognized for almost 30 years [15, 33]. The accumulation of sorbitol in the lens of the eye, pericytes, and neural tissue has many effects, including changes in osmotic gradients, decreased myoinositol concentrations, and perturbation of energy metabolism [21, 33, 34]. Despite the early enthusiasm for the sorbitol hypothesis as an explanation for diabetic complications, especially neuropathy, and the promising results of animal studies using aldose reductase inhibitors [35, 36], the results in studies of human diabetes have not been convincing [37-39]. Whether the failure to improve neuropathy with various relatively potent aldose reductase inhibitors is secondary to inadequate treatment periods, poor penetration of drugs into clinically relevant tissues, an incorrect hypothesis, or to other factors is not known. Glycation was first recognized by identifying minor hemoglobin fractions that could be separated from adult hemoglobin on the basis of charge. These minor hemoglobin fractions were increased in diabetic patients and eventually identified as products of nonenzymatic glycation [40, 41]. The major clinical utility of glycation products has been in the monitoring of chronic glycemia; glycated hemoglobin measurements reflect the average, integrated level of glucose control during the previous 2 to 3 months and are widely used in clinical practice [4]. Glycation occurs in virtually all proteins exposed to glucose, and the potential for glycation to cause complications has been espoused for more than a decade. The most convincing manifestation of glycation in tissues has been with regard to diabetic cheiropathy, including the development of thickened, stiff periarticular structures resulting in the prayer sign (inability to extend fully the