Mechanism of insulin resistance in a rat model of kidney disease and the risk of developing type 2 diabetes
Article [Version publiée]
Résumé·s
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.