Abstract:
The fibroblast growth factor receptor 4 (FGFR4), a monomeric receptor protein tyrosine kinase, regulates angiogenic, mitogenic and differentiation responses in cells, as well as insulin sensitivity and fat accumulation in the liver of mice. A functional polymorphism in FGFR4 (Gly388Arg) was found to be associated with disease progression in cancer patients. In the present study it was investigated whether this polymorphism determines glucose tolerance, insulin resistance and hepatic steatosis in subjects at high risk for type 2 diabetes.
A total of 170 individuals participated in a lifestyle intervention program with diet modification and increase in physical activity. Total body fat and visceral fat were determined by magnetic resonance (MR) Tomography and liver fat and intramyocellular fat by 1H-MR spectroscopy. Insulin sensitivity was estimated from the oral glucose tolerance test.
At baseline the polymorphism was not associated with glucose tolerance, insulin sensitivity or liver fat (all p greater than or equal 0,13). During 9 month of intervention, subjects carrying the minor 388 Arg encoding allele (n=87) displayed a mean increase in 2h glycemia (+3 %), less increase in insulin sensitivity (+21%) and less decrease in liver fat (-13%) compared to homozygous carriers of the 388 Gly allele (n=83; -5%, p=0,006; +34%, p=0,003; and -21%, p=0,007, respectively). In contrast, changes in total body fat, visceral fat and intramyocellular fat were not different between the genotypes (all p greater than or equal 0, 30).
These data provide evidence that the functional Gly388Arg polymorphism in FGFR4 is associated with the improvement of glucose tolerance and insulin sensitivity during a lifestyle intervention, possibly via regulation of liver fat.