Microvascular metabolism in diabetes

Hyperglycemia has been implicated in the development of retinal vascular disease. Consequently, the effects of excessive hexose concentration on cells of the vascular wall are receiving increasing attention. Techniques for isolating metabolically active microvessels from tissues such as those from the retina and cerebral cortex are providing new opportunities for the study of the uptake and metabolism of hexose by microvessels. Such studies indicate that hexose uptake by microvessels is not insulin dependent and that microvessels are capable of metabolizing hexose by pathways common to many diverse tissues, including anaerobic and aerobic glycolysis, pentose phosphate shunt, and glycogenogenesis. Microvessels isolated from diabetic animals metabolize glucose at a subnormal rate. Hexitol production and accumulation has been implicated in the pathogenesis of diabetic complications in a variety of tissues and might also play a role in the development of diabetic microvascular disease. We have quantitated hexitol-producing metabolic activity of retinal and cerebral microvessels isolated from dogs, a species known to develop a retinopathy similar to that seen in diabetic patients. Erythrocytes were removed by perfusion prior to microvessel isolation because they are known to have hexitol-producing activity. Both retinal and cerebral microvessels produce galactitol from galactose, and this activity is inhibited in the presence of the aldose reductase inhibitor sorbinil. The presence of hexitol-producing activity within microvessels is consistent with a possible role of polyol production in the etiology of diabetic microvascular disease. Nevertheless, it is not even clear that the primary defect leading to vascular disease in diabetes resides in the vasculature itself; nonvascular cells such as erythrocytes, platelets, and glial cells have been postulated to play a role in the development of the vascular lesions. The steps linking diabetic retinopathy to hyperglycemia await clarification.