Tissue sensitivity to insulin (euglycemia insulin clamp technique) in normal weight maturity onset diabetics is significantly reduced (by 30%; p less than 0.01) compared to controls. The decrease in glucose metabolism is highly correlated to the decrease in insulin binding to monocytes (r equals 0.88; p less than 0.001). Hyperglycemia in the diabetic subjects serves as a compensatory mechanism to enhance insulin-mediated glucose uptake. Tissue sensitivity to insulin following chronic metabolic acidosis is significantly reduced (p less 0.01) both when measured at basal levels (euglycemic insulin clamp) and hyperglycemic levels (hyperglycemic clamp). The beta cell response to this peripheral insulin antagonism is to enhance insulin secretion (p less than 0.01) in an attempt to normalize glucose metabolism. Hyperglycemia and hyperinsulinemia induced by the intravenous infusion of insulin cause only a small uptake of glucose by the splanchnic bed (0.5 plus or minus 0.2 and 1.0 plus or minus 0.2 mg/kg min respectively). In contrast, oral glucose markedly increased splanchnic glucose uptake to 5.9 plus or minus 0.2 mg/kg min (p less than 0.001). These findings suggest that orally consumed glucose causes the release of a gastronintestinal factor that enhances insulin-mediated glucose uptake by the liver.