An Insertion/Deletion Polymorphism in the alpha2B Adrenoceptor Gene is Associated with Age at Onset of Type 2 Diabetes Mellitus

Abstract

Alpha2B adrenoceptor (alpha2B-AR) mediates a variety of functions, including insulin secretion. An insertion/deletion (I/D) polymorphism of the alpha2B-AR gene located on chromosome 2 has recently been described. The aim of the present study was to examine if there is a difference in the D allele frequency of alpha2B-AR gene between type 2 diabetic patients and controls, as well as to ascertain whether the D allele confers an increased risk for earlier onset of diabetes. This study included 199 type 2 diabetic patients and 204 age- and sex-matched healthy volunteers. Genotyping of I/D polymorphism was performed by PCR. No significant difference in the D allele frequency was observed between the two groups (22.1% vs. 19.1%, p=0.409). Among type 2 diabetic patients, however, presence of the D allele was associated with significantly younger age at onset of diabetes (51.4±8.6 vs. 59.2±9.7 years, p<0.001). Multiple stepwise linear regression identified alpha2B I/D genotype as an independent predictor of age at onset of DMT2, explaining 14.3% of its variance. This result indicates that the D allele may be implicated in impaired glucose metabolism leading to earlier manifestation of diabetes in predisposed subjects.

Diabetes mellitus - adrenoceptor - polymorphism

References

• 1 Baldwin CT, Schwartz F, Baima J, Burzstyn M, DeStefano AL, Gavras I, Handy DE, Joost O, Martel T, Manolis A, Nicolaou M, Bresnahan M, Farrer L, Gavras H. Identification of a polymorphic glutamic acid stretch in the alpha2B-adrenergic receptor and lack of linkage with essential hypertension.  Am J Hypertens. 1999;  12 853-857
• 2 Broadstone VL, Pfeifer MA, Bajaj V, Stagner JI, Samols E. Alpha-adrenergic blockade improves glucose-potentiated insulin secretion in non-insulin-dependent diabetes mellitus.  Diabetes. 1987;  36 932-937
• 3 Clerk LH, Vincent MA, Lindner JR, Clark MG, Rattigan S, Barrett EJ. The vasodilatory actions of insulin on resistance and terminal arterioles and their impact on muscle glucose uptake.  Diabetes Metab Res Rev. 2004;  20 3-12
• 4 Devedjian JC, Pujol A, Cayla C, George M, Casellas A, Paris H, Bosch F. Transgenic mice overexpressing alpha2A-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasis.  Diabetologia. 2000;  43 899-906
• 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
• 6 Heinonen P, Koulu M, Pesonen U, Karvonen MK, Rissanen A, Laakso M, Valve R, Uusitupa M, Scheinin M. Identification of a three-amino acid deletion in the alpha2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects.  J Clin Endocrinol Metab. 1999;  84 2429-2433
• 7 Kahn CR, Vicent D, Doria A. Genetics of non-insulin-dependent (type-II) diabetes mellitus.  Annu Rev Med. 1996;  47 509-531
• 8 Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.  Diabetologia. 2003;  46 3-19
• 9 Kirstein SL, Insel PA. Autonomic nervous system pharmacogenomics: a progress report.  Pharmacol Rev. 2004;  56 31-52
• 10 Kobilka BK, Matsui H, Kobilka TS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ, Regan JW. Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor.  Science. 1987;  238 650-656
• 11 LeRoith D. Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities.  Am J Med. 2002;  113 ((Suppl 6A)) 3S-11S
• 12 Link RE, Desai K, Hein L, Stevens ME, Chruscinski A, Bernstein D, Barsh GS, Kobilka BK. Cardiovascular regulation in mice lacking alpha2-adrenergic receptor subtypes b and c.  Science. 1996;  273 803-805
• 13 Lomasney JW, Lorenz W, Allen LF, King K, Regan JW, Yang-Feng TL, Caron MG, Lefkowitz RJ. Expansion of the alpha 2-adrenergic receptor family: cloning and characterization of a human alpha 2-adrenergic receptor subtype, the gene for which is located on chromosome 2.  Proc Natl Acad Sci USA. 1990;  87 5094-5098
• 14 Millikan R. The changing face of epidemiology in the genomics era.  Epidemiology. 2002;  13 472-480
• 15 Philipp M, Brede M, Hein L. Physiological significance of alpha(2)-adrenergic receptor subtype diversity: one receptor is not enough.  Am J Physiol Regul Integr Comp Physiol. 2002;  283 R287-295
• 16 Regan JW, Kobilka TS, Yang-Feng TL, Caron MG, Lefkowitz RJ, Kobilka BK. Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype.  Proc Natl Acad Sci USA. 1988;  85 6301-6305
• 17 , Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) Express National Heart, Lung, and Blood Institute. Bethesda, Md. 2003. JAMA. 2003;  289 2560-2571
• 18 Siitonen N, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Laakso M, Uusitupa M. Association between a deletion/insertion polymorphism in the alpha2B-adrenergic receptor gene and insulin secretion and Type 2 diabetes. The Finnish Diabetes Prevention Study.  Diabetologia. 2004;  47 1416-1424
• 19 Small KM, Liggett SB. Identification and functional characterization of alpha2-adrenoceptor polymorphisms.  Trends Pharmacol Sci. 2001;  22 471-477
• 20 Von Wowern F, Bengtsson K, Lindblad U, Rastam L, Melander O. Functional variant in the (alpha)2B adrenoceptor gene, a positional candidate on chromosome 2, associates with hypertension.  Hypertension. 2004;  43 592-597

Correspondence