In non-insulin-dependent diabetes mellitus (NIDDM), both liver and peripheral tissues are resistant to insulin, but the relative severity and contribution of these abnormalities to fasting hyperglycemia are poorly understood. We, therefore, determined the dose-response characteristics for insulin-mediated suppression of hepatic glucose production (GP) and stimulation of peripheral glucose uptake (GU) in 14 NIDDM subjects and 14 age- and weight-matched nondiabetic volunteers (NV) using the glucose clamp sequential insulin infusion technique along with isotopic estimation of glucose flux. Postabsorptive rates of both GP (94 ± 7 v 72 ± 2 mg/M2/min in NV, P < .01) and GU (88 ± 5 v 72 ± 2 in NV, P < .01) were significantly increased in NIDDM subjects. The ED50 (half-maximally effective plasma insulin concentration) in NIDDM subjects for suppression of GP (64 ± 14 μU/mL) and stimulation of GU (118 ± 20 μU/mL were both increased more than twofold above normal (26 ± 2 and 58 ± 5 μU/mL, respectively, both P < .01) and were significantly correlated with one another (r = .68, P < .01). Although GP could be totally suppressed in the NIDDM subjects, their maximal GU was reduced 30% (287 ± 20 v 372 ± 15 mg/m2/min in NV, P < .01). Nevertheless, at all physiologically relevant plasma insulin concentrations studied, there was comparable impairment in GP and GU responses. Moreover, fasting plasma glucose concentrations in NIDDM subjects were highly correlated with their increased basal rates of GP (r = .81, P < .005) but not with their reduced GU. We conclude that hepatic and peripheral tissues are equally resistant to insulin in NIDDM. Because insulin exerts an appreciable suppressive effect on hepatic GP in the postabsorptive state when only 20% to 30% of GU is insulin-mediated, our findings suggest that hepatic, rather than peripheral, insulin resistance is the major factor responsible for fasting hyperglycemia in this disorder.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism