The G-allele in the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain containing 3 (PNPLA3) gene associates with increased risk of nonalcoholic fatty liver disease (NAFLD) and its progression. As the recently-described severe insulin resistant diabetes (SIRD) cluster specifically relates to NAFLD, the present study examined whether this SNP differently associates with insulin sensitivity and hepatic lipid content (HCL) in clusters of new-onset diabetes patients. Participants (n=917) of the prospective German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps and magnetic resonance spectroscopy. SIRD had the 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 G-allele compared to other clusters and the glucose tolerant controls (p<0.05). Also, HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%], MARD [3.0 (1.0;7.9)%], SAID [0.4 (0.0;1.5)%] and the glucose tolerant group [0.9 (0.4;4.9)%] (all p<0.05). Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity or HCL in SIRD, G-allele carriers of this cluster had higher free fatty acids and greater adipose-tissue insulin resistance than non-carriers.

In conclusion, SIRD patients are more frequently carriers of the G-allele which is associated with adipose-tissue insulin resistance and lipolysis. Together, these alterations may mutually accelerate NAFLD and progression of SIRD.


O.P. Zaharia: None. K. Strassburger: None. B. Knebel: None. Y. Kupriyanova: None. Y. Karusheva: None. K. Bodis: None. M. Wolkersdorfer: None. D.F. Markgraf: None. V. Burkart: None. J. Hwang: None. J. Kotzka: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S.


German Federal Ministry of Health; Ministry of Culture and Science of North Rhine-Westphalia; German Federal Ministry of Education and Research; German Center for Diabetes Research

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