1: Diabetes. 2005 Jul;54(7):2256-60. Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Laukkanen O, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M; Finnish Diabetes Prevention Study. Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. Impaired insulin secretion is a fundamental defect in type 2 diabetes. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study. With the exception of SLC2A2, other genes were not associated with the risk of type 2 diabetes. All four SNPs of SLC2A2 predicted the conversion to diabetes, and rs5393 (AA genotype) increased the risk of type 2 diabetes in the entire study population by threefold (odds ratio 3.04, 95% CI 1.34-6.88, P = 0.008). The risk for type 2 diabetes in the AA genotype carriers was increased in the control group (5.56 [1.78-17.39], P = 0.003) but not in the intervention group. We conclude that the SNPs of SLC2A2 predict the conversion to diabetes in obese subjects with IGT. PMID: 15983230 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 2: J Clin Endocrinol Metab. 2005 Aug;90(8):4607-14. Epub 2005 May 31. Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1. Johansen A, Ek J, Mortensen HB, Pedersen O, Hansen T. Steno Diabetes Center and Hagedorn Research Institute, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. adjo@steno.dk AIMS/HYPOTHESIS: Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of diabetes characterized by an autosomal dominant inheritance, an early clinical onset, and a primary defect in beta-cell function. The aims of the present study were to examine the prevalence and nature of mutations in the three common MODY genes, HNF4A, GCK, and TCF1, in Danish patients with a clinical diagnosis of MODY and to describe metabolic differences in probands with and without mutations in HNF4A, GCK, and TCF1. METHODS: Seventy-eight unrelated subjects of Danish Caucasian origin (29 men, 49 women) and their 351 family members were examined. The promotor and coding regions including intron-exon boundaries of HNF4A, GCK, and TCF1 were examined by denaturing HPLC and/or direct sequencing. Results: We identified 29 different mutations in 38 MODY families. Fifteen of the mutations were novel. The variants segregated with diabetes within the families, and none of the variants were found in 100 normal Danish chromosomes. Our findings suggest a relative prevalence of 3% of MODY1 (two different mutations in two families), 10% of MODY2 (seven in eight), and 36% of MODY3 (21 in 28) among Danish kindred clinically diagnosed as MODY. No significant differences in biochemical and anthropometric measurements were observed at baseline examinations. CONCLUSIONS: Forty-nine percent of the families carried mutations in the three examined MODY genes. Our findings highlight that unidentified MODY genes may play a central role for diabetes characterized by autosomal dominant transmission. Furthermore, baseline measurements of various anthropometric and biochemical variables are not appropriate markers of MODYX. PMID: 15928245 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Mol Genet Metab. 2002 Sep-Oct;77(1-2):35-43. The role of transcription factors in maturity-onset diabetes of the young. Mitchell SM, Frayling TM. Department of Diabetes and Vascular Medicine, University of Exeter, Barrack Road, EX2 5AX, Exeter, UK. s.m.s.mitchell@exeter.ac.uk The study of maturity-onset diabetes of the young (MODY), an autosomal dominant form of early-onset diabetes mellitus characterised by defective insulin secretion has been extremely successful in two ways. Firstly it has enabled definitive diagnosis for patients. This allows more accurate prediction of disease and treatment requirements. Secondly it has facilitated an increased understanding of the genes and pathways that are crucial for normal beta-cell function. Five of the six MODY genes, TCF1 (encoding HNF-1alpha), TCF2 (encoding HNF-1beta) HNF4A, insulin promoter factor (IPF)1, and NEUROD1, are transcription factors that operate in a complex network of gene regulation. Several genes have been shown to be regulated by the MODY transcription factors in a beta-cell specific manner. This includes the co-regulation of HNF-1alpha and HNF-4alpha by each other. The exact mechanism of how mutations in these transcription factors result in diabetes in humans remains unknown. However, current opinion favours pleiotropic adverse effects on many genes; extensive in vitro and in vivo studies of these genes has highlighted their importance in both glucose sensing-insulin secretion coupling and maintaining the fully differentiated beta-cell phenotype. Publication Types: Review Review, Tutorial PMID: 12359128 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: Hum Mutat. 2002 Sep;20(3):230-1. Large Family With Maturity-Onset Diabetes of the Young and a Novel V121I Mutation in HNF4A. Monney CT, Kaltenrieder V, Cousin P, Bonny C, Schorderet DF. Division Autonome de Genetique Medicale, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. Maturity-onset diabetes of the young (MODY) is a subtype of early-onset diabetes mellitus which is characterized by autosomal dominant inheritance. Several genes are known to induce MODY : HNF4A/MODY1, GCK/MODY2, TCF1/MODY3, IPF1/MODY4, TCF2/MODY5 and NEUROD1/MODY6. We studied a Swiss family with 13 diabetic patients over 3 generations. The average age at diagnosis was 35 +/- 15 years (7 subjects before 30). In addition, 2 individuals had an abnormal oral glucose tolerance. The mutation present in this family was located in the DNA binding domain of HNF4A, a strongly conserved region across almost all species, and segregated in all the MODY patients. Identification of this missense mutation allowed for presymptomatic diagnosis in the younger generations and will improve medical follow-up of the predisposed individuals. Copyright 2002 Wiley-Liss, Inc. PMID: 12203996 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------