Myocardial insulin resistance in experimental uraemia

Aksentijevic, Dunja

Abstract

Cardiac complications are a major cause of death in patients with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) is a significant contributing factor to uraemic cardiomyopathy and results in significant molecular, cellular and metabolic remodelling. Progression of LVH leads to the development of insulin resistance, a feature common to CKD and heart failure, further jeopardising survival of the uraemic heart.

The aim of this thesis was to investigate the effect of uraemia on cardiac physiology, function and metabolism. Specifically, the aim of the study was to examine the cellular mechanisms underlying the development of myocardial insulin resistance in uraemia.

The experimental model was induced surgically via a two-stage 5/6 nephrectomy in adult male Sprague-Dawley rats over three, six weeks or nine weeks. An integrated experimental approach combining in vivo and ex vivo methods was used to characterize the morphology and physiology of the experimental model, examine myocardial function and energy provision; assess alterations in myocardial protein expression and determine potential mechanism involved in the development of insulin resistance.

Uraemic animals exhibited impaired renal function (creatinine 69±2 vs. 40±2 uM n=41; p<0.05), cardiac hypertrophy (dry heart weight: tibia length 0.5±0.01 vs. 0.4±0.01 g/cm; n=30; p<0.05), impaired glucose tolerance, hyperinsulinaemia, anaemia and hypertension.

In perfused hearts, uraemia caused a limited response of the uraemic heart to an increase in workload, demonstrated by cardiac dysfunction and metabolic adaptation. This profile was exacerbated in the presence of insulin. In vivo studies highlighted that insulin sensitivity was reduced in uraemic animals (HOMA-IR 1.27±0.3 vs. 0.58±0.1; n=8 p<0.02) and declined progressively with renal dysfunction. LV tissue from the uraemic model showed an increase in myocardial GLUT4 and normal insulin mediated translocation mechanism.

In conclusion, uraemic animals exhibited a reduction in insulin sensitivity, glucose intolerance and hyperinsulinaemia, indicating onset of insulin resistance after 6 weeks of uraemia. Profile of myocardial GLUT4 expression and response to insulin stimulation suggested that insulin resistance is not a consequence of impaired translocation. The lack of overt metabolic remodelling suggests a compensatory phase of left ventricular hypertrophy.

Citation

Aksentijevic, D. Myocardial insulin resistance in experimental uraemia. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4212871

• Thesis Type: Thesis
• Deposit Date: Aug 21, 2012
• Publicly Available Date: Feb 22, 2023
• Keywords: Biological sciences
• Public URL: https://hull-repository.worktribe.com/output/4212871
• Additional Information: Department of Biological Sciences, The University of Hull
• Award Date: Feb 1, 2008