Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes
Research Design and Methods: A total of 917 participants of the German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution and magnetic resonance spectroscopy.
Results: The G allele associated positively with HCL (β=0.36, p<0.01), independent of age, sex and BMI across the whole cohort, but not in the individual clusters. SIRD exhibited lowest whole-body insulin sensitivity compared to severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the rs738409(G) SNP compared to other clusters and the glucose-tolerant control group (p<0.05). HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%, p<0.05], MARD [3.0 (1.0;7.9)%, p<0.001], SAID [0.4 (0.0;1.5)%, p<0.001] and the glucose tolerant group [0.9 (0.4;4.9)%, p<0.001]. Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G allele carriers had higher circulating free fatty acid concentrations and greater adipose-tissue insulin resistance compared to non-carriers (both p<0.001).Conclusions: Members of the severe insulin resistant diabetes cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose-tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.