The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels, and reduces type 2 diabetes risk in a prospective general French population: the D.E.S.I.R. Study

Abstract

Objective: Hepatic glucokinase (GCK) is a key regulator of glucose storage and disposal in the liver, where its activity is competitively modulated with respect to glucose by binding to glucokinase regulatory protein (GCKR) in the presence of fructose 6-phosphate. Genome-wide association studies for type 2 diabetes identified GCKR as a potential locus for modulating triglyceride levels. We evaluate in a general French population the contribution of the GCKR rs1260326-P446L polymorphism to quantitative metabolic parameters, and to dyslipidemia and hyperglycemia risk.

Research Design and Methods: Genotype effects of rs1260326 were studied in 4,833 participants from the prospective 9-year D.E.S.I.R. cohort: both at inclusion and using the up-to-four repeated measurements of the follow-up.

Results: The minor T-allele of rs1260326 was strongly associated with lower fasting glucose (-1.43% per T-allele, p = 8x10^-13), fasting insulin (-4.23%, p = 3x10^-7), HOMA-IR (-5.69%, p = 1x10^-8), and conversely higher triglyceride levels (+3.41%, p = 1x10^-4) during the 9-year study. These effects relate to a lower risk of hyperglycemia (OR = 0.79 [0.70-0.88], p = 4x10^-5), and of incident cases during the study (HR = 0.83 [0.74-0.95], p=0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (-30G) alleles conferred lower fasting glycemia (p = 1x10^-13), insulinemia (p = 5x10^-6), and hyperglycemia risk (p = 1x10^-6).

Conclusions: The GCKR-L446 carriers are protected against type 2 diabetes despite higher triglyceride levels and risk of dyslipidemia, which suggests a potential molecular mechanism by which these two components of the metabolic syndrome can be dissociated.