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- Title
Role of Patatin-Like Phospholipase Domain-Containing 3 Gene for Hepatic Lipid Content and Insulin Resistance in Diabetes.
- Authors
Zaharia, Oana P.; Strassburger, Klaus; Knebel, Birgit; Kupriyanova, Yuliya; Karusheva, Yanislava; Wolkersdorfer, Martin; Bódis, Kálmán; Markgraf, Daniel F.; Burkart, Volker; Hwang, Jong-Hee; Kotzka, Jörg; Al-Hasani, Hadi; Szendroedi, Julia; Roden, Michael; Roden, M.; Al-Hasani, H.; Burkart, V.; Buyken, A.E.; Eckel, J.; Geerling, G.
- Abstract
<bold>Objective: </bold>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 the recently described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (hepatocellular lipids [HCL]) and insulin sensitivity in recent-onset diabetes.<bold>Research Design and Methods: </bold>A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS.<bold>Results: </bold>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. Those with SIRD exhibited lowest whole-body insulin sensitivity compared with those with severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD), and severe autoimmune diabetes (SAID) clusters (all P < 0.001). Interestingly, the SIRD group presented with higher prevalence of the rs738409(G) SNP compared with other clusters and the glucose-tolerant control group (P < 0.05). HCL was higher in the SIRD group (median 13.6% [1st quartile 5.8; 3rd quartile 19.1] compared with the 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 glucose-tolerant (0.9% [0.4; 4.9), P < 0.001) group. 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 with noncarriers (both P < 0.001).<bold>Conclusions: </bold>Members of the SIRD 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.
- Subjects
GERMANY; INSULIN resistance; SINGLE nucleotide polymorphisms; TRACERS (Chemistry); DIABETES; FREE fatty acids; HEMODILUTION; LIPOLYSIS; GLUCOSE clamp technique; OBESITY complications; LIPASES; OBESITY; RESEARCH; LIVER; FATTY liver; CROSS-sectional method; RESEARCH methodology; GENETIC disorders; GENETIC polymorphisms; CASE-control method; ALLELES; MEDICAL cooperation; EVALUATION research; TYPE 2 diabetes; INSULIN; COMPARATIVE studies; GENES; DISEASE susceptibility; LIPID metabolism disorders; MEMBRANE proteins; GENETIC techniques; DISEASE complications
- Publication
Diabetes Care, 2020, Vol 43, Issue 9, p2161
- ISSN
0149-5992
- Publication type
journal article
- DOI
10.2337/dc20-0329