Insulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes. In this study, we characterized the metabolic phenotypes of the adult GIRKO mice acutely switched to high-fat diet (HFD) feeding in order to identify additional metabolic challenges required for disease progression. Distinct from other diet-induced obesity (DIO) and genetic models (e.g., db/db mice), GIRKO mice remained leaner on HFD feeding, but developed other cardinal features of insulin resistance syndrome. GIRKO mice rapidly developed hyperglycemia despite compensatory increases in β-cell mass and hyperinsulinemia. Furthermore, GIRKO mice also had impaired oral glucose tolerance and a limited glucose-lowering benefit from exendin-4, suggesting that the blunted incretin effect contributed to hyperglycemia. Secondly, GIRKO mice manifested severe dyslipidemia while on HFD due to elevated hepatic lipid secretion, serum triglyceride concentration, and lipid droplet accumulation in hepatocytes. Thirdly, GIRKO mice on HFD had increased inflammatory cues in the gut, which were associated with the HFD-induced microbiome alterations and increased serum lipopolysaccharide (LPS). In conclusion, our studies identified important gene/diet interactions contributing to diabetes progression, which might be leveraged to develop more efficacious therapies.

中文翻译：

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高脂肪饮食会催化 Glut4 表达组织中胰岛素作用选择性受损的小鼠进展为高血糖症。

胰岛素抵抗通过 4 型葡萄糖转运蛋白 (GLUT4) 损害餐后葡萄糖摄取，是 2 型糖尿病之前的主要缺陷。我们之前在肌肉、脂肪和神经元亚群中生成了一种具有人 GLUT4 启动子驱动的胰岛素受体敲除 (GIRKO) 的胰岛素抵抗小鼠模型。然而，在正常饮食 (NCD) 的 6 个月大之前，GIRKO 小鼠的糖尿病发病率仍然很低，这表明其他因素/机制是导致不良代谢影响最终导致明显糖尿病进展的原因。在这项研究中，我们表征了成年 GIRKO 小鼠的代谢表型，这些小鼠急性转为高脂饮食 (HFD) 喂养，以确定疾病进展所需的额外代谢挑战。与其他饮食诱导的肥胖 (DIO) 和遗传模型（例如，db/db 小鼠）不同，GIRKO 小鼠在 HFD 喂养方面仍然较瘦，但出现了胰岛素抵抗综合征的其他主要特征。尽管 β 细胞量和高胰岛素血症代偿性增加，GIRKO 小鼠仍迅速出现高血糖症。此外，GIRKO 小鼠的口服葡萄糖耐量也受损，exendin-4 的降糖作用有限，这表明肠促胰岛素作用减弱会导致高血糖症。其次，由于肝脏脂质分泌、血清甘油三酯浓度和肝细胞中脂滴积累升高，GIRKO 小鼠在 HFD 时表现出严重的血脂异常。第三，HFD 上的 GIRKO 小鼠肠道中的炎症信号增加，这与 HFD 诱导的微生物组改变和血清脂多糖 (LPS) 增加有关。总之，我们的研究确定了导致糖尿病进展的重要基因/饮食相互作用，这可能被用来开发更有效的治疗方法。