A serine/alanine polymorphism in the nucleotide-binding fold-2 of the sulphonylurea receptor-1 (S1369A) is associated with enhanced glucose-induced insulin secretion during pregnancy

The sulphonylurea receptor-1 (SUR-1) regulates glucose-induced insulin secretion by controlling K+-ATP channel activity of the pancreatic β-cell membrane. In this study, we investigated the putative role of a T/G-polymorphism (exon 33, codon 1369; S1369A) in the adenosine diphosphate-sensing nucleotide-binding fold-2 (NBF-2) of the SUR-1 on glucose-induced insulin secretion during an oral glucose tolerance test in pregnant women (PW; n=182). Compared to PW with the T/T genotype, statistically significant elevated C-peptide concentrations were found 60 min after glucose intake in PW with the T/G and G/G genotype (T/T 9.0±0.4 ng/ml vs T/G 10.8±0.4 ng/ml or G/G 10.8±0.7 ng/ml, p=0.01). Furthermore, compared to PW with T/T genotype the ΔC-peptide (60/0 min) was significantly enhanced in PW with T/G or G/G genotype (T/T 6.7±0.3 vs T/G 8.9±0.4 or G/G 8.9±0.7, p=0.0009). A significant correlation of C-peptide concentrations with blood glucose (BG) 60 min after glucose intake was only found in PW with the T/T genotype (r=0.6, p<0.0004). Similarly, a significant correlation of insulin concentrations with BG 60 min after glucose intake was observed in PW with T/T genotype (r=0.5, p<0.0001) and T/G genotype (r=0.24, p<0.03) but not in PW with G/G genotype (r=0.01, p=0.9). From our data we conclude that in PW with the alanine substitution in the NBF-2 region, the insulin response of the pancreatic β-cell after glucose intake is enhanced and does not correlate with actual BG levels