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

• Published in: Diabetes care Vol. 43; no. 9; pp. 2161 - 2168
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-09-2020
• Subjects: Adipose tissue; Adult; Age; Aged; Alleles; Autoimmune diseases; Case-Control Studies; Clamps; Clusters; Cross-Sectional Studies; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Dilution; Domains; Fatty acids; Fatty liver; Female; Gene Frequency; Gene polymorphism; Genetic Association Studies; Genetic Predisposition to Disease; Genotyping; Germany - epidemiology; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin - genetics; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; Lipase - genetics; Lipase - physiology; Lipid Metabolism - genetics; Lipids; Lipolysis; Liver - metabolism; Liver diseases; Male; Membrane Proteins - genetics; Membrane Proteins - physiology; Middle Aged; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Nucleotides; Obesity - complications; Obesity - epidemiology; Obesity - genetics; Obesity - metabolism; Phospholipase; Polymorphism; Polymorphism, Single Nucleotide; Research design; Sensitivity; Single-nucleotide polymorphism; Germany
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/dc20-0329

The rs738409(G) single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (
) 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.
A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS.
The G allele associated positively with HCL (β = 0.36,
< 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
< 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 (
< 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],
< 0.05), MARD (3.0% [1.0; 7.9],
< 0.001), SAID (0.4% [0.0; 1.5],
< 0.001), and glucose-tolerant (0.9% [0.4; 4.9),
< 0.001) group. Although the
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
< 0.001).
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.