Glucokinase regulatory proten genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome

Authors: PEREZ-MARTINEZ, PABLO - Universidad De Cordoba; DELGADO-LISTA, JAVIER - Universidad De Cordoba; GARCIA-RIOS, ANTONIO - Reina Sofia University; MCMONAGLE, JOLENE - University College Dublin; GULSETH, HANNE - University Of Oslo; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SHAW, DANIELLE - University Of Reading; KARLSTROM, BRITA - Uppsala University; KIEC-WILK, BEATA - Jagiellonian University; HELAL, OLFA - University Of The Mediterranean; MALCZEWSKA-MALEC, MALGORZATA - Jagiellonian University; DEFOORT, CATHERINE - Institut National De La Recherche Agronomique (INRA); RISERUS, ULF - Uppsala University; SARIS, WIM H.M. - Maastricht University; LOVEGROVE, JULIE - University Of Reading; DREVON, CHRISTIAN - University Of Oslo; ROCHE, HELEN - University College Dublin; LOPEZ-MIRANDA, JOSE (S) - Reina Sofia University; BLAAK, ELLEN - Maastricht University

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/3/2011
Publication Date: 6/6/2011
Citation: Perez-Martinez, P., Delgado-Lista, J., Garcia-Rios, A., Mcmonagle, J., Gulseth, H.L., Ordovas, J.M., Shaw, D.I., Karlstrom, B., Kiec-Wilk, B., Blaak, E.E., Helal, O., Malczewska-Malec, M., Defoort, C., Riserus, U., Saris, W., Lovegrove, J.A., Drevon, C.A., Roche, H.M., Lopez-Miranda, J. 2011. Glucokinase regulatory proten genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome. PLoS One. 6(6):e20555.

Interpretive Summary: Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Specifically, omega-3 polyunsaturated fatty acids (n-3 polyunsaturated fatty acids (PUFA)) have been of considerable interest, due to their potential to reduce metabolic syndrome (MetS) risk. Glucokinase Regulatory Protein (GCKR) plays a central role regulating both triglyceride and glucose metabolism. Our objective was to examine whether genetic variability at the GCKR gene was associated with risk factors associated with diabetes and inflammation in subjects with MetS. Relevant biomarkers and the GCKR rs1260326-P446L polymorphism, were determined in 379 subjects with MetS participating in the LIPGENE dietary cohort. Our results show a significant interaction between the GCKR rs1260326-P446L polymorphism and n-3 polyunsaturated fatty acids (PUFA) levels found in blood modulating insulin resistance and inflammatory markers in MetS subjects. This suggests that targeted dietary prevention can alleviate the risk of diabetes in genetically susceptible individuals.

Technical Abstract: Glucokinase Regulatory Protein (GCKR) plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been of considerable interest, due to their potential to reduce metabolic syndrome (MetS) risk. To examine whether genetic variability at the GCKR gene locus was associated with the degree of insulin resistance, plasma concentrations of C-reactive protein (CRP) and n-3 polyunsaturated fatty acids (PUFA) in MetS subjects. Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-B, plasma concentrations of C-peptide, CRP, fatty acid composition and the GCKR rs1260326-P446L polymorphism, were determined in a cross-sectional analysis of 379 subjects with MetS participating in the LIPGENE dietary cohort. Among subjects with n-3 polyunsaturated fatty acids (PUFA) levels below the population median, carriers of the common C/C genotype had higher plasma concentrations of fasting insulin (P=0.019), C-peptide (P=0.004), HOMA-IR (P=0.008) and CRP (P=0.032) as compared with subjects carrying the minor T-allele (Leu446). In contrast, homozygous C/C carriers with n-3 polyunsaturated fatty acids (PUFA) levels above the median showed lower plasma concentrations of fasting insulin, peptide C, HOMA-IR and CRP, as compared with individuals with the T-allele. We have demonstrated a significant interaction between the GCKR rs1260326-P446L polymorphism and plasma n-3 polyunsaturated fatty acids (PUFA) levels modulating insulin resistance and inflammatory markers in MetS subjects. Further studies are needed to confirm this gene-diet interaction in the general population and whether targeted dietary recommendations can prevent MetS in genetically susceptible individuals.