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Previous Volume 333:343-347 August 10, 1995 Number 6 Next

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ABSTRACT

Background The ₃-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis.

Methods To investigate whether mutations in the gene for the ₃-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM).

Results A missense mutation was identified in the gene for the ₃-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic and diabetic subjects. However, in subjects homozygous for the mutation the mean (±SD) age at the onset of NIDDM was significantly lower (36±10 years) than in Trp64Arg heterozygotes (40±10 years) or normal homozygotes (41±11 years; P = 0.02). Furthermore, subjects with the mutation tended to have a lower adjusted resting metabolic rate (P = 0.14 by analysis of covariance).

Conclusions Pima subjects homozygous for the Trp64Arg ₃-adrenergic–receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.

Source Information

From the Divisions of Geriatric Medicine and Gerontology (J.W., F.S.C., S.A., J.R., A.R.S.) and Endocrinology and Metabolism (K.S.), Johns Hopkins University School of Medicine, Baltimore; the Clinical Diabetes and Nutrition Section (C.B.) and the Diabetes and Arthritis Epidemiology Section (W.C.K.), National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Ariz.; the Laboratory of Clinical Physiology, National Institute on Aging, Baltimore (F.S.C., J.D.S.); the Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md. (N.R.); the Laboratoire d'Immunopharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, Paris (B.M., A.D.S.); and the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center, San Antonio (M.P.S.).

Address reprint requests to Dr. Shuldiner at the Johns Hopkins University School of Medicine, 5501 Bayview Cir., Rm. 5A42, Baltimore, MD 21224.

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• Fujisawa, T., Ikegami, H., Kawaguchi, Y., Ogihara, T. (1998). Meta-Analysis of the Association of Trp64Arg Polymorphism of {beta}3-Adrenergic Receptor Gene with Body Mass Index. J. Clin. Endocrinol. Metab. 83: 2441-2444 [Abstract] [Full Text]  
• Silver, K., Walston, J., Plotnick, L., Taylor, S. I., Kahn, C. R., Shuldiner, A. R. (1997). Molecular Scanning of {beta}-3-Adrenergic Receptor Gene in Total Congenital Lipoatrophic Diabetes Mellitus. J. Clin. Endocrinol. Metab. 82: 3395-3398 [Abstract] [Full Text]  
• Dagogo-Jack, S., Santiago, J. V. (1997). Pathophysiology of Type 2 Diabetes and Modes of Action of Therapeutic Interventions. Arch Intern Med 157: 1802-1817 [Abstract]  
• Elbein, S. C. (1997). The Genetics of Human Noninsulin-Dependent (Type 2) Diabetes Mellitus. J. Nutr. 127: 1891-1891 [Abstract] [Full Text]  
• Nagase, T., Aoki, A., Yamamoto, M., Yasuda, H., Kado, S., Nishikawa, M., Kugai, N., Akatsu, T., Nagata, N. (1997). Lack of Association between the Trp64Arg Mutation in the {beta}3-Adrenergic Receptor Gene and Obesity in Japanese Men: A Longitudinal Analysis. J. Clin. Endocrinol. Metab. 82: 1284-1287 [Abstract] [Full Text]  
• Meyers, D. S., Skwish, S., Dickinson, K. E. J., Kienzle, B., Arbeeny, C. M. (1997). {beta}3-Adrenergic Receptor-Mediated Lipolysis and Oxygen Consumption in Brown Adipocytes from Cynomolgus Monkeys. J. Clin. Endocrinol. Metab. 82: 395-401 [Abstract] [Full Text]  
• Zilberfarb, V, Pietri-Rouxel, F, Jockers, R, Krief, S, Delouis, C, Issad, T, Strosberg, A. (1997). Human immortalized brown adipocytes express functional beta3-adrenoceptor coupled to lipolysis. J. Cell Sci. 110: 801-807 [Abstract]  
• Soloveva, V., Graves, R. A., Rasenick, M. M., Spiegelman, B. M., Ross, S. R. (1997). Transgenic Mice Overexpressing the {beta}1-Adrenergic Receptor in Adipose Tissue Are Resistant to Obesity. Mol. Endocrinol. 11: 27-38 [Abstract] [Full Text]  
• Jezek, P., Hanus, J., Semrad, C., Garlid, K. D. (1996). Photoactivated Azido Fatty Acid Irreversibly Inhibits Anion and Proton Transport through the Mitochondrial Uncoupling Protein. J. Biol. Chem. 271: 6199-6205 [Abstract] [Full Text]  
• Insel, P. A. (1996). Adrenergic Receptors -- Evolving Concepts and Clinical Implications. NEJM 334: 580-585 [Full Text]  
• Susulic, V. S., Frederich, R. C., Lawitts, J., Tozzo, E., Kahn, B. B., Harper, M.-E., Himms-Hagen, J., Flier, J. S., Lowell, B. B. (1995). Targeted Disruption of the beta(3)-Adrenergic Receptor Gene. J. Biol. Chem. 270: 29483-29492 [Abstract] [Full Text]  
• Widen, E., Lehto, M., Kanninen, T., Walston, J., Shuldiner, A. R., Groop, L. C. (1995). Association of a Polymorphism in the {beta}3-Adrenergic-Receptor Gene with Features of the Insulin Resistance Syndrome in Finns. NEJM 333: 348-352 [Abstract] [Full Text]  
• Clement, K., Vaisse, C., Manning, B. St. J., Basdevant, A., Guy-Grand, B., Ruiz, J., Silver, K. D., Shuldiner, A. R., Froguel, P., Strosberg, A. D. (1995). Genetic Variation in the {beta}3-Adrenergic Receptor and an Increased Capacity to Gain Weight in Patients with Morbid Obesity. NEJM 333: 352-354 [Abstract] [Full Text]  
• Arner, P. (1995). The {beta}3-Adrenergic Receptor -- A Cause and Cure of Obesity?. NEJM 333: 382-383 [Full Text]  
• Ranade, K., Chang, M.-S., Ting, C.-T., Pei, D., Hsiao, C.-F., Olivier, M., Pesich, R., Hebert, J., Chen, Y.-D. I., Dzau, V. J., Curb, D., Olshen, R., Risch, N., Cox, D. R., Botstein, D. (2001). High-Throughput Genotyping with Single Nucleotide Polymorphisms. Genome Res 11: 1262-1268 [Abstract] [Full Text]