Henriksen J E, Levin K, Thye-Rønn P, Alford F, Hother-Nielsen O, Holst J J, Beck-Nielsen H
Diabetes Research Centre, Department of Endocrinology M, Odense University Hospital, Denmark.
Diabetes. 2000 Jul;49(7):1209-18. doi: 10.2337/diabetes.49.7.1209.
With the aim of investigating glucose-mediated glucose disposal (glucose effectiveness [GE]) in 15 (3 female and 12 male subjects) insulin-resistant normoglycemic relatives of patients with type 2 diabetes (DM2), and 15 age-, sex-, and BMI-matched control subjects without a family history of DM2, we performed 2 studies: 1) a 5-h euglycemic near-normoinsulinemic pancreatic clamp with somatostatin (360 microg/h), insulin (0.25 mU x kg(-1) x min(-1)), glucagon (0.5 ng x kg(-1) x min(-1)), growth hormone (6 ng x kg(-1) x min(-1)), and tritiated glucose infusion and indirect calorimetry; and 2) on a separate day, an identical 5-h clamp but at hyperglycemia (approximately 12 mmol/l) over the last 2 h. Fasting plasma insulin (PI) concentrations were elevated in the relatives compared with control subjects (49 +/- 6 vs. 32 +/- 5 pmol/l, P < 0.04), whereas plasma glucose (PG) was not (5.6 +/- 0.1 vs. 5.5 +/-0.1 mmol/l). At the end (i.e., 4.5-5.0 h) of the euglycemic clamp (PG, 6.1 +/- 0.4 vs. 5.6 +/- 0.1 mmol/l; PI, 78 +/- 5 vs. 73 +/-6 pmol/l), peripheral glucose uptake (Rd(euglycemia)) was decreased in the relatives (2.93 +/- 0.08 vs. 3.70 +/-0.23 mg x min(-1) x kg(-1) fat free mass [FFM], P < 0.005), due to a decreased nonoxidative glucose disposal (0.83 +/-0.21 vs. 1.62 +/- 0.19 mg x min(-1) x kg(-1) FFM, P < 0.01), but hepatic glucose production (HGP) was increased (1.97 +/-0.19 vs. 1.50 +/- 0.13 mg x min(-1) x kg(-1) FFM, P < 0.05). At the matched end of the hyperglycemic clamp (PG, 12.7 +/-0.2 vs. 12.6 +/- 0.2 mmol/l; PI, 87 +/- 5 vs. 78 +/- 7 pmol/l), peripheral glucose disposal (Rd(hyperglycemia)) (5.52 +/- 0.22 vs. 5.92 +/- 0.29 mg x min(-1) x kg(-1) FFM, NS), nonoxidative glucose disposal (2.93 +/- 0.18 vs. 2.78 +/- 0.25 mg x min(-1) x kg(-1) FFM, NS), and HGP(hyperglycemia) (1.20 +/- 0.09 vs. 1.37 +/-0.23 mg x min(-1) x kg(-1) FFM, NS) were all identical. When the effectiveness of glucose itself on glucose uptake and production [(Rd(hyperglycemia) - Rd(euglycemia))/deltaPG and (HGP(euglycemia)- HGP(hyperglycemia))/deltaPG] was calculated, the relatives had a 22% increase in peripheral uptake (0.022 +/- 0.002 vs. 0.018 +/- 0.002 mg x min(-1) x kg(-1) FFM per mg/dl), due to a significantly increased nonoxidative glucose metabolism and enhanced suppression of HGP (0.0076 +/- 0.0021 vs. 0.0011 +/- 0.0022 mg x min(-1) x kg(-1) FFM per mg/dl, P < 0.05). In conclusion, in insulin-resistant relatives of DM2 patients, whole-body glucose-mediated glucose disposal is increased by GE enhancement of the muscle nonoxidative glucose pathway and by GE enhancement of the suppression of HGP. These mechanisms may represent a compensatory mechanism to the ongoing insulin resistance of these relatives.
为了研究15名（3名女性和12名男性受试者）2型糖尿病（DM2）患者的胰岛素抵抗正常血糖亲属以及15名年龄、性别和BMI相匹配且无DM2家族史的对照受试者中葡萄糖介导的葡萄糖处置（葡萄糖效能[GE]），我们进行了两项研究：1）一项为期5小时的正常血糖、接近正常胰岛素水平的胰腺钳夹试验，使用生长抑素（360微克/小时）、胰岛素（0.25微单位·千克⁻¹·分钟⁻¹）、胰高血糖素（0.5纳克·千克⁻¹·分钟⁻¹）、生长激素（6纳克·千克⁻¹·分钟⁻¹），并进行氚标记葡萄糖输注和间接测热法；2）在另一天，进行相同的5小时钳夹试验，但在最后2小时处于高血糖状态（约12毫摩尔/升）。与对照受试者相比，亲属的空腹血浆胰岛素（PI）浓度升高（49±6对32±5皮摩尔/升，P<0.04），而血浆葡萄糖（PG）浓度无差异（5.6±0.1对5.5±0.1毫摩尔/升）。在正常血糖钳夹试验结束时（即4.5 - 5.0小时）（PG，6.1±0.4对5.6±0.1毫摩尔/升；PI，78±5对73±6皮摩尔/升），亲属的外周葡萄糖摄取（Rd（正常血糖））降低（2.93±0.08对3.70±0.23毫克·分钟⁻¹·千克⁻¹去脂体重[FFM]，P<0.005），原因是非氧化葡萄糖处置减少（0.83±0.21对1.62±0.19毫克·分钟⁻¹·千克⁻¹FFM，P<0.0]），但肝脏葡萄糖生成（HGP）增加（1.97±0.19对1.50±0.13毫克·分钟⁻¹·千克⁻¹FFM，P<0.05）。在高血糖钳夹试验的匹配结束时（PG，12.7±0.2对12.6±0.2毫摩尔/升；PI，87±5对78±7皮摩尔/升），外周葡萄糖处置（Rd（高血糖））（5.52±0.22对5.92±0.29毫克·分钟⁻¹·千克⁻¹FFM，无显著性差异）、非氧化葡萄糖处置（2.93±0.18对2.78±0.25毫克·分钟⁻¹·千克⁻¹FFM，无显著性差异）和HGP（高血糖）（1.20±0.09对1.37±0.23毫克·分钟⁻¹·千克⁻¹FFM，无显著性差异）均无差异。当计算葡萄糖本身对葡萄糖摄取和生成的效能[（Rd（高血糖） - Rd（正常血糖））/ΔPG和（HGP（正常血糖） - HGP（高血糖））/ΔPG]时，亲属的外周摄取增加了22%（0.022±0.002对0.018±0.002毫克·分钟⁻¹·千克⁻¹FFM每毫克/分升），这是由于非氧化葡萄糖代谢显著增加以及对HGP的抑制增强（0.0076±0.0021对0.0011±0.0022毫克·分钟⁻¹·千克⁻¹FFM每毫克/分升，P<0.05）。总之，在DM2患者的胰岛素抵抗亲属中，全身葡萄糖介导的葡萄糖处置通过肌肉非氧化葡萄糖途径的GE增强以及对HGP抑制的GE增强而增加。这些机制可能代表了这些亲属对持续存在的胰岛素抵抗的一种代偿机制。
