Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney |
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| Authors: | Lamont B J Andrikopoulos S Funkat A Favaloro J Ye J M Kraegen E W Howlett K F Zajac J D Proietto J |
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| Affiliation: | (1) University of Melbourne Department of Medicine, Royal Melbourne Hospital, 3050 Parkville, Victoria, Australia;(2) Garvan Institute of Medical Research, Sydney, New South Wales, Australia;(3) Deakin University, Melbourne, Victoria, Australia;(4) University of Melbourne Department of Medicine, Austin and Repatriation Medical Centre, Victoria, Australia |
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| Abstract: | Aims/hypothesis To study the secondary consequences of impaired suppression of endogenous glucose production (EGP) we have created a transgenic rat overexpressing the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in the kidney. The aim of this study was to determine whether peripheral insulin resistance develops in these transgenic rats.Methods Whole body rate of glucose disappearance (Rd) and endogenous glucose production were measured basally and during a euglycaemic/hyperinsulinaemic clamp in phosphoenolpyruvate carboxykinase transgenic and control rats using [6-3H]-glucose. Glucose uptake into individual tissues was measured in vivo using 2-[1-14C]-deoxyglucose.Results Phosphoenolpyruvate carboxykinase transgenic rats were heavier and had increased gonadal and infrarenal fat pad weights. Under basal conditions, endogenous glucose production was similar in phosphoenolpyruvate carboxykinase transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min). Moderate hyperinsulinaemia (810 pmol/l) completely suppressed EGP in control rats (–0.6±5.5 µmol/kg/min, p<0.05) while there was no suppression in phosphoenolpyruvate carboxykinase rats (45.2±7.9 µmol/kg/min). Basal Rd was comparable between PEPCK transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min) but under insulin-stimulated conditions the increase in Rd was greater in control compared to phosphoenolpyruvate carboxykinase transgenic rats indicative of insulin resistance (73.4±11.2 vs 112.0±8.0 µmol/kg/min, p<0.05). Basal glucose uptake was reduced in white and brown adipose tissue, heart and soleus while insulin-stimulated transport was reduced in white and brown adipose tissue, white quadriceps, white gastrocnemius and soleus in phosphoenolpyruvate carboxykinase transgenic compared to control rats. The impairment in both white and brown adipose tissue glucose uptake in phosphoenolpyruvate carboxykinase transgenic rats was associated with a decrease in GLUT4 protein content. In contrast, muscle GLUT4 protein, triglyceride and long-chain acylCoA levels were comparable between PEPCK transgenic and control rats.Conclusions/interpretation A primary defect in suppression of EGP caused adipose tissue and muscle insulin resistance.Abbreviations EGP endogenous glucose production - Rd rate of glucose disappearance - LCACoA long chain acyl CoA - TG triglycerides - MCR metabolic clearance rate |
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| Keywords: | Phosphoenolpyruvate carboxykinase GLUT4 muscle glucose uptake adipose tissue glucose uptake tissue triglycerides long chain acyl CoA glycogen |
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