Gastaldelli Amalia, Miyazaki Yoshinori, Pettiti Maura, Santini Eleonora, Ciociaro Demetrio, Defronzo Ralph A, Ferrannini Ele
Metabolism Unit, National Research Center, Institute of Clinical Physiology, Via Moruzzi 1, 56100 Pisa, Italy.
J Clin Endocrinol Metab. 2006 Mar;91(3):806-12. doi: 10.1210/jc.2005-1159. Epub 2005 Dec 13.
AIMS/HYPOTHESIS: Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones have been shown to improve glycemic control and increase peripheral insulin sensitivity. Whether chronic thiazolidinedione treatment is associated with a decrease in GNG has not been determined.
We studied 26 diet-treated type 2 diabetic patients randomly assigned to rosiglitazone (RSG; 8 mg/d; n = 13) or placebo (n = 13) for 12 wk. At baseline and 12 wk, we measured endogenous glucose production (by [3H]glucose infusion) and GNG (by the [2H]2O technique) after a 15-h fast. Peripheral insulin sensitivity was evaluated by a two-step (240 and 960 pmol/min/m(-2)) euglycemic insulin clamp.
Compared with placebo, RSG reduced fasting plasma glucose (9.7 +/- 0.7 to 7.4 +/- 0.3 mmol/liter; P < 0.001), fasting fractional GNG (-15 +/- 4%; P = 0.002), and fasting GNG flux (-3.9 +/- 1.2 micromol/min/kg fat-free mass; P = 0.004), with no effect on glycogenolytic flux. Changes in GNG flux and fasting glucose were tightly correlated (r = 0.83; P < 0.0001). During both clamp steps, RSG enhanced insulin-mediated glucose clearance (by 26% and 31%; P = 0.01 and P < 0.02, respectively). In a subgroup of patients studied with magnetic resonance imaging, the reduction in GNG flux was correlated (r = 0.65; P < 0.02) with the reduction in visceral fat area.
CONCLUSION/INTERPRETATION: RSG increases peripheral tissue insulin sensitivity and decreases endogenous glucose release via an inhibition of gluconeogenesis.
目的/假设：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。噻唑烷二酮类药物已被证明可改善血糖控制并提高外周胰岛素敏感性。慢性噻唑烷二酮治疗是否与GNG的降低有关尚未确定。
我们研究了26例接受饮食治疗的2型糖尿病患者，他们被随机分配接受罗格列酮（RSG；8毫克/天；n = 13）或安慰剂（n = 13）治疗12周。在基线和12周时，我们在禁食15小时后测量了内源性葡萄糖生成（通过[3H]葡萄糖输注）和GNG（通过[2H]2O技术）。通过两步（240和960皮摩尔/分钟/平方米）正常血糖胰岛素钳夹评估外周胰岛素敏感性。
与安慰剂相比，RSG降低了空腹血糖（从9.7±0.7降至7.4±0.3毫摩尔/升；P < 0.001）、空腹分数GNG（-15±4%；P = 0.002）和空腹GNG通量（-3.9±1.2微摩尔/分钟/千克去脂体重；P = 0.004），对糖原分解通量无影响。GNG通量和空腹血糖的变化密切相关（r = 0.83；P < 0.0001）。在两个钳夹步骤中，RSG均增强了胰岛素介导的葡萄糖清除率（分别提高了26%和31%；P = 0.01和P < 0.02）。在一组接受磁共振成像研究的患者亚组中，GNG通量的降低与内脏脂肪面积的减少相关（r = 0.65；P < 0.02）。
结论/解读：RSG通过抑制糖异生增加外周组织胰岛素敏感性并减少内源性葡萄糖释放。
