Requirement for Intracellular Hyperglycemia

Clinical and animal model data indicate that chronic hyperglycemia is the central initiating factor for all types of diabetic microvascular disease. Duration and magnitude of hyperglycemia are both strongly correlated with the extent and rate of progression of diabetic microvascular disease. In the Diabetes Control and Complications Trial (DCCT), for example, type 1 diabetic patients whose intensive insulin therapy resulted in HbA1c levels 2% lower than those receiving conventional insulin therapy had a 76% lower incidence of retinopathy, a 54% lower incidence of nephropathy, and a 60% reduction in neuropathy (3). Similarly, several studies have shown that glycohemoglobin A1 is an independent risk factor for cardiovascular disease (6,7) in type 1 diabetes. Intimal-medial thickness (IMT) of the carotid artery, which is strongly correlated with coronary heart disease (CHD), was demonstrated to be increased in type 1 diabetes (8,9).

Although all cells in a person with diabetes are exposed to elevated levels of plasma glucose, hyperglycemic damage is limited to those cell types, such as endothelial cells, that develop intracellular hyperglycemia. Endothelial cells develop intracellular hyper-glycemia because, unlike most other cells, they are unable to downregulate glucose transport when exposed to extracellular hyperglycemia. As illustrated in Fig. 1, vascular smooth muscle cells, which are not damaged by hyperglycemia, show an inverse relationship between extracellular glucose concentration and subsequent rate of glucose transport measured as 2-deoxyglucose uptake (Fig. 1A). In contrast, vascular endothelial cells show no significant change in subsequent rate of glucose transport after exposure to elevated glucose concentrations (Fig. 1B) (10). That intracellular hyperglycemia is necessary and sufficient for the development of diabetic pathology is demonstrated by the fact that overexpression of the glucose transporter (GLUT)-1 glucose transporter in mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype, inducing the same increases in collagen type IV, collagen type I, and fibronectin gene expression as diabetic hyperglycemia (11).

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