Département de Pharmacologie et Physiologie/Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada.
Département de Médecine, Service d'Endocrinologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada.
Sci Rep. 2018 Jan 11;8(1):424. doi: 10.1038/s41598-017-18896-5.
The epidemic of type 2 diabetes mellitus (T2DM) is fueled by added fructose consumption. Here, we thus combined high-fat/high-fructose diet, with multiple low-dose injections of streptozotocin (HF/HF/Stz) to emulate the long-term complications of T2DM. HF/HF/Stz rats, monitored over 56 weeks, exhibited metabolic dysfunctions associated with the different stages of the T2DM disease progression in humans: an early prediabetic phase characterized by an hyperinsulinemic period with modest dysglycemia, followed by a late stage of T2DM with frank hyperglycemia, normalization of insulinemia, marked dyslipidemia, hepatic fibrosis and pancreatic β-cell failure. Histopathological analyses combined to [F]-FDG PET imaging further demonstrated the presence of several end-organ long-term complications, including reduction in myocardial glucose utilization, renal dysfunction as well as microvascular neuropathy and retinopathy. We also provide for the first time a comprehensive µ-PET whole brain imaging of the changes in glucose metabolic activity within discrete cerebral regions in HF/HF/Stz diabetic rats. Altogether, we developed and characterized a unique non-genetic preclinical model of T2DM adapted to the current diet and lifestyle that recapitulates the major metabolic features of the disease progression, from insulin resistance to pancreatic β-cell dysfunction, and closely mimicking the target-organ damage occurring in type 2 diabetic patients at advanced stages.
2 型糖尿病（T2DM）的流行是由于果糖摄入的增加。在这里，我们结合高脂肪/高果糖饮食和多次小剂量链脲佐菌素（HF/HF/Stz）注射，模拟 T2DM 的长期并发症。HF/HF/Stz 大鼠在 56 周的监测期间，表现出与人类 T2DM 疾病进展的不同阶段相关的代谢功能障碍：早期糖尿病前期阶段表现为胰岛素血症期伴有轻度糖代谢异常，随后是 T2DM 的晚期阶段，出现明显的高血糖、胰岛素血症正常化、显著的血脂异常、肝纤维化和胰腺β细胞衰竭。组织病理学分析结合 [F]-FDG PET 成像进一步证明了存在几种终末器官长期并发症，包括心肌葡萄糖利用减少、肾功能障碍以及微血管神经病和视网膜病变。我们还首次提供了 HF/HF/Stz 糖尿病大鼠离散脑区葡萄糖代谢活性变化的综合 µ-PET 全脑成像。总之，我们开发并表征了一种独特的非遗传 T2DM 临床前模型，适用于当前的饮食和生活方式，从胰岛素抵抗到胰腺β细胞功能障碍，重现了疾病进展的主要代谢特征，并密切模拟了 2 型糖尿病患者在晚期发生的靶器官损伤。
