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Pathophysiology/Complications

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

  1. Oana P. Zaharia1,2,
  2. Klaus Strassburger2,3,
  3. Birgit Knebel2,4,
  4. Yuliya Kupriyanova1,2,
  5. Yanislava Karusheva1,2,
  6. Martin Wolkersdorfer5,
  7. Kálmán Bódis1,2,6,
  8. Daniel F. Markgraf1,2,
  9. Volker Burkart1,2,
  10. Jong-Hee Hwang1,2,
  11. Jörg Kotzka2,4,
  12. Hadi Al-Hasani2,4,
  13. Julia Szendroedi1,2,6 and
  14. Michael Roden1,2,6⇑, for the GDS Group*
  1. 1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  2. 2German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
  3. 3Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  4. 4Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  5. 5Landesapotheke Salzburg, Salzburg, Austria
  6. 6Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  1. Corresponding author: Michael Roden, michael.roden{at}ddz.de
    Diabetes Care 2020 Sep; 43(9): 2161-2168. https://doi.org/10.2337/dc20-0329
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    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.

    Footnotes

    • Clinical trial reg. no. NCT01055093, clinicaltrials.gov

    • ↵* A list of the GDS Group members and their affiliations is provided in the supplementary material online.

    • This article contains supplementary material online at https://doi.org/10.2337/figshare.12315737.

    • Received February 17, 2020.
    • Accepted May 14, 2020.
    • © 2020 by the American Diabetes Association
    https://www.diabetesjournals.org/content/license

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.

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    Role of Patatin-Like Phospholipase Domain–Containing 3 Gene for Hepatic Lipid Content and Insulin Resistance in Diabetes
    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
    Diabetes Care Sep 2020, 43 (9) 2161-2168; DOI: 10.2337/dc20-0329

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    Role of Patatin-Like Phospholipase Domain–Containing 3 Gene for Hepatic Lipid Content and Insulin Resistance in Diabetes
    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
    Diabetes Care Sep 2020, 43 (9) 2161-2168; DOI: 10.2337/dc20-0329
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