Mechanism of insulin resistance in a rat model of kidney disease and the risk of developing type 2 diabetes

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.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Disease Progression
  • Glucose / metabolism
  • Glucose Transporter Type 4 / metabolism
  • Glycosuria / metabolism
  • Insulin Resistance / physiology*
  • Liver / metabolism
  • Male
  • Muscle, Skeletal / metabolism
  • Nephrectomy
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Rats, Zucker
  • Renal Insufficiency, Chronic / metabolism*
  • Risk
  • Sodium-Glucose Transport Proteins / metabolism
  • Tissue Culture Techniques


  • Glucose Transporter Type 4
  • RNA, Messenger
  • Slc2a4 protein, rat
  • Sodium-Glucose Transport Proteins
  • Glucose