Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

Lamont, B. J., Andrikopoulos, S., Funkat, A., Favaloro, J., Ye, J. M., Kraegen, E. W., Howlett, Kirsten, Zajac, J. D. and Proietto, J. 2003, Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney, Diabetologia, vol. 46, no. 10, pp. 1338-1347.

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Title Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney
Author(s) Lamont, B. J.
Andrikopoulos, S.
Funkat, A.
Favaloro, J.
Ye, J. M.
Kraegen, E. W.
Howlett, Kirsten
Zajac, J. D.
Proietto, J.
Journal name Diabetologia
Volume number 46
Issue number 10
Start page 1338
End page 1347
Publisher Springer-Verlag
Place of publication New York, N.Y.
Publication date 2003
ISSN 0012-186X
1432-0428
Keyword(s) phosphoenolpyruvate carboxykinase
glycogen
tissue triglycerides
long chain acyl CoA
adipose tissue glucose uptake
muscle glucose uptake
GLUT4
Summary 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.
Language eng
Field of Research 111603 Systems Physiology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2003, Springer-Verlag
Persistent URL http://hdl.handle.net/10536/DRO/DU:30008574

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