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

L. J. Mandarino, J. E. Gerich

    Research output: Contribution to journalArticle

    48 Scopus citations

    Abstract

    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 (≃4 mo) administration of tolazamide to 18 patients with NIDDM. Before tolazamide administration, 15 patients had decreased insulin secretion (50 ± 31 vs 577 ± 176 μU/ml.10 min in nondiabetic subjects, P < 0.05) and insulin resistance (Km 166 ± 31 vs 58 ± 3 μU/ml in nondiabetic subjects, P < 0.05; V(max) 7.3 ± 0.6 vs 9.8 ± 0.2 mg/kg/min in nondiabetic subjects, P < 0.05), whereas the other three patients had comparably impaired insulin secretion (56 ± 52 μU/ml.min) but were not insulin resistant (Km 70 ± 6 μU/ml; V(max) 10.8 ± 0.6 mg/kg/min). The insulin-resistant patients had fasting hyperinsulinemia (19 ± 4 vs 11 ± 1 μU/ml in nondiabetic subjects, P < 0.05), decreased erythrocyte insulin receptor binding (4.8 ± 0.4 vs 5.8 ± 0.3%/1.6 x 109 cells in nondiabetic subjects, P < 0.05), and impairment in both insulin-induced suppression of glucose production (Km 97 ± 31 vs 21 ± 7 μU/ml in nondiabetic subjects, P < 0.05), and insulin-induced stimulation of glucose utilization (Km and V(max) 176 ± 29 μU/ml and 5.8 ± 0.7 mg/kg/min vs 50 ± 2 μU/ml and 9.1 ± 0.6 mg/kg/min in nondiabetic subjects, both P < 0.05). The nonresistant patients were not hyperinsulinemic (12 ± 2 μU/ml), had normal insulin receptor binding (5.9 ± 0.5%/1.6 x 109 cells), and were less hyperglycemic than the insulin-resistant patients (128 ± 11 vs 181 ± 12 mg/dl, P < 0.05). After tolazamide administration, both the early phase of glucose-induced insulin secretion (56 ± 52 vs 141 ± 68 μU/ml.10 min) and insulin binding (5.9 ± 0.5 vs 7.0 ± 0.5%/1.6 x 109 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 μU/ml; V(max) 10.8 ± 0.6 vs 10.1 ± 0.2 mg/kg/min). In contrast, in the insulin-resistant patients, after tolazamide administration fasting hyperglycemia decreased (181 ± 12 vs 135 ± 9 mg/dl, P < 0.05), insulin secretion increased (50 ± 31 vs 106 ± 26 μU/ml.min), and both intravenous glucose tolerance (Kivgtt 0.46 ± 0.05 vs 0.63 ± 0.06%/min, P < 0.05) and facilitation of glucose disposal by insulin improved (V(max) 7.3 ± 0.6 vs 8.3 ± 0.4 mg/kg/min, P < 0.05); the latter was due to improvement in both insulin-induced suppression of glucose production (Km 176 ± 29 vs 50 ± 2 μU/ml, P < 0.05) and insulin-induced stimulation of glucose utilization (V(max) 5.8 ± 0.7 vs 7.5 ± 0.6 mg/kg/min, P < 0.05), which could not be wholly accounted for by the small increase in insulin receptor binding (4.8 ± 0.4 vs 5.1 ± 3%/1.6 x 109 cells, P < 0.05). Our results indicate that NIDDM is a heterogeneous disorder characterized by impaired insulin secretion that is usually but not invariably accompanied by insulin resistance in both hepatic and extrahepatic tissues. Prolonged administration of the sulfonylurea tolazamide to patients with NIDDM increases insulin secretion and decreases insulin resistance in both hepatic and extrahepatic tissues. The latter appears to be the major mechanism by which prolonged sulfonylurea administration improves glucose homeostasis in patients with insulin resistance, and this effect occurs predominantly at a postbinding site.

    Original languageEnglish (US)
    Pages (from-to)89-99
    Number of pages11
    JournalDiabetes Care
    Volume7
    Issue numberSUPPL. 1
    StatePublished - Jan 1 1984

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism
    • Advanced and Specialized Nursing

    Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this