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Diabetes 54:3560-3566, 2005
© 2005 by the American Diabetes Association, Inc.

A Functional Variant in the Human Betacellulin Gene Promoter Is Associated With Type 2 Diabetes

Yoshio Nakano1, Hiroto Furuta1, Asako Doi1, Shohei Matsuno1, Takayuki Nakagawa1, Hiroko Shimomura1, Setsuya Sakagashira1, Yukio Horikawa2, Masahiro Nishi1, Hideyuki Sasaki1, Tokio Sanke3, and Kishio Nanjo1

1 The First Department of Medicine, Wakayama Medical University, Wakayama, Japan
2 Department of Diabetes and Endocrinology, Gifu University School of Medicine, Gifu, Japan
3 Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan

Betacellulin (BTC) plays an important role in differentiation, growth, and antiapoptosis of pancreatic ß-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.

Address correspondence and reprint requests to Hiroto Furuta, MD, PhD, The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. E-mail: hfuruta{at}wakayama-med.ac.jp

Abbreviations: BTC, betacellulin; CPR, C-peptide response; EGF, epidermal growth factor


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.