Hepatic insulin action in adolescents with insulin-dependent diabetes mellitus: relationship with long-term glycemic control.

Abstract The relationship between hepatic insulin action and long-term glycemic control was assessed in 20 adolescents with insulin-dependent diabetes mellitus (IDDM) and five healthy matched controls using a two-step (0.8 and 1.6 mU/kg/min) hyperinsulinemic-euglycemic clamp and [6,6- 2 H 2 ]glucose. The night before the study, diabetic patients received variable-rate intravenous insulin in an attempt to normalize fasting plasma glucose concentrations. In the postabsorptive state, hepatic glucose production (HGP) was similar in IDDM patients and controls (593 ± 40 v 518 ± 27 μmol/m 2 /min); however, plasma glucose and free insulin concentrations were higher in IDDM patients than in controls (6.5 ± 0.4 v 5.4 ± 0.1 mmol/L [ P = .01], and 207 ± 21 v 104 ± 10 pmol/L [ P r = .62 P = .002) between basal HGP and glucohemoglobin level (HbA 1 ). Separation of the patients at the median HbA 1 (group no. 1 11.4% HbA 1 ) revealed two distinct patient populations with regard to hepatic and peripheral insulin action and plasma free fatty acid (FFA) suppression. During hyperinsulinemia, the percent suppression of HGP was lower in group no. 2 compared with group no. 1 (65.7% ± 9.8% v 94.4% ± 3.8%; P = .018). Rates of glucose disposal were lower in group no. 2 compared with controls and with group no. 1. Postabsorptive FFA levels were similar between group no. 2 and group no. 1 (0.45 ± 0.03 and 0.43 ± 0.04 mmol/L) despite higher free-insulin concentrations in group no. 2 (260 ± 30 v 171 ± 25 pmol/L; P = .04). Hyperinsulinemia in group no. 2 did not produce a significant decrease in FFA levels, unlike group no. 1 and controls. Group no. 2 patients compared with group no. 1 patients had higher basal growth hormone (GH) levels (8.5 ± 1.6 v 3.0 ± 0.9 μg/L; P = .008). We conclude that (1) poorly controlled adolescents with IDDM have significant degrees of hepatic insulin resistance, (2) insulin action in suppressing FFA levels in impaired in these adolescents, and (3) long-term glycemic/metabolic control adversely affects hepatic insulin action, possibly through elevated GH levels.