Effect of Rapid Normalization of Plasma Glucose Levels on Microvascular Dysfunction and Polyol Metabolism in Diabetic Rats

Effects of rapid normalization of plasma glucose levels (by insulin infused via Alzet pumps implanted intraperitoneally) on plasma insulin-like growth factor I (IGF-I) levels, granulation tissue polyol levels, and vascular permeation by ¹²⁵I-labeled albumin were examined in male Sprague-Dawley rats with streptozocin-induced (60–65 mg/kg) diabetes. Two days after implantation of pumps, plasma insulin levels were twice normal levels and remained elevated (1.4–2.5 times normal) throughout the remainder of the study. Plasma glucose levels and granulation tissue polyol levels were normalized within 2 days after initiation of insulin treatment. Plasma IGF-I levels were significantly increased (2 times) by 2 days, but were not normalized until 7 days. In contrast, ¹²⁵I-albumin permeation normalized at a much slower relatively linear rate and was still not completely normal after 14 days of insulin treatment. In view of 1) previous studies demonstrating that diabetes-induced increases in ¹²⁵I-albumin permeation in this tissue are linked to increased metabolism of glucose to sorbitol and 2) the rapid normalization of tissue polyol levels in this study, the relatively linear rate of normalization of vascular permeability over 14 days in these studies suggests that impaired vascular barrier functional integrity in this model is mediated by structural and/or functional vascular alterations associated with sustained increased polyol metabolism rather than by increased polyol levels per se and/or by readily reversible functional and metabolic alterations associated with acute increases in polyol metabolism. The relatively long lag time after normalization of plasma glucose and tissue polyol levels before near normalization of vascular permeability in this model isconsistent with corresponding observations on the relationship between improved glycemic control and normalization of microangiopathy and neuropathy in diabetic humans and animals. The slow relatively linear rate of normalization of vascular permeability after normalization of plasma insulin and glucose levels and tissue polyol levels suggests that normalization of impaired vascular barrier function in this model is accomplished by a repair process (probably involving turnover of altered vascular constituents), the precise nature of which remains to be elucidated.