Abstract

Betacellulin (BTC) plays an important role in differentiation, growth, and antiapoptosis of pancreatic β-cells. We characterized about 2.3 kb of the 5′-flanking region of human BTC gene and identified six polymorphisms (−2159A>G, −1449G>A, −1388C>T, −279C>A, −233G>C, and −226A>G). The G allele in the −226A>G polymorphism was more frequent in type 2 diabetic patients (n = 250) than in nondiabetic subjects (n = 254) (35.6% vs. 27.8%, P = 0.007), and the −2159G, −1449A, and −1388T alleles were in complete linkage disequilibrium with the −226G allele. The frequencies of the −279A and −233C alleles were low (7.0 and 2.0% in diabetic patients), and no significant differences were observed. In the diabetic group, insulin secretion ability, assessed by the serum C-peptide response to intravenous glucagon stimulation, was lower in patients with the −226G allele (G/G, 2.96 ± 0.16 ng/ml; G/A, 3.65 ± 0.18 ng/ml; A/A, 3.99 ± 0.16 ng/ml at 5 min after stimulation; P = 0.008). Furthermore, in vitro functional analyses indicated that both the −226G and the −233C alleles caused an ∼50% decrease in the promoter activity, but no effects of the −2159A>G, −1449G>A, −1388C>T, and −279C>A polymorphisms were observed. These results suggest that the −226A/G polymorphism of the BTC gene may contribute to the development of diabetes.