The Common C49620T Polymorphism in the Sulfonylurea Receptor Gene (ABCC8), Pancreatic Beta Cell Function and Long-Term Diabetic Complications in Obese Patients with Long-Lasting Type 2 Diabetes Mellitus

Abstract

Hypothesis: A gene polymorphism associated with accelerated β-cell failure may lead to a more rapid development of long-term complications of type 2 diabetes (T2DM) due to a worse metabolic control of the disease.

Aim of the study: Evaluation of an association between the intronic C49620T (exon 16 -3c→t) polymorphism in the ABCC8 (SUR1) gene and β-cell function, as well as the prevalence of long-term diabetic complications in obese patients with long-lasting type 2 diabetes.

Methods: Two hundred and fifteen obese patients with at least a 10-year history of T2DM were thoroughly characterized clinically. In all the patients the intravenous glucagon test was performed and the C49620T ABCC8 polymorphism was assessed. Subgroups of patients, classified either according to genotype or to allele carriage, were compared.

Results: No difference was found between the groups in variables describing β-cell function and the prevalence of chronic diabetic complications, with the exception of a significantly lower incidence of brain stroke in CC homozygotes than in patients carrying T allele (CT+TT). Body mass index was higher in patients carrying C allele than in TT homozygotes. HDL-cholesterol was higher in CT heterozygous than in homozygous CC or TT patients.

Conclusions: There is no association between the ABCC8 polymorphism gene and the β-cell function or the prevalence of chronic diabetic complications in obese patients with long-term T2DM, except for brain stroke. The results might suggest that the homozygous CC subjects are at lower risk of the complication, but additional studies are warranted to test this finding.

Key words

type 2 diabetes - β-cell function - glucagon test - ABCC8 gene polymorphism

References

• 1 Albareda M, Rigla M, Rodriguez-Espinosa J, Caballero A, Chico A, Cabezas R, Carreras G, Perez A. Influence of exogenous insulin on C-peptide levels in subjects with type 2 diabetes.  Diabetes Res Clin Pract. 2005;  68 202-206
• 2 Arner P, Pollare T, Lithell H. Different aetiologies of type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects.  Diabetologia. 1991;  34 483-487
• 3 Ashcroft FM. ATP-sensitive potassium channelopathies: focus on insulin secretion.  J Clin Invest. 2005;  115 2047-2058
• 4 Elbein SC, Sun J, Scroggin E, Teng K, Hasstedt SJ. Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds: the sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1alpha genes.  Diabetes Care. 2001;  24 472-478
• 5 Hansen T, Echwald SM, Hansen L, Moller AM, Almind K, Clausen JO, Urhammer SA, Inoue H, Ferrer J, Bryan J, Aguilar-Bryan L, Permutt MA, Pedersen O. Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene.  Diabetes. 1998;  47 598-605
• 6 Hart LM, de Knijff P, Dekker JM, Stolk RP, Nijpels G, van der Does FE, Ruige JB, Grobbee DE, Heine RJ, Maassen JA. Variants in the sulfonylurea receptor gene: association of the exon 16-3t variant with type II diabetes mellitus in Dutch Caucasians.  Diabetologia. 1999;  42 617-620
• 7 Hart LM, Dekker JM, van Haeften TW, Ruige JB, Stehouwer CD, Erkelens DW, Heine RJ, Maassen JA. Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus.  Diabetologia. 2000;  43 515-519
• 8 Holman R, Hines G, Kennedy I, Stevens R, Matthews D, Levy J. A calculator for HOMA.  Diabetologia. 2004;  47 ((Suppl 1)) A222
• 9 Inoue H, Ferrer J, Welling CM, Elbein SC, Hoffman M, Mayorga R, Warren-Perry M, Zhang Y, Millns H, Turner R, Province M, Bryan J, Permutt MA, Aguilar-Bryan L. Sequence variants in the sulfonylurea recepor (SUR) gene are associated with NIDDM in caucasians.  Diabetes. 1996;  45 825-831
• 10 Lahiri DK, Bye S, Nurnberger Jr JI, Hodes ME, Crisp M. A non-organic and non-enzymatic extraction method gives higher yields of genomic DNA from whole-blood samples than do nine other methods tested.  J Biochem Biophys Methods. 1992;  25 193-205
• 11 Meirhaeghe A, Helbecque N, Cottel D, Arveiler D, Ruidavets JB, Haas B, Ferrieres J, Tauber JP, Bingham A, Amouyel P. Impact of sulfonylurea receptor 1 genetic variability on non-insulin-dependent diabetes mellitus prevalence and treatment: a population study.  Am J Med Genet.. 2001;  101 4-8
• 12 Schneider S, Feilen PJ, Schreckenberger M, Schwanstecher M, Schwanstecher C, Buchholz HG, Thews O, Oberholzer K, Korobeynikov A, Bauman A, Comagic S, Piel M, Schirrmacher E, Shiue CY, Alavi AA, Bartenstein P, Rosch F, Weber MM, Klein HH, Schirrmacher R. In vitro and in vivo evaluation of novel glibenclamide derivatives as imaging agents for the non-invasive assessment of the pancreatic islet cell mass in animals and humans.  Exp Clin Endocrinol Diabetes. 2005;  113 388-395
• 13 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling.  Diabetes Care. 2004;  27 1487-1495
• 14 Weisnagel SJ, Rankinen T, Nadeau A, Rao DC, Chagnon YC, Perusse L, Bouchard C. Decreased Fasting and Oral Glucose Stimulated C-peptide in Nondiabetic Subjects With Sequence Variants in the Sulfonylurea Receptor 1 Gene.  Diabetes. 2001;  50 697-702
• 15 Wright A, Burden AC, Paisey RB, Cull CA, Holman RR. U.K. Prospective Diabetes Study Group . Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57).  Diabetes Care. 2002;  25 330-336
• 16 Zychma MJ, Gumprecht J, Strojek K, Grzeszczak W, Moczulski D, Trautsolt W, Karasek D. Sulfonylurea receptor gene 16-3 polymorphism - association with sulfonylurea or insulin treatment in type 2 diabetic subjects.  Med Sci Monit. 2002;  8 CR512-515

Correspondence