Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medical Genetics
Published in: BMC Medical Genetics 1/2006

Open Access 01-12-2006 | Research article

Analysis of coding variants in the betacellulin gene in type 2 diabetes and insulin secretion in African American subjects

Authors: Steven C Elbein, Xiaoqin Wang, Mohammad A Karim, Winston S Chu, Kristi D Silver

Published in: BMC Medical Genetics | Issue 1/2006

Login to get access

Abstract

Background

Betacellulin is a member of the epidermal growth factor family, expressed at the highest levels predominantly in the pancreas and thought to be involved in islet neogenesis and regeneration. Nonsynonymous coding variants were reported to be associated with type 2 diabetes in African American subjects. We tested the hypotheses that these previously identified variants were associated with type 2 diabetes in African Americans ascertained in Arkansas and that they altered insulin secretion in glucose tolerant African American subjects.

Methods

We typed three variants, exon1 Cys7Gly (C7G), exon 2 Leu44Phe (L44F), and exon 4 Leu124Met (L124M), in 188 control subjects and 364 subjects with type 2 diabetes. We tested for altered insulin secretion in 107 subjects who had undergone intravenous glucose tolerance tests to assess insulin sensitivity and insulin secretion.

Results

No variant was associated with type 2 diabetes, and no variant altered insulin secretion or insulin sensitivity. However, an effect on lipids was observed for all 3 variants, and variant L124M was associated with obesity measures.

