Ayala Julio E, Bracy Deanna P, James Freyja D, Julien Brianna M, Wasserman David H, Drucker Daniel J
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Endocrinology. 2009 Mar;150(3):1155-64. doi: 10.1210/en.2008-0945. Epub 2008 Nov 13.
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-(3)H]glucose and 2[(14)C]deoxyglucose were used to determine whole-body glucose turnover and glucose metabolic index (R(g)), an indicator of glucose uptake. R(g) in sedentary and treadmill exercised mice was determined using 2[(3)H]deoxyglucose. Glp1r(-/-) mice exhibited increased glucose disappearance, muscle R(g), 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 R(g) 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.
胰高血糖素样肽-1（GLP-1）通过激活β细胞GLP-1受体（Glp1r）增强胰岛素分泌，从而减少餐后血糖波动。GLP-1也可能通过独立于这种肠促胰岛素效应的机制来控制血糖水平。采用高胰岛素-正常血糖钳夹技术（胰岛素钳夹）和运动来研究Glp1r不依赖肠促胰岛素的葡萄糖调节特性，因为这两种干预措施均能在不依赖胰岛素分泌的情况下刺激葡萄糖通量。将Glp1r功能破坏的正常饮食小鼠（Glp1r(-/-)）与野生型同窝小鼠（Glp1r(+/+)）进行比较。对植入动脉和静脉导管分别用于取样和输注的禁食5小时小鼠进行研究。在胰岛素钳夹期间，使用[3-(3)H]葡萄糖和2[(14)C]脱氧葡萄糖来测定全身葡萄糖周转率和葡萄糖代谢指数（R(g)），后者是葡萄糖摄取的一个指标。使用2[(3)H]脱氧葡萄糖测定久坐和跑步机运动小鼠的R(g)。在胰岛素钳夹期间，Glp1r(-/-)小鼠的葡萄糖消失、肌肉R(g)和肌肉糖原水平增加。这与肌肉胰岛素信号增强无关。在胰岛素钳夹期间，Glp1r(-/-)小鼠内源性葡萄糖生成的抑制和肝糖原积累受损。这与肝脏胰岛素信号受损有关。Glp1r(-/-)小鼠在运动期间出现明显的高血糖。运动的Glp1r(-/-)小鼠的肌肉R(g)正常，表明高血糖是由于刺激葡萄糖生成的额外驱动力所致。运动的Glp1r(-/-)小鼠的肌肉AMP激活的蛋白激酶磷酸化水平较高。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Glp1r独立于其增强胰岛素分泌的能力来调节肝脏和肌肉的葡萄糖通量。
