A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads

Aims/hypothesis: An association between elevated fasting plasma glucose and the common rs560887 G allele in the G6PC2/ABCB11 locus has been reported. In Danes we aimed to examine rs560887 in relation to plasma glucose and serum insulin responses following oral and i.v. glucose loads and in relation to hepatic glucose production during a hyperinsulinaemic-euglycaemic clamp. Furthermore, we examined rs560887 for association with impaired fasting glycaemia (IFG), impaired glucose tolerance (IGT), type 2 diabetes and components of the metabolic syndrome. Methods: rs560887 was genotyped in the Inter99 cohort (n=5,899), in 366 young, healthy Danes, in non-diabetic relatives of type 2 diabetic patients (n=196), and in young and elderly twins (n=159). Participants underwent an OGTT, an IVGTT or a 2 h hyperinsulinaemic-euglycaemic clamp. Results: The rs560887 G allele associated with elevated fasting plasma glucose (p=2×10^-14) but not with plasma glucose levels at 30 min (p=0.9) or 120 min (p=0.9) during an OGTT. G allele carriers had elevated levels of serum insulin at 30 min during an OGTT (p=1×10^-4) and relatives of type 2 diabetes patients carrying the G allele had an increased acute insulin response (p=4×10^-4) during an IVGTT. Among elderly twins, G allele carriers had higher basal hepatic glucose production (p=0.04). Finally, the G allele associated with the risk of having IFG (OR 1.26, 95% CI 1.08-1.47, p=0.002), but not with IGT (OR 0.94, 95% CI 0.82-1.08, p=0.4) or type 2 diabetes (OR 0.93, 95% CI 0.84-1.04, p=0.2). Conclusions/ interpretation: The common rs560887 G allele in the G6PC2/ABCB11 locus is associated with increased fasting glycaemia and increased risk of IFG, associations that may be partly related to an increased basal hepatic glucose production rate.