Gastaldelli Amalia, Miyazaki Yoshinori, Mahankali Archana, Berria Rachele, Pettiti Maura, Buzzigoli Emma, Ferrannini Eleuterio, DeFronzo Ralph A
Stable Isotope Lab, Institute of Clinical Physiology-CNR, via Moruzzi 1, 56100 Pisa, Italy.
Diabetes Care. 2006 Oct;29(10):2275-81. doi: 10.2337/dc05-2445.
Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on the liver is less clear. The goal of this study was to examine the effect of TZDs on GNG.
Twenty sulfonylurea-treated type 2 diabetic subjects were randomly assigned (double-blind study) to receive pioglitazone (PIO group; 45 mg/day) or placebo (Plc group) for 4 months to assess endogenous glucose production (EGP) (3-(3)H-glucose infusion), GNG (D2O technique), and insulin sensitivity by two-step hyperinsulinemic-euglycemic clamp (240 and 960 pmol/min per m2).
Fasting plasma glucose (FPG) (10.0 +/- 0.8 to 7.7 +/- 0.7 mmol/l) and HbA1c (9.0 +/- 0.4 to 7.3 +/- 0.6%) decreased in the PIO and increased in Plc group (P < 0.05 PIO vs. Plc). Insulin sensitivity increased approximately 40% during high insulin clamp after pioglitazone (P < 0.01) and remained unchanged in the Plc group (P < 0.05 PIO vs. Plc). EGP did not change, while GNG decreased in the PIO group (9.6 +/- 0.7 to 8.7 +/- 0.6 micromol x min(-1) x kg(ffm)(-1)) and increased in the Plc group (8.0 +/- 0.5 to 9.6 +/- 0.8) (P < 0.05 PIO vs. Plc). Change in FPG correlated with change in GNG flux (r = 0.63, P < 0.003) and in insulin sensitivity (r = 0.59, P < 0.01). Plasma adiponectin increased after pioglitazone (P < 0.001) and correlated with delta FPG (r = -0.54, P < 0.03), delta GNG flux (r = -0.47, P < 0.05), and delta insulin sensitivity (r = 0.65, P < 0.005). Plasma free fatty acids decreased after pioglitazone and correlated with delta GNG flux (r = 0.54, P < 0.02). From stepwise regression analysis, the strongest determinant of change in FPG was change in GNG flux.
Pioglitazone improves FPG, primarily by reducing GNG flux in type 2 diabetic subjects.
糖尿病高血糖症是由外周组织的胰岛素抵抗以及由于糖异生（GNG）增加导致的葡萄糖过度生成引起的。噻唑烷二酮类药物（TZDs）可改善外周胰岛素敏感性，但对肝脏的作用尚不清楚。本研究的目的是检验TZDs对GNG的影响。
20名接受磺脲类药物治疗的2型糖尿病受试者被随机分配（双盲研究）接受吡格列酮（PIO组；45毫克/天）或安慰剂（Plc组）治疗4个月，以通过两步高胰岛素正血糖钳夹法（每平方米240和960皮摩尔/分钟）评估内源性葡萄糖生成（EGP）（3-(3)H-葡萄糖输注）、GNG（重水技术）和胰岛素敏感性。
PIO组空腹血糖（FPG）（10.0±0.8至7.7±0.7毫摩尔/升）和糖化血红蛋白（HbA1c）（9.0±0.4至7.3±0.6%）下降，Plc组升高（PIO组与Plc组比较，P<0.05）。吡格列酮治疗后高胰岛素钳夹期间胰岛素敏感性增加约40%（P<0.01），Plc组保持不变（PIO组与Plc组比较，P<0.05）。EGP无变化，而PIO组GNG下降（9.6±0.7至8.7±0.6微摩尔·分钟(-1)·千克(去脂体重)(-1)），Plc组升高（8.0±0.5至9.6±0.8）（PIO组与Plc组比较，P<0.05）。FPG的变化与GNG通量的变化相关（r = 0.63，P<0.003）以及与胰岛素敏感性的变化相关（r = 0.59，P<0.01）。吡格列酮治疗后血浆脂联素升高（P<0.001），并与FPG变化量（r = -0.54，P<0.03）、GNG通量变化量（r = -0.47，P<0.05）和胰岛素敏感性变化量（r = 0.65，P<0.005）相关。吡格列酮治疗后血浆游离脂肪酸下降，并与GNG通量变化量相关（r = 0.54，P<0.02）。通过逐步回归分析，FPG变化的最强决定因素是GNG通量的变化。
吡格列酮主要通过降低2型糖尿病受试者的GNG通量来改善FPG。