Conclusion

We were unable to confirm a role for nonsynonymous variants of betacellulin in the propensity to type 2 diabetes or to impaired insulin secretion.
Literature
1.
DeFronzo RA: Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Reviews. 1997, 5: 177-270.
2.
Kahn SE: The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. 2003, 46: 3-19. 10.1007/s00125-003-1190-9.CrossRefPubMed
3.
Ferrannini E, Mari A: Beta cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia. 2004, 47: 943-956. 10.1007/s00125-004-1381-z.CrossRefPubMed
4.
Weyer C, Bogardus C, Mott DM, Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999, 104: 787-794.CrossRefPubMedPubMedCentral
5.
Elbein SC, Hasstedt SJ, Wegner K, Kahn SE: Heritability of pancreatic beta-cell function among nondiabetic members of Caucasian familial type 2 diabetic kindreds. J Clin Endocrinol Metab. 1999, 84: 1398-1403. 10.1210/jc.84.4.1398.PubMed
6.
Watanabe RM, Valle T, Hauser ER, Ghosh S, Eriksson J, Kohtamaki K, Ehnholm C, Tuomilehto J, Collins FS, Bergman RN, Boehnke M: Familiarity of quantitative metabolic traits in Finnish families with non-insulin-dependent diabetes mellitus. Finland-United States Investigation of NIDDM Genetics (FUSION) Study investigators. Hum Hered. 1999, 49: 159-168. 10.1159/000022865.CrossRefPubMed
7.
Poulsen P, Levin K, Petersen I, Christensen K, Beck-Nielsen H, Vaag A: Heritability of insulin secretion, peripheral and hepatic insulin action, and intracellular glucose partitioning in young and old danish twins. Diabetes. 2005, 54: 275-283.CrossRefPubMed
8.
Polonsky KS, Sturis J, Bell GI: Non-insulin-dependent diabetes mellitus – a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996, 334: 777-783. 10.1056/NEJM199603213341207.CrossRefPubMed
9.
Yamamoto K, Miyagawa J, Waguri M, Sasada R, Igarashi K, Li M, Nammo T, Moriwaki M, Imagawa A, Yamagata K, Nakajima H, Namba M, Tochino Y, Hanafusa T, Matsuzawa Y: Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion. Diabetes. 2000, 49: 2021-2027.CrossRefPubMed
10.
Ishiyama N, Kanzaki M, Seno M, Yamada H, Kobayashi I, Kojima I: Studies on the betacellulin receptor in pancreatic AR42J cells. Diabetologia. 1998, 41: 623-628. 10.1007/s001250050959.CrossRefPubMed
11.
Li L, Yi Z, Seno M, Kojima I: Activin A and betacellulin: effect on regeneration of pancreatic beta-cells in neonatal streptozotocin-treated rats. Diabetes. 2004, 53: 608-615.CrossRefPubMed
12.
Miyagawa J, Hanafusa O, Sasada R, Yamamoto K, Igarashi K, Yamamori K, Seno M, Tada H, Nammo T, Li M, Yamagata K, Nakajima H, Namba M, Kuwajima M, Matsuzawa Y: Immunohistochemical localization of betacellulin, a new member of the EGF family, in normal human pancreas and islet tumor cells. Endocr J. 1999, 46: 755-764.CrossRefPubMed
13.
Mashima H, Ohnishi H, Wakabayashi K, Mine T, Miyagawa J, Hanafusa T, Seno M, Yamada H, Kojima I: Betacellulin and activin A coordinately convert amylase-secreting pancreatic AR42J cells into insulin-secreting cells. J Clin Invest. 1996, 97: 1647-1654.CrossRefPubMedPubMedCentral
14.
Silver K, Tolea M, Wang J, Pollin TI, Yao F, Mitchell BD: The exon 1 Cys7Gly polymorphism within the betacellulin gene is associated with type 2 diabetes in African Americans. Diabetes. 2005, 54: 1179-1184.CrossRefPubMed
15.
Silver KD, Magnuson VL, Tolea M, Wang J, Hagopian WA, Mitchell BD: Association of a polymorphism in the betacellulin gene with type 1 diabetes mellitus in two populations. J Mol Med. 2006
16.
Ward WK, Bolgiano DC, McKnight B, Halter JB, Porte D: Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984, 74: 1318-1328.CrossRefPubMedPubMedCentral
17.
Boston RC, Stefanovski D, Moate PJ, Sumner AE, Watanabe RM, Bergman RN: MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther. 2003, 5: 1003-1015. 10.1089/152091503322641060.CrossRefPubMed
18.
Pacini G, Bergman RN: MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput Methods Programs Biomed. 1986, 23: 113-122. 10.1016/0169-2607(86)90106-9.CrossRefPubMed
19.
Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte D: Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects: evidence for a hyperbolic function. Diabetes. 1993, 42: 1663-1672.CrossRefPubMed
20.
Ott J: Analysis of Human Genetic Linkage. 1999, Johns Hopkins University Press, Baltimore and London, Third
21.
Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005, 21: 263-265. 10.1093/bioinformatics/bth457.CrossRefPubMed
22.
Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001, 68: 978-989. 10.1086/319501.CrossRefPubMedPubMedCentral
23.
Saad MF, Steil GM, Kades WW, Ayad MF, Elsewafy WA, Boyadjian R, Jinagouda SD, Bergman RN: Differences between the tolbutamide-boosted and the insulin-modified minimal model protocols. Diabetes. 1997, 46: 1167-1171.CrossRefPubMed
24.
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science. 2002, 296: 2225-2229. 10.1126/science.1069424.CrossRefPubMed
25.
Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM: Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003, 52: 568-572.CrossRefPubMed
26.
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000, 26: 76-80. 10.1038/79839.CrossRefPubMed
27.
Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D: Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004, 53: 1360-1368.CrossRefPubMed
28.
Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A, Pankow JS, Province MA, Hunt SC, Boerwinkle E, Schork NJ, Risch NJ: Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet. 2005, 76: 268-275. 10.1086/427888.CrossRefPubMed
29.
Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A, Kessing BD, Malasky MJ, Scafe C, Le E, De Jager PL, Mignault AA, Yi Z, De The G, Essex M, Sankale JL, Moore JH, Poku K, Phair JP, Goedert JJ, Vlahov D, Williams SM, Tishkoff SA, Winkler CA, De La Vega FM, Woodage T, Sninsky JJ, Hafler DA, Altshuler D, Gilbert DA, O'Brien SJ, Reich D: A high-density admixture map for disease gene discovery in african americans. Am J Hum Genet. 2004, 74: 1001-1013. 10.1086/420856.CrossRefPubMedPubMedCentral
Metadata
Title
Analysis of coding variants in the betacellulin gene in type 2 diabetes and insulin secretion in African American subjects
Authors
Steven C Elbein
Xiaoqin Wang
Mohammad A Karim
Winston S Chu
Kristi D Silver
Publication date
01-12-2006
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2006
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-7-62

Other articles of this Issue 1/2006

BMC Medical Genetics 1/2006 Go to the issue

Research article

Evidence for a gene influencing heart rate on chromosome 5p13-14 in a meta-analysis of genome-wide scans from the NHLBI Family Blood Pressure Program

Research article

Paraoxonase gene polymorphisms and haplotype analysis in a stroke population

Software

GAIA: An easy-to-use web-based application for interaction analysis of case-control data

Research article

Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study

Research article

Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3)

Study protocol

Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability