Role of Patatin-Like Phospholipase Domain–Containing 3 Gene for Hepatic Lipid Content and Insulin Resistance in Diabetes

• DOI: 10.2337/dc20-0329
• Publication Date: 2020-06-19T23:32:09Z
• Authors: Oana P. Zaharia; Klaus Strassburger; Birgit Knebel; Yuliya Kupriyanova; Yanislava Karusheva; Martin Wolkersdorfer; Kálmán Bódis; Daniel F. Markgraf; Volker Burkart; Jong-Hee Hwang; Jörg Kotzka; Hadi Al-Hasani; Julia Szendroedi; Michael Roden; ; M. Roden; H. Al-Hasani; V. Burkart; A.E. Buyken; J. Eckel; G. Geerling; J.H. Hwang; C. Herder; A. Icks; K. Jandeleit-Dahm; S. Kahl; J. Kotzka; O. Kuss; E. Lammert; S. Trenkamp; W. Rathmann; J. Szendroedi; D. Ziegler
• Keywords: SNP

The rs738409(G) single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As recently described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether SNP differently hepatic lipid content (hepatocellular lipids [HCL]) insulin sensitivity recent-onset diabetes.A total 917 participants German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps stable isotopic tracer dilution, MRS.The G allele associated positively HCL (β = 0.36, P < 0.01), independent age, sex, BMI across whole cohort, but not individual clusters. Those SIRD exhibited lowest whole-body compared those insulin-deficient (SIDD), moderate obesity-related (MOD), age-related (MARD), autoimmune (SAID) clusters (all 0.001). Interestingly, group presented higher prevalence other glucose-tolerant control (P 0.05). was (median 13.6% [1st quartile 5.8; 3rd 19.1] MOD (6.4 % [2.1; 12.4], 0.05), MARD (3.0% [1.0; 7.9], 0.001), SAID (0.4% [0.0; 1.5], (0.9% [0.4; 4.9), 0.001) group. Although PNPLA3 did directly associate SIRD, G-allele carriers had circulating free acid concentrations greater adipose tissue resistance noncarriers (both 0.001).Members are more frequently variant. SNP-associated excessive lipolysis may contribute their NAFLD.