The DGAT2 gene is a candidate for dissociation between fatty liver and insulin resistance in humans
Résumé
The enzyme acyl-CoA:diacylglycerol acyltransferase (DGAT) catalyzes the final step of triglyceride synthesis. Mice overexpressing hepatic DGAT2, fed a high-fat diet, develop fatty liver, but not insulin resistance, suggesting that DGAT2 induces dissociation between fatty liver and insulin resistance. We investigated whether such a phenotype also exists in humans. For this purpose, we determined the relationships of genetic variability in the DGAT2 gene with changes in liver fat and in insulin sensitivity in 187 extensively phenotyped subjects during a lifestyle intervention with diet modification and increase in physical activity. Changes in body fat composition [magnetic resonance (MR) tomography], liver fat and intramyocellular fat (1H-MR spectroscopy) and insulin sensitivity (OGTT and euglycemic, hyperinsulinemic clamp) were determined after 9 months of intervention. Change in insulin sensitivity correlated inversely with changes in total body fat, visceral fat intramyocellular fat and liver fat (OGTT: all p<0.05; clamp: all p≤0.03). Changes in total body fat, visceral fat and intramyocellular fat were not different between the genotypes of the single nucleotide polymorphisms (SNP) rs10899116 C>T and rs1944438 C>T (all p≥0.39). However, individuals carrying two or one copies of the minor T allele of SNP rs1944438 had less decrease in liver fat (-17±10 and -24±5%, mean ± standard error) compared to subjects homozygous for the C allele (-39±7%, p=0.008). In contrast, changes in insulin sensitivity were not different among the genotypes (OGTT: p=0.76; clamp: p=0.53). Our findings suggest that DGAT2 mediates dissociation between fatty liver and insulin resistance in humans. This finding may be important in the prevention and treatment of insulin resistance and type 2 diabetes in subjects with fatty liver.
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