Characteristics of non-insulin-dependent diabetic patients with secondary failure to oral antidiabetic therapy

Purpose Secondary failure to treatment with oral antidiabetic agents frequently occurs in patients with non-insulin-dependent diabetes mellitus. In the search for causes of such failures, we examined patient- and disease-related factors in nonresponders and in responders to treatment with oral antidiabetic agents. Patients and Methods The study population consisted of three groups: (1) 34 nonresponders to treatment with sulfonylureas; (2) 25 patients who still responded to treatment with sulfonylureas; and (3) 10 age-matched healthy control subjects. In addition to patient-related factors such as adherence to diet and knowledge of diabetes, we examined insulin response to a test meal and hepatic and peripheral insulin sensitivity during a euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3-]glucose. Results Patient-related factors such as daily nutrient intake, activity score, knowledge of diabetes, and “stress level” were similar in both groups. However, nonresponders had a higher rate of basal hepatic glucose production (4.60 ± 0.14 versus 3.63 ± 0.26 mg/minute/kg of lean body weight; p < 0.001), which was less suppressed by euglycemic hyperinsulinemia (about 100 μU/mL) than was that of the responders (p < 0.001). In addition, total insulin-stimulated glucose metabolism was reduced (5.07 ± 0.22 versus 7.09 ± 0.56 mg/kg·LBM·minute; p < 0.001), and this was mainly accounted for by a reduction in non-oxidative glucose metabolism (glycogen synthesis and anaerobic glycolysis) (1.78 ±0.22 versus 3.54 ± 0.49 mg/kg·LBM·minute; p < 0.001). The severity of hepatic and peripheral insulin resistance correlated with the plasma glucose concentration but was unrelated to insulin secretion. In a multiple linear regression analysis, glucose overproduction in the liver (26.1% ), impaired peripheral glucose metabolism (17.3%), and insulin deficiency (12.6%) could explain only 56% of the causes of secondary drug failure. Conclusions Secondary failure to treatment with oral hypoglycemic agents is determined by the disease itself rather than by patient-related factors. Treatment of secondary drug failure should therefore aim at ameliorating both hepatic and peripheral insulin resistance. Secondary failure to treatment with oral antidiabetic agents frequently occurs in patients with non-insulin-dependent diabetes mellitus. In the search for causes of such failures, we examined patient- and disease-related factors in nonresponders and in responders to treatment with oral antidiabetic agents. The study population consisted of three groups: (1) 34 nonresponders to treatment with sulfonylureas; (2) 25 patients who still responded to treatment with sulfonylureas; and (3) 10 age-matched healthy control subjects. In addition to patient-related factors such as adherence to diet and knowledge of diabetes, we examined insulin response to a test meal and hepatic and peripheral insulin sensitivity during a euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3-]glucose. Patient-related factors such as daily nutrient intake, activity score, knowledge of diabetes, and “stress level” were similar in both groups. However, nonresponders had a higher rate of basal hepatic glucose production (4.60 ± 0.14 versus 3.63 ± 0.26 mg/minute/kg of lean body weight; p < 0.001), which was less suppressed by euglycemic hyperinsulinemia (about 100 μU/mL) than was that of the responders (p < 0.001). In addition, total insulin-stimulated glucose metabolism was reduced (5.07 ± 0.22 versus 7.09 ± 0.56 mg/kg·LBM·minute; p < 0.001), and this was mainly accounted for by a reduction in non-oxidative glucose metabolism (glycogen synthesis and anaerobic glycolysis) (1.78 ±0.22 versus 3.54 ± 0.49 mg/kg·LBM·minute; p < 0.001). The severity of hepatic and peripheral insulin resistance correlated with the plasma glucose concentration but was unrelated to insulin secretion. In a multiple linear regression analysis, glucose overproduction in the liver (26.1% ), impaired peripheral glucose metabolism (17.3%), and insulin deficiency (12.6%) could explain only 56% of the causes of secondary drug failure. Secondary failure to treatment with oral hypoglycemic agents is determined by the disease itself rather than by patient-related factors. Treatment of secondary drug failure should therefore aim at ameliorating both hepatic and peripheral insulin resistance.