Abstract
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.
Highlights
The prevalence of chronic kidney disease (CKD) is steadily increasing [1], and its metabolic and hormonal complications have been the subject of many studies [2, 3]
The purpose of this study was to determine whether: 1) CKD leads to insulin resistance in a nephrectomised rat model of CKD, 2) CKD modulates key transporters involved in glucose homeostasis which could lead to insulin resistance, 3) CKD is associated with impaired glucose uptake in insulin-sensitive organs and 4) insulin resistance in CKD leads to type 2 diabetes (T2D)
Fructosamine levels were 25% higher (p
Summary
The prevalence of chronic kidney disease (CKD) is steadily increasing [1], and its metabolic and hormonal complications have been the subject of many studies [2, 3]. Type 2 diabetes (T2D), a leading cause of end-stage renal disease (ESRD), is an important and growing health problem [4, 5]. The convergence of these two conditions could lead to mutual exacerbation and worsening of patient health [6, 7]. Numerous studies suggest that peripheral insulin resistance and/or impaired insulin secretion are causative factors for diminished carbohydrate metabolism [10,11,12,13]. As insulin resistance in CKD is associated with diabetes, kidney disease could lead to a deterioration of insulin sensitivity [11, 14]. Given that insulin resistance may contribute to the development of cardiovascular disease, insulin resistance is an important target to prevent such complications in patients with CKD
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