Unraveling the mechanism of diabetes resistance in GLUT4 knockout mice

Abstract

Using homologous recombination and embryonic stem cell technology, Katz et al. (1995) generated global GLUT4 knockout mice (GLUT4 Null). Surprisingly these mice maintain normal fed and fasted glucose levels. This led us to investigate the role of increased liver glucose uptake as a mechanism to compensate for reduced whole body glucose utilization. Results demonstrated enhanced liver glucose utilization via increased GLUT2 with no alterations in gluconeogenesis, and increased fatty acid synthesis (FAS) in GLUT4 Null compared to wild type (Control) mice. We also examined peripheral lipid clearance. GLUT4 Null mice have enhanced triglyceride clearance due to increased skeletal muscle lipoprotein lipase activity. This coincides with increased lipid oxidation and mitochondrial hypertrophy/hyperplasia in GLUT4 Null muscle. Disruption of FAS and lowering of serum triglycerides by feeding a PPARalpha agonist (fenofibrate) was lethal to GLUT4 Null mice suggesting insufficient substrate availability for GLUT4 Null muscle. These findings demonstrate that altered lipid metabolism is crucial for survival of GLUT4 Null mice. Restoration of GLUT4 in fast twitch skeletal muscle of GLUT4 Null mice was previously reported to correct whole body insulin sensitivity but did not alter the reduction in adipose mass and adipocyte size characteristic of GLUT4 Null mice. We examined the effect of GLUT4 restoration in GLUT4 Null muscle on liver substrate handling and noted a complete normalization of hepatic lipid metabolism. Additionally, mitochondrial hyperplasia/hypertrophy was abolished only in skeletal muscles with GLUT4 content restored. These studies illustrate the importance of substrate availability/utilization on directing metabolism, not only in the target tissue, but systemically by altering nutrient handling.;Diet studies were conducted to test whether the altered lipid utilization could protect GLUT4 Null mice from diet induced obesity. After 11 weeks of high fat (11.9% fat-kcal/gm) feeding there were no significant differences in body weight of GLUT4 Null and Control mice. Therefore GLUT4 Null mice are susceptible to diet induced obesity and male GLUT4 Null mice become hyperglycemic. Interestingly, male adiponectin (AD) Null (-/-) mice were protected from diet-induced obesity. Despite greatly reduced adipose tissue, female GLUT4 Null mice maintain normal levels of AD through increased mRNA and protein expression. To test the role of AD overexpression in mediating the altered lipid metabolism, GLUT4 Null mice were crossed with AD Null mice. (Abstract shortened by UMI.).