Oana P Zaharia1,2, Klaus Strassburger2,3, Birgit Knebel2,4, Yuliya Kupriyanova1,2, Yanislava Karusheva1,2, Martin Wolkersdorfer5, Kálmán Bódis1,2,6, Daniel F Markgraf1,2, Volker Burkart1,2, Jong-Hee Hwang1,2, Jörg Kotzka2,4, Hadi Al-Hasani2,4, Julia Szendroedi1,2,6, Michael Roden. 1. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 2. German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany. 3. Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 4. Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 5. Landesapotheke Salzburg, Salzburg, Austria. 6. Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Abstract
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 (hepatocellular lipids [HCL]) and insulin sensitivity in recent-onset diabetes. RESEARCH DESIGN AND METHODS: A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS. 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. 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). CONCLUSIONS: 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.
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 (hepatocellular lipids [HCL]) and insulin sensitivity in recent-onset diabetes. RESEARCH DESIGN AND METHODS: A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS. 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. 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). CONCLUSIONS: 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.
Authors: Jiexun Wang; Jian-Jun Liu; Resham L Gurung; Sylvia Liu; Janus Lee; Yiamunaa M; Keven Ang; Yi Ming Shao; Justin I-Shing Tang; Peter I Benke; Federico Torta; Markus R Wenk; Subramaniam Tavintharan; Wern Ee Tang; Chee Fang Sum; Su Chi Lim Journal: Diabetologia Date: 2022-06-28 Impact factor: 10.460
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