Diabetes Basic Research

Introduction and Aims: Chronic kidney disease (CKD) is associated with a large range of metabolic alterations among which insulin resistance and dyslipidemia are well-documented features of renal failure.Numerous studies point toward an important role of ectopic fat accumulation in the pathophysiology of type 2 diabetes and cardiovascular disease.Many data from literature indicated a positive correlation between visceral tissue mass and insulin resistance both in diabetic patients than in CKD patients reinforcing the idea that the adipose tissue could be a source of metabolic disturbances in CKD patients.We hypothesize that a phenomenon of lipotoxicity and ectopic fat redistribution could begin at an early stage of kidney disease as a result of early adipocyte dysfunction and be responsible for the insulin-resistance associated to CKD.Methods: C57BL/6 mice underwent a 5/6 nephrectomy and were compared to pair fed sham-operated mice.Mice had free access to water with 80mM Na2CO3 to prevent acidosis.Insulin sensitivity was estimated through intra-peritoneal insulin (ipITT) and glucose tolerance (ipGTT) tests.Anthropometric (body weight, lean and fad pad mass) and metabolic parameters (glycemia, insulin, cholesterol, triglycerides) were measured.The phosphorylation of a key protein of insulin signaling pathway ( protein kinase B, PKB/Akt) was studied by Western blot after ex-vivo insulin stimulation (100nM, 30 min) of gastrocnemius muscle.The intra-muscular and intra-hepatic lipids were extracted using Chloroform-Methanol (2:1, v/v).Results: The CKD mice exhibited a marked decrease in insulin sensitivity (-76%, p<0.01) and altered glucose tolerance (+24%, p<0.001).CKD mice exhibited a profile of insulin resistance with hyperglycemia (84±3 vs 97 ±5 mg/dl, +16%, p<0.05), hyperinsulinemia (11±6 vs 60 ±11 pg/dl +455%, p<0.05), hypertriglycidemia (70±5 vs 118 ±12 mg/dl +67%, p<0.05), hypercholesterolemia (64±4 vs 123±11 mg/dl +79%, p<0.05).CKD mice exhibited a significant decrease in white adipose tissue accretion (-57%, p< 0.001) associated with increased muscle (+138%, p <0.05) and liver (+38%, P <0.05) lipid contents compared to sham-operated mice.The CKD mice presented a blunted insulin-induced Akt phosphorylation (-34%, p< 0.05) in gastrocnemius muscle.Conclusions: In subtotally nephrectomized mouse model we showed an ectopic intramuscular and intrahepatic lipid redistribution concomitant with insulin resistance.Insulin resistance and lipotoxicity may represent the missing links (beyond the classical cardiovascular risk factors) that may help explain the increased risk of cardiovascular disease in CKD.Further studies are however needed to thoroughly decipher the molecular mechanisms linking this ectopic lipid accumulation and the associated insulin resistance and to also assess the role of adipose tissue dysfunction in the altered fat distribution.