Effects of combined insulin and sorbinil treatment on diabetes-induced vascular dysfunction in rats

These experiments were undertaken to assess the effects of combined treatment with insulin (designed to partially restore metabolic control) and sorbinil (an aldose reductase inhibitor [ARI]) versus the effects of sorbinil alone or of two insulin regimens providing different degrees of glycemic control on diabetes-induced metabolic derangements and vascular function. Streptozocin-diabetic rats were divided into the following five groups: (1) untreated (D); (2) treated with approximately 1 U NPH insulin/100 g body weight/d administered in one subcutaneous (SC) injection (DI-1); (3) treated with the same total daily dose of insulin administered in two SC injections (DI-2); (4) treated with approximately 0.2 mmol sorbinil in the diet/kg body weight/d (DS); and (5) treated with once-daily insulin plus sorbinil (DSI-1). Two groups of nondiabetic rats, untreated (C) and sorbinil-treated (CS), served as controls. Metabolic parameters were unaffected by sorbinil treatment in controls and diabetics, whereas insulin administration in the diabetics virtually normalized body growth, food consumption, urine volume, and plasma glucose levels, and markedly decreased hemoglobin A₁ (HbA₁) levels. Two daily injections were more effective than one in improving metabolic control as measured by HbA₁ levels. Regional vascular ¹³¹I-albumin permeation was increased about twofold to threefold by diabetes in ocular tissues, sciatic nerve, aorta, diaphragm, and new granulation tissue; it was decreased (but not normalized) by insulin treatment in accordance with improved metabolic control, and was completely normalized by sorbinil. ¹³¹I-albumin kidney clearance, as well as urinary albumin and IgG excretion, were markedly increased in diabetic rats and were significantly decreased but not completely normalized by sorbinil and by twice-daily insulin treatment. The combined therapy significantly ameliorated the effect of insulin alone (which still did not completely normalize glucose and HbA₁ levels despite prevention of diabetes-induced weight loss and polyuria), although it did not produce an effect on vascular function beyond that of sorbinil alone (which had no impact on glycemia, HbA₁ level, urine volume, or weight gain). These findings suggest that a dual pharmacologic approach, ie, treatment with a combination of insulin, designed to decrease glucose levels (without risking hypoglycemia), and ARIs, to block excess flux of glucose via the sorbitol pathway due to the residual hyperglycemia, may be advantageous for promoting normal growth and metabolism and for preventing vascular complications while minimizing the risk of increased incidence of hypoglycemia.