Growth hormone treatment does not augment the anti-diabetic effects of liraglutide in UCD-T2DM rats.
Growth hormone treatment does not augment the anti-diabetic effects of liraglutide in UCD-T2DM rats.
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DOI：
10.1002/edm2.392
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发表时间：
2023-01
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肠促胰岛素激素胰高血糖素样肽-1（GLP-1）减缓胃排空，增加饱腹感并增强胰岛素分泌。GLP-1受体激动剂（如利拉鲁肽）用于人体治疗，以改善血糖控制并延迟2型糖尿病（T2 DM）的发作。在UCD-T2 DM大鼠（一种多基因肥胖和胰岛素抵抗模型）中，我们先前曾报道每日给予利拉鲁肽可延迟糖尿病发作>4个月。生长激素（GH）可发挥抗糖尿病作用，包括增加β细胞质量和胰岛素分泌，而破坏小鼠中的GH信号传导可减少胰岛的大小和数量。因此，我们假设GH补充剂将增强利拉鲁肽的抗糖尿病作用。雄性UCD‐ T2 DM大鼠从2月龄开始每天接受GH（0.3 mg/kg）和/或利拉鲁肽（0.2 mg/kg）给药。还研究了对照（溶剂）和限食（摄食量与利拉鲁肽给药大鼠相匹配）组。评估治疗对糖尿病发作和体重增加的影响，以及葡萄糖耐量、脂质和胰岛形态的测量。与对照组相比，利拉鲁肽治疗显著降低了摄食量和体重，并改善了葡萄糖耐量和胰岛素敏感性。4.5个月后，利拉鲁肽给药大鼠均未发生T2 DM（总体p = .019）。与对照大鼠相比，利拉鲁肽给药大鼠还显示出空腹甘油三酯（TG）浓度较低和肝脏TG含量较低。利拉鲁肽给药大鼠的胰岛形态得到改善，胰腺胰岛素含量显著增加（与对照组相比，p <0.05）。虽然GH治疗倾向于增加体重（和腓肠肌重量），但对糖尿病发作或其他糖尿病相关结局无明显影响。GH补充未增强利拉鲁肽的抗糖尿病作用。生长激素（GH）可直接对胰岛发挥抗糖尿病作用，增加β细胞质量和胰岛素分泌。在此，我们使用2型糖尿病啮齿动物模型（UCD‐ T2 DM大鼠）研究GH补充是否可以增强利拉鲁肽（GLP‐1受体激动剂）治疗的抗糖尿病作用。
The incretin hormone glucagon‐like peptide‐1 (GLP‐1) slows gastric emptying, increases satiety and enhances insulin secretion. GLP‐1 receptor agonists, such as liraglutide, are used therapeutically in humans to improve glycaemic control and delay the onset of type 2 diabetes mellitus (T2DM). In UCD‐T2DM rats, a model of polygenic obesity and insulin resistance, we have previously reported that daily liraglutide administration delayed diabetes onset by >4 months. Growth hormone (GH) may exert anti‐diabetic effects, including increasing β‐cell mass and insulin secretion, while disrupting GH signalling in mice reduces both the size and number of pancreatic islets. We therefore hypothesized that GH supplementation would augment liraglutide's anti‐diabetic effects. Male UCD‐T2DM rats were treated daily with GH (0.3 mg/kg) and/or liraglutide (0.2 mg/kg) from 2 months of age. Control (vehicle) and food‐restricted (with food intake matched to liraglutide‐treated rats) groups were also studied. The effects of treatment on diabetes onset and weight gain were assessed, as well as measures of glucose tolerance, lipids and islet morphology. Liraglutide treatment significantly reduced food intake and body weight and improved glucose tolerance and insulin sensitivity, relative to controls. After 4.5 months, none of the liraglutide‐treated rats had developed T2DM (overall p = .019). Liraglutide‐treated rats also displayed lower fasting triglyceride (TG) concentrations and lower hepatic TG content, compared to control rats. Islet morphology was improved in liraglutide‐treated rats, with significantly increased pancreatic insulin content (p < .05 vs. controls). Although GH treatment tended to increase body weight (and gastrocnemius muscle weight), there were no obvious effects on diabetes onset or other diabetes‐related outcomes. GH supplementation did not augment the anti‐diabetic effects of liraglutide. Growth hormone (GH) may directly exert anti‐diabetic effects on pancreatic islets, increasing beta‐cell mass and insulin secretion. Here we used a rodent model of type 2 diabetes (UCD‐T2DM rats) to investigate whether GH supplementation could augment the anti‐diabetic effects of liraglutide (a GLP‐1 receptor agonist) treatment.