Dion François, Dumayne Christopher, Henley Nathalie, Beauchemin Stéphanie, Arias Edward B, Leblond François A, Lesage Sylvie, Lefrançois Stéphane, Cartee Gregory D, Pichette Vincent
Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada.
Département de pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
PLoS One. 2017 May 1;12(5):e0176650. doi: 10.1371/journal.pone.0176650. eCollection 2017.
Chronic kidney disease is associated with homeostatic imbalances such as insulin resistance. However, the underlying mechanisms leading to these imbalances and whether they promote the development of type 2 diabetes is unknown. The effect of chronic kidney disease on insulin resistance was studied on two different rat strains. First, in a 5/6th nephrectomised Sprague-Dawley rat model of chronic kidney disease, we observed a correlation between the severity of chronic kidney disease and hyperglycemia as evaluated by serum fructosamine levels (p<0.0001). Further, glucose tolerance tests indicated an increase of 25% in glycemia in chronic kidney disease rats (p<0.0001) as compared to controls whereas insulin levels remained unchanged. We also observed modulation of glucose transporters expression in several tissues such as the liver (decrease of ≈40%, p≤0.01) and muscles (decrease of ≈29%, p≤0.05). Despite a significant reduction of ≈37% in insulin-dependent glucose uptake in the muscles of chronic kidney disease rats (p<0.0001), the development of type 2 diabetes was never observed. Second, in a rat model of metabolic syndrome (Zucker Leprfa/fa), chronic kidney disease caused a 50% increased fasting hyperglycemia (p<0.0001) and an exacerbated glycemic response (p<0.0001) during glucose challenge. Similar modulations of glucose transporters expression and glucose uptake were observed in the two models. However, 30% (p<0.05) of chronic kidney disease Zucker rats developed characteristics of type 2 diabetes. Thus, our results suggest that downregulation of GLUT4 in skeletal muscle may be associated with insulin resistance in chronic kidney disease and could lead to type 2 diabetes in predisposed animals.
慢性肾脏病与胰岛素抵抗等体内稳态失衡有关。然而，导致这些失衡的潜在机制以及它们是否会促进2型糖尿病的发展尚不清楚。我们在两种不同的大鼠品系上研究了慢性肾脏病对胰岛素抵抗的影响。首先，在一种5/6肾切除的慢性肾脏病Sprague-Dawley大鼠模型中，我们观察到慢性肾脏病的严重程度与血清果糖胺水平评估的高血糖之间存在相关性（p<0.0001）。此外，葡萄糖耐量试验表明，与对照组相比，慢性肾脏病大鼠的血糖升高了25%（p<0.0001），而胰岛素水平保持不变。我们还观察到几种组织中葡萄糖转运蛋白表达的调节情况，如肝脏（下降约40%，p≤0.01）和肌肉（下降约29%，p≤0.05）。尽管慢性肾脏病大鼠肌肉中胰岛素依赖的葡萄糖摄取显著降低了约37%（p<0.0001），但从未观察到2型糖尿病的发生。其次，在一种代谢综合征大鼠模型（Zucker Leprfa/fa）中，慢性肾脏病导致空腹高血糖增加了50%（p<0.0001），并且在葡萄糖激发试验期间血糖反应加剧（p<0.0001）。在这两种模型中观察到了相似的葡萄糖转运蛋白表达和葡萄糖摄取调节情况。然而，30%（p<0.05）的慢性肾脏病Zucker大鼠出现了2型糖尿病的特征。因此，我们的结果表明，骨骼肌中GLUT4的下调可能与慢性肾脏病中的胰岛素抵抗有关，并可能导致易感动物发生2型糖尿病。
