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Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes

posted on 25.06.2020 by 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, the GDS Group
Objective: 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 (HCL) and insulin sensitivity in recent-onset diabetes mellitus.

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.


The German Diabetes Study was initiated and is financed by the German Diabetes Center (which is funded by the German Federal Ministry of Health and the Ministry of Culture and Science of the state of North Rhine-Westphalia) and the German Federal Ministry of Education and Research (to the German Center for Diabetes Research). Parts of the study are also supported by grants from Research Network SFB 1116 of the German Research Foundation, the German Diabetes Association and the Schmutzler Stiftung. The funding sources had no role in study design, data collection, data analysis, data interpretation, or writing of the report.