The Glucagon-Like Peptide-1 Receptor Regulates Endogenous Glucose Production and Muscle Glucose Uptake Independent of Its Incretin Action
The Glucagon-Like Peptide-1 Receptor Regulates Endogenous Glucose Production and Muscle Glucose Uptake Independent of Its Incretin Action
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DOI：
10.1210/en.2008-0945
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发表时间：
2009-03-01
期刊：
影响因子：
4.8
通讯作者：
Drucker, Daniel J.
中科院分区：
文献类型：
--
作者：
Ayala, Julio E.;Bracy, Deanna P.;Drucker, Daniel J.
胰高血糖素样肽-1（GLP-1）通过激活β细胞GLP-1受体（Glp 1 r）增强胰岛素分泌，减少餐后血糖波动。GLP-1还可以通过独立于肠促胰岛素效应的机制控制葡萄糖水平。高胰岛素-正葡萄糖钳夹（胰岛素钳夹）和运动被用来检查Glp 1 r的肠促胰岛素非依赖性葡萄糖调节特性，因为这两种扰动刺激葡萄糖流量独立于胰岛素分泌。将具有Glp 1 r功能性破坏（Glp 1 r（-/-））的Chow喂养小鼠与野生型同窝小鼠（Glp 1 r（+/+））进行比较。对分别植入用于采样和输注的动脉和静脉导管的5小时禁食小鼠进行研究。在胰岛素钳夹期间，[3-H-3]葡萄糖和2[C-14]脱氧葡萄糖用于测定全身葡萄糖周转和葡萄糖代谢指数（R-g），葡萄糖摄取的指标。用2[H-3]脱氧葡萄糖测定安静和跑台运动小鼠的Rg。Glp 1 r（-/-）小鼠在胰岛素钳夹期间表现出葡萄糖消失、肌肉Rg和肌糖原水平增加。这与增强的肌肉胰岛素信号传导无关。Glp 1 r（-/-）小鼠在胰岛素钳夹过程中表现出内源性葡萄糖产生和肝糖原积累的抑制受损。这与肝脏胰岛素信号传导受损有关。Glp 1 r（-/-）小鼠在运动过程中血糖明显升高。肌肉Rg在运动Glp 1 r（-/-）小鼠中是正常的，这表明高血糖症是由刺激葡萄糖产生的额外驱动引起的。肌肉AMP活化蛋白激酶磷酸化在运动Glp 1 r（-/-）小鼠中更高。这与相对运动强度增加和运动耐力降低有关。总之，这些结果表明，内源性Glp 1 r调节肝脏和肌肉葡萄糖通量独立于其能力，以提高胰岛素分泌。（内分泌学150：1155-1164，2009）
Glucagon-like peptide-1 (GLP-1) diminishes postmeal glucose excursions by enhancing insulin secretion via activation of the beta-cell GLP-1 receptor (Glp1r). GLP-1 may also control glucose levels through mechanisms that are independent of this incretin effect. The hyperinsulinemic-euglycemic clamp (insulin clamp) and exercise were used to examine the incretin-independent glucoregulatory properties of the Glp1r because both perturbations stimulate glucose flux independent of insulin secretion. Chow-fed mice with a functional disruption of the Glp1r (Glp1r(-/-)) were compared with wild-type littermates (Glp1r(+/+)). Studies were performed on 5-h-fasted mice implanted with arterial and venous catheters for sampling and infusions, respectively. During insulin clamps, [3-H-3] glucose and 2[C-14] deoxyglucose were used to determine whole-body glucose turnover and glucose metabolic index (R-g), an indicator of glucose uptake. Rg in sedentary and treadmill exercised mice was determined using 2[H-3] deoxyglucose. Glp1r(-/-) mice exhibited increased glucose disappearance, muscle Rg, and muscle glycogen levels during insulin clamps. This was not associated with enhanced muscle insulin signaling. Glp1r(-/-) mice exhibited impaired suppression of endogenous glucose production and hepatic glycogen accumulation during insulin clamps. This was associated with impaired liver insulin signaling. Glp1r(-/-) mice became significantly hyperglycemic during exercise. Muscle Rg was normal in exercised Glp1r(-/-) mice, suggesting that hyperglycemia resulted from an added drive to stimulate glucose production. Muscle AMP-activated protein kinase phosphorylation was higher in exercised Glp1r(-/-) mice. This was associated with increased relative exercise intensity and decreased exercise endurance. In conclusion, these results show that the endogenous Glp1r regulates hepatic and muscle glucose flux independent of its ability to enhance insulin secretion. (Endocrinology 150: 1155-1164, 2009)