Introduction & Objective: Weight loss is pivotal for, but variably effective in type 2 diabetes (T2D) and comorbidities. The G-allele in the rs738409 single nucleotide polymorphism within the patatin-like phospholipase domain-containing protein 3 (PNPLA3) associates with liver steatosis and differently with insulin resistance. We hypothesized that this G-allele may affect response to dietary interventions.
Methods: T2D volunteers (age 18-69 years, BMI ≥30 kg/m2, HbA1c <9.0%) were randomly assigned to 8-w hypocaloric diets (1.256 kJ reduction in total daily energy intake), either high in cereal fiber and coffee, but red meat-free (healthy diet [HD]; n=16), or low in fiber, devoid of coffee, but rich in red meat (unhealthy diet [UD]; n=15). Genotyping was performed for the PNPLA3 gene. Insulin sensitivity (M-value) was measured by hyperinsulinemic-euglycemic clamps, hepatic lipid content (HCL) by 1H magnetic resonance spectroscopy before and after the intervention.
Results: Baseline HCL was similar between groups (carriers: UD 18.5±8.5%, HD 14.6±8.4%; non-carriers: UD 13.5±4.2%, HD 17.8±7.3%). In the face of comparable body weight reduction (~4.7%), carriers and non-carriers decreased HCL from 0 to 8 weeks of UD (-57% and -46%, p<0.05), with no difference between groups. HD also led to reduction in HCL in non-carriers, but to lesser extent in carriers (-65% vs. -36%, p<0.05 vs baseline and between groups). Changes from baseline in liver fibrosis markers (fibrosis-4 index, AST/platelet ratio index, Forns score) and inflammation (interleukins) did not differ by carrier status. M-value improved in all groups (carriers +27% and non-carriers +21% on HD and carriers on UD +37%, all p<0.05 vs baseline) except for the non-carriers on UD.
Conclusion: Low-energy diets improve insulin sensitivity and steatosis in T2D but the presence of the G allele of PNPLA3 reduces the beneficial effects of a healthy (cereal- and coffee-enriched, but red meat-free) diet on liver lipid content.
K. Pafili: None. O.P. Zaharia: None. K. Strassburger: None. B. Knebel: None. C. Herder: None. M. Huttasch: None. Y. Karusheva: None. S. Kabisch: Other Relationship; Sanofi, Boehringer-Ingelheim, Berlin-Chemie AG. Research Support; J. Rettenmaier & Söhne, Rosenberg, Germany, California Walnut Commission, Almond Board of California, Wilhelm-Doerenkamp-Foundation. Other Relationship; JuZo-Akademie, Lilly Diabetes. A. Strom: Consultant; Wörwag Pharma. J. Szendroedi: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca.
