The enzyme DGAT (acyl-CoA:diacylglycerol acyltransferase) catalyses the final step of triacylglycerol (triglyceride) synthesis. Mice overexpressing hepatic DGAT2 fed a high-fat diet develop fatty liver, but not insulin resistance, suggesting that DGAT2 induces a dissociation between fatty liver and insulin resistance. In the present study, we investigated whether such a phenotype also exists in humans. For this purpose, we determined the relationships between genetic variability in the DGAT2 gene with changes in liver fat and insulin sensitivity in 187 extensively phenotyped subjects during a lifestyle intervention programme with diet modification and an increase in physical activity. Changes in body fat composition [MR (magnetic resonance) tomography], liver fat and intramyocellular fat (1H-MR spectroscopy) and insulin sensitivity [OGTT (oral glucose tolerance test) and euglycaemic–hyperinsulinaemic clamp] were determined after 9 months of intervention. A 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 SNPs (single nucleotide polymorphisms) rs10899116 C>T and rs1944438 C>T (all P≥0.39) of the DGAT2 gene. However, individuals carrying two or one copies of the minor T allele of SNP rs1944438 had a smaller decrease in liver fat (−17±10 and −24±5%; values are means±S.E.M.) compared with 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). In conclusion, our findings suggest that DGAT2 mediates the 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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