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

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.

• 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, GDS Group
• Journal: Diabetes care (Diabetes Care) Vol. 43 Issue 9 Pg. 2161-2168 (09 2020) ISSN: 1935-5548 [Electronic] United States
• PMID: 32910776 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by the American Diabetes Association.

Chemical References

• Insulin
• Membrane Proteins
• Lipase
• adiponutrin, human

Topics

• Adult
• Aged
• Alleles
• Case-Control Studies
• Cross-Sectional Studies
• Diabetes Mellitus, Type 2 (complications, epidemiology, genetics, metabolism)
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Germany (epidemiology)
• Glucose Clamp Technique
• Humans
• Insulin (genetics, metabolism)
• Insulin Resistance (genetics)
• Lipase (genetics, physiology)
• Lipid Metabolism (genetics)
• Liver (metabolism)
• Male
• Membrane Proteins (genetics, physiology)
• Middle Aged
• Non-alcoholic Fatty Liver Disease (complications, genetics, metabolism)
• Obesity (complications, epidemiology, genetics, metabolism)
• Polymorphism, Single Nucleotide