Prolonged sulfonylurea administration decreases insulin resistance and increases insulin secretion in non-insulin-dependent diabetes mellitus: evidence for improved insulin action at a postreceptor site in hepatic as well as extrahepatic tissues.
To determine whether long-term sulfonylurea therapy ameliorates glucose homeostasis in patients with NIDDM predominantly by improving insulin secretion or by improving insulin action, we evaluated changes in fasting plasma glucose concentrations, intravenous glucose tolerance, glucose-stimulated insulin secretion, facilitation of glucose disposal by exogenous insulin, and erythrocyte insulin receptor binding before and after prolonged (congruent to 4 mo) administration of tolazamide to 18 patients with NIDDM. Before tolazamide administration, 15 patients had decreased insulin secretion (50 +/- 31 vs 577 +/- 176 microU/ml X 10 min in nondiabetic subjects, P less than 0.05) and insulin resistance (Km 166 +/- 31 vs 58 +/- 3 microU/ml in nondiabetic subjects, P less than 0.05; Vmax 7.3 +/- 0.6 vs 9.8 +/- 0.2 mg/kg/min in nondiabetic subjects, P less than 0.05), whereas the other three patients had comparably impaired insulin secretion (56 +/- 52 microU/ml X min) but were not insulin resistant (Km 70 +/- 6 microU/ml; Vmax 10.8 +/- 0.6 mg/kg/min). The insulin-resistant patients had fasting hyperinsulinemia (19 +/- 4 vs 11 +/- 1 microU/ml in nondiabetic subjects, P less than 0.05), decreased erythrocyte insulin receptor binding (4.8 +/- 0.4 vs 5.8 +/- 0.3%/1.6 X 10(9) cells in nondiabetic subjects, P less than 0.05), and impairment in both insulin-induced suppression of glucose production (Km 97 +/- 31 vs 21 +/- 7 microU/ml in nondiabetic subjects, P less than 0.05), and insulin-induced stimulation of glucose utilization (Km and Vmax 176 +/- 29 microU/ml and 5.8 +/- 0.7 mg/kg/min vs 50 +/- 2 microU/ml and 9.1 +/- 0.6 mg/kg/min in nondiabetic subjects, both P less than 0.05). The nonresistant patients were not hyperinsulinemic (12 +/- micU/ml), had normal insulin receptor binding (5.9 +/- 0.5%/1.6 X 10(9) cells), and were less hyperglycemic than the insulin-resistant patients (128 +/- 11 vs 181 +/- 12 mg/dl, P less than 0.05). After tolazamide administration, both the early phase of glucose-induced insulin secretion (56 +/- 52 vs 141 +/- 68 microU/ml . 10 min) and insulin binding (5.9 +/- 0.5 vs 7.0 +/- 0.5%/1.6 X 10(9) cells) increased in all three nonresistant patients, but there was no consistent improvement in fasting hyperglycemia (128 +/- 11 vs 130 +/- 24 mg/dl), intravenous glucose tolerance (Kivgtt 0.77 +/- 0.18 vs 0.89 +/- 0.29%/min), or facilitation of glucose disposal by insulin (Km 70 +/- 5 vs 64 +/- 5 microU/ml; Vmax 10.8 +/- 0.6 vs 10.1 +/- 0.2 mg/kg/min).(ABSTRACT TRUNCATED AT 400 WORDS)
D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011972:Receptor, Insulin / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014042:Tolazamide / Q000494:pharmacology
D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D014042:Tolazamide; D011972:Receptor, Insulin; D005947:Glucose