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

Pablo Perez-Martinez, Javier Delgado-Lista, Antonio Garcia-Rios, Jolene Mc Monagle, Hanne L Gulseth, Jose M Ordovas, Danielle I Shaw, Brita Karlström, Beata Kiec-Wilk, Ellen E Blaak, Olfa Helal, Małgorzata Malczewska-Malec, Catherine Defoort, Ulf Risérus, Wim H M Saris, Julie A Lovegrove, Christian A Drevon, Helen M Roche, Jose Lopez-Miranda, Pablo Perez-Martinez, Javier Delgado-Lista, Antonio Garcia-Rios, Jolene Mc Monagle, Hanne L Gulseth, Jose M Ordovas, Danielle I Shaw, Brita Karlström, Beata Kiec-Wilk, Ellen E Blaak, Olfa Helal, Małgorzata Malczewska-Malec, Catherine Defoort, Ulf Risérus, Wim H M Saris, Julie A Lovegrove, Christian A Drevon, Helen M Roche, Jose Lopez-Miranda

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.

Objective: 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 PUFA in MetS subjects.

Design: 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.

Results: Among subjects with n-3 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 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.

Conclusions: We have demonstrated a significant interaction between the GCKR rs1260326-P446L polymorphism and plasma n-3 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.

Trial registration: ClinicalTrials.gov NCT00429195.

Conflict of interest statement

Competing Interests: Author Christian A. Drevon has a relationship with Aktieselskabet Freia Chocolade Fabrik's Medical Foundation. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Interaction between the GCKR rs1260326-P446L…
Figure 1. Interaction between the GCKR rs1260326-P446L polymorphism and plasma concentrations of omega-3 polyunsaturated fatty acids (n-3 PUFA), above or below the median within the same genotype group of fasting insulin (A), C-peptide levels (B), homeostasis model assessment of insulin resistance (HOMA-IR) (C) and C-reactive protein levels (CRP) (D).
Values are means ± SD. P values were adjusted for age, sex, BMI, anti-hypertension pharmacological treatment and LIPGENE centre of origin.
Figure 2. Predicted values for homeostasis model…
Figure 2. Predicted values for homeostasis model assessment of insulin resistance (HOMA-IR) (A) and C-reactive protein levels (CRP) (B) for the GCKR rs1260326-P446L polymorphism.
A difference was observed between the genotype groups, with the minor T-allele genotype group (triangles) appearing to be “high responders” to plasma concentration of omega-3 polyunsaturated fatty acids (n-3 PUFA) and the major C allele homozygote group (circles) appearing to be “low responders”.

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