Diabetes, Vol 44, Issue 1 1-10, Copyright © 1995 by American Diabetes Association

ARTICLES

Type II diabetes: clinical aspects of molecular biological studies

RC Turner, AT Hattersley, JT Shaw and JC Levy
Diabetes Research Laboratories, Radcliffe Infirmary, Oxford, U.K.

Type II diabetes remains a genetic nightmare. The major problem is identifying suitable pedigrees, sib-pairs, and populations for study. Segregation analysis data suggest that type II diabetes is likely to be polygenic, although one or more major genes could also be involved. This and the high prevalence of diabetes affect the strategies for searching for genetic mutations. Linkage analysis in classical type II diabetes pedigrees is unlikely to be successful. In addition, affected sib-pair analysis is limited because both parents are often affected, leading to bilineal inheritance. Sib-pairs with both parents alive are unusual, so identity by descent analysis is rarely feasible. Strategies to reduce bilineal inheritance by identifying sib-pairs with one known nondiabetic parent or with the second sibling having mild subclinical diabetes may be worthwhile. Identification of individuals or pedigrees with an unusual phenotype that suggests a single gene disorder, such as maturity-onset diabetes of the young, will continue to be important, for this allows linkage analysis with markers near candidate genes and exclusion mapping of chromosomal regions using highly polymorphic markers. Population association studies with candidate genes can detect mutations that have a minor role in the majority proportion of diabetic subjects, but large numbers are required and great care must be taken to exclude ethnic group differences between the diabetic and normoglycemic populations. The study of small inbred communities might be helpful because they may have fewer diabetogenic genes than outbred populations, and this would increase the power of sib-pair and population association studies. Direct screening for mutations in candidate genes (with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing) in patients with the appropriate pathophysiological abnormality can be a successful strategy. The identification of well-defined diabetic pedigrees, sib-pairs, and suitable matched diabetic and nondiabetic populations will be key to the discovery of the genes for diabetes.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Stumvoll, A. Fritsche, and H.-U. Haring Clinical Characterization of Insulin Secretion as the Basis for Genetic Analyses Diabetes, February 1, 2002; 51(90001): S122 - 129. [Abstract] [Full Text] [PDF]

				J.-M. Lin, H. Ortsater, H. Fakhrai-Rad, J. Galli, H. Luthman, and P. Bergsten Phenotyping of Individual Pancreatic Islets Locates Genetic Defects in Stimulus Secretion Coupling to Niddm1i Within the Major Diabetes Locus in GK Rats Diabetes, December 1, 2001; 50(12): 2737 - 2743. [Abstract] [Full Text] [PDF]

				G. Yosipovitch, B. Mevorah, M. David, M. Feinmesser, E. Hodak, B. Gabay, J. Ammash, and P. M. Elias Migratory Ichthyosiform Dermatosis With Type 2 Diabetes Mellitus and Insulin Resistance Arch Dermatol, October 1, 1999; 135(10): 1237 - 1242. [Abstract] [Full Text] [PDF]

				J. E. Gerich The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity Endocr. Rev., August 1, 1998; 19(4): 491 - 503. [Abstract] [Full Text] [PDF]

				J. Rowles, S. W. Scherer, T. Xi, M. Majer, D. C. Nickle, J. M. Rommens, K. M. Popov, R. A. Harris, N. L. Riebow, J. Xia, et al. Cloning and Characterization of PDK4 on 7q21.3 Encoding a Fourth Pyruvate Dehydrogenase Kinase Isoenzyme in Human J. Biol. Chem., September 13, 1996; 271(37): 22376 - 22382. [Abstract] [Full Text] [PDF]

				Y. Urata, H. Yamamoto, S. Goto, H. Tsushima, S. Akazawa, S. Yamashita, S. Nagataki, and T. Kondo Long Exposure to High Glucose Concentration Impairs the Responsive Expression of gamma -Glutamylcysteine Synthetase by Interleukin-1beta and Tumor Necrosis Factor-alpha in Mouse Endothelial Cells J. Biol. Chem., June 21, 1996; 271(25): 15146 - 15152. [Abstract] [Full Text] [PDF]

				J. Walston, K. Silver, C. Bogardus, W. C. Knowler, F. S. Celi, S. Austin, B. Manning, A. D. Strosberg, M. P. Stern, N. Raben, et al. Time of Onset of Non-Insulin-Dependent Diabetes Mellitus and Genetic Variation in the {beta}3-Adrenergic-Receptor Gene N. Engl. J. Med., August 10, 1995; 333(6): 343 - 347. [Abstract] [Full Text] [PDF]