Pendergrass Merri, Bertoldo Alessandra, Bonadonna Riccardo, Nucci Gianluca, Mandarino Lawrence, Cobelli Claudio, Defronzo Ralph A
Univ. of Texas Health Science Center, Diabetes Division, 703 Floyd Curl Dr., San Antonio, TX 78229, USA.
Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E92-100. doi: 10.1152/ajpendo.00617.2005. Epub 2006 Aug 8.
Our objectives were to quantitate insulin-stimulated inward glucose transport and glucose phosphorylation in forearm muscle in lean and obese nondiabetic subjects, in lean and obese type 2 diabetic (T2DM) subjects, and in normal glucose-tolerant, insulin-resistant offspring of two T2DM parents. Subjects received a euglycemic insulin (40 mU.m(-2).min(-1)) clamp with brachial artery/deep forearm vein catheterization. After 120 min of hyperinsulinemia, a bolus of d-mannitol/3-O-methyl-d-[(14)C]glucose/d-[3-(3)H]glucose (triple-tracer technique) was given into brachial artery and deep vein samples obtained every 12-30 s for 15 min. Insulin-stimulated forearm glucose uptake (FGU) and whole body glucose metabolism (M) were reduced by 40-50% in obese nondiabetic, lean T2DM, and obese T2DM subjects (all P < 0.01); in offspring, the reduction in FGU and M was approximately 30% (P < 0.05). Inward glucose transport and glucose phosphorylation were decreased by approximately 40-50% (P < 0.01) in obese nondiabetic and T2DM groups and closely paralleled the decrease in FGU. The intracellular glucose concentration in the space accessible to glucose was significantly greater in obese nondiabetic, lean T2DM, obese T2DM, and offspring compared with lean controls. We conclude that 1) obese nondiabetic, lean T2DM, and offspring manifest moderate-to-severe muscle insulin resistance (FGU and M) and decreased insulin-stimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus T2DM; and 2) the increase in intracelullar glucose concentration under hyperinsulinemic euglycemic conditions in obese and T2DM groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport.
我们的目标是对非糖尿病的瘦人和肥胖者、2型糖尿病（T2DM）的瘦人和肥胖者以及有两个T2DM父母的糖耐量正常但胰岛素抵抗的后代的前臂肌肉中胰岛素刺激的葡萄糖内向转运和葡萄糖磷酸化进行定量。受试者接受了通过肱动脉/前臂深静脉插管的正常血糖胰岛素（40 mU·m⁻²·min⁻¹）钳夹试验。在高胰岛素血症120分钟后，向肱动脉注射一剂d-甘露醇/3-O-甲基-d-[(¹⁴)C]葡萄糖/d-[3-(³)H]葡萄糖（三重示踪技术），并在15分钟内每隔12 - 30秒采集一次前臂深静脉样本。在非糖尿病肥胖者、瘦的T2DM患者和肥胖的T2DM患者中，胰岛素刺激的前臂葡萄糖摄取（FGU）和全身葡萄糖代谢（M）降低了40 - 50%（所有P < 0.01）；在后代中，FGU和M的降低约为30%（P < 0.05）。在非糖尿病肥胖组和T2DM组中，葡萄糖内向转运和葡萄糖磷酸化降低了约40 - 50%（P < 0.01），且与FGU的降低密切平行。与瘦对照组相比，非糖尿病肥胖者、瘦的T2DM患者、肥胖的T2DM患者及后代中葡萄糖可进入空间内的细胞内葡萄糖浓度显著更高。我们得出结论：1）非糖尿病肥胖者、瘦的T2DM患者及后代表现出中度至重度的肌肉胰岛素抵抗（FGU和M），且前臂肌肉中胰岛素刺激的葡萄糖转运和葡萄糖磷酸化降低；肥胖加T2DM并未进一步加重这些胰岛素作用缺陷；2）在高胰岛素血症正常血糖条件下，肥胖组和T2DM组细胞内葡萄糖浓度升高表明葡萄糖磷酸化缺陷超过葡萄糖转运缺陷。
