Staehr P, Hother-Nielsen O, Levin K, Holst J J, Beck-Nielsen H
Diabetes Research Centre, Medical Department M, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark.
Diabetes. 2001 Jun;50(6):1363-70. doi: 10.2337/diabetes.50.6.1363.
Defects in hepatic insulin action in type 2 diabetes and its possible underlying mechanisms were assessed in euglycemic-hyperinsulinemic clamp studies, using improved tracer methods (constant specific activity technique). Ten obese diabetic patients (age 54 years, BMI 29 +/- 0.5 kg/m(2)) and ten matched control subjects were studied at baseline (after an overnight fast) and during insulin infusions of 20- and 40-mU. m(-2). min(-1). In the diabetic patients, plasma glucose levels were normalized overnight before the studies by low-dose insulin infusion. Hepatic sinusoidal insulin levels were estimated, and plasma levels of free fatty acids (FFAs) and glucagon were determined to assess the direct and indirect effects of insulin on hepatic glucose production (HGP) in type 2 diabetes. Baseline rates of HGP (86 +/- 3 vs. 76 +/- 3 mg. m(-2). min(-1), P < 0.05) were slightly elevated in the diabetic patients compared with control subjects, despite much higher hepatic sinusoidal insulin levels (26 +/- 3 vs. 12 +/- 2 mU/l, P < 0.001). Consequently, a marked defect in the direct (hepatic) effect of insulin on HGP appeared to be present at low insulin levels. However, in response to a small increase in baseline hepatic sinusoidal insulin levels of 11 mU/l (26 +/- 3 to 37 +/- 3 mU/l, P < 0.05) in the 20-mU clamp, a marked suppression of HGP was observed in the diabetic patients (86 +/- 3 to 32 +/- 5 mg. m(-2). min(-1), P < 0.001), despite only minimal changes in FFAs (0.33 +/- 0.05 to 0.25 +/- 0.05 mmol/l, NS) and glucagon (14 +/- 1 to 11 +/- 2 pmol/l, P < 0.05) levels, suggesting that the impairment in the direct effect of insulin can be overcome by a small increase in insulin levels. Compared with control subjects, suppression of HGP in the diabetic patients was slightly impaired in the 20-mU clamp (32 +/- 5 vs. 22 +/- 4 mg. m(-2). min(-1), P < 0.05) but not in the 40-mU clamp (25 +/- 2 vs. 21 +/- 3 mg. m(-2). min(-1), NS). In the 20-mU clamp, hepatic sinusoidal insulin levels in the diabetic patients were comparable with control subjects (37 +/- 3 vs. 36 +/- 3 mU/l, NS), whereas both FFA and glucagon levels were higher (i.e., less suppressed) and correlated with the rates of HGP (R = 0.71, P < 0.02; and R = 0.69, P < 0.05, respectively). Thus, at this insulin level impaired indirect (extrahepatic) effects of insulin seemed to prevail. In conclusion, hepatic insulin resistance is present in obese type 2 diabetic patients but is of quantitative significance only at low physiological insulin levels. Defects in both the direct and the indirect effects of insulin on HGP appear to contribute to this resistance.
采用改进的示踪方法（恒定比活度技术），在正常血糖 - 高胰岛素钳夹试验中评估2型糖尿病患者肝脏胰岛素作用缺陷及其可能的潜在机制。研究了10名肥胖糖尿病患者（年龄54岁，体重指数29±0.5kg/m²）和10名匹配的对照受试者，分别在基线期（过夜禁食后）以及胰岛素输注速率为20和40mU·m⁻²·min⁻¹时进行研究。在糖尿病患者中，研究前通过低剂量胰岛素输注使血浆葡萄糖水平在夜间恢复正常。估计肝窦胰岛素水平，并测定血浆游离脂肪酸（FFA）和胰高血糖素水平，以评估胰岛素对2型糖尿病患者肝脏葡萄糖生成（HGP）的直接和间接影响。与对照受试者相比，糖尿病患者的HGP基线速率（86±3 vs. 76±3mg·m⁻²·min⁻¹，P<0.05）略有升高，尽管肝窦胰岛素水平要高得多（26±3 vs. 12±2mU/L，P<0.001）。因此，在低胰岛素水平时，胰岛素对HGP的直接（肝脏）作用似乎存在明显缺陷。然而，在20mU钳夹试验中，糖尿病患者肝窦胰岛素水平在基线基础上小幅升高11mU/L（从26±3升至37±3mU/L，P<0.05）时，观察到HGP明显受到抑制（从86±3降至32±5mg·m⁻²·min⁻¹，P<0.001），尽管FFA（从0.33±0.05降至0.25±0.05mmol/L，无显著性差异）和胰高血糖素水平（从14±1降至11±2pmol/L，P<0.05）仅有微小变化，这表明胰岛素直接作用的损害可通过胰岛素水平的小幅升高得以克服。与对照受试者相比，糖尿病患者在20mU钳夹试验中对HGP的抑制略有受损（32±5 vs. 22±4mg·m⁻²·min⁻¹，P<0.05），但在40mU钳夹试验中未受损（25±2 vs. 21±3mg·m⁻²·min⁻¹，无显著性差异）。在20mU钳夹试验中，糖尿病患者的肝窦胰岛素水平与对照受试者相当（37±3 vs. 36±3mU/L，无显著性差异），而FFA和胰高血糖素水平均较高（即抑制程度较低），且与HGP速率相关（分别为R =
