Portal de Periódicos da CAPES

Type 2 diabetes: pathogenesis and treatment

2008; Elsevier BV; Volume: 371; Issue: 9631 Linguagem: Inglês

10.1016/s0140-6736(08)60932-0

1474-547X

Michael Stümvoll, Barry J. Goldstein, Timon W. van Haeften,

Genetics and Neurodevelopmental Disorders

In the 3 years since our Lancet Seminar on type 2 diabetes mellitus, 1 Stumvoll M Goldstein BJ van Haeften TW Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005; 365: 1333-1346 Summary Full Text Full Text PDF PubMed Scopus (1681) Google Scholar several important developments have taken place. Further evidence that the disease has a strong hereditary component led to a vigorous search to identify candidate genes (table). This approach uncovered two prevalent polymorphisms (in addition to PPARy and KCNJ11). HNF1B (MODY5) bears a polymorphism associated with type 2 diabetes that is inversely related to risk of prostate cancer, suggesting it is important for cell-cycle regulation. 2 Gudmundsson J Sulem P Steinthorsdottir V et al. Two variants on chromosome 17 confer risk for prostate cancer, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007; 39: 977-983 Crossref PubMed Scopus (591) Google Scholar Studies of Wolfram's syndrome, a rare diabetic condition, also led to the discovery of a polymorphism in WFS1 that is associated with type 2 diabetes. 3 Sandhu MS Weedon MN Fawcett KA et al. Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet. 2007; 39: 951-953 Crossref PubMed Scopus (285) Google Scholar TableCandidate genes and genetic polymorphisms associated with type 2 diabetes Gene Encoded protein(s) Function of protein Odds ratio of diabetes-related allele Putative mechanism PPARG Peroxisome-proliferator-activated receptor γ Nuclear receptor (transcription factor) 1·25 Adipose-tissue-related insulin resistance KCNJ11 Potassium-inward rectifier 6·2 Potassium channel, β cell 1·12 β-cell dysfunction WFS1 Wolframin Activation of endoplasmic reticulum stress-pathway 1·19 β-cell apoptosis HNF1B Transcription factor 2 Transcription factor, β-cell development, growth 1·12 β-cell dysfunction TCF7L2 Transcription-factor-7-like 2 Wnt-signalling, pancreas 1·4 Insulin, glucagon secretion SLC30A8 Solute carrier family 30, member 8 Zinc transporter in β cell 1·12 β-cell dysfunction FTO Fat mass and obesity associated gene protein 2-oxoglutarate-dependent nucleic acid demethylase (brain, hypothalamus expressed) 1·23 Obesity (via insulin resistance) HHEX or insulin-degrading enzyme region Haemopoietically expressed homoeobox or insulin-degrading enzyme .. 1·14 HHEX: pancreas or liver development; IDE: insulin action, insulin-release disturbance? CDKN2A/2B region Cyclin-dependent kinase inhibitor 2A/2B Cell-cycle function 1·2 β-cell dysfunction? IGF2BP2 Insulin-like growth factor 2 mRNA binding protein 2 Transport IGF2 mRNA (translation) 1·17 β-cell function (growth?) CDKAL1 CDK5-regulatory-subunit-associated-protein 1-like 1 Regeneration 1·12 β-cell development, regeneration JAZF1 Juxtaposed with another zinc finger gene 1 Encoding repressor of NR2C2, possibly related to growth 1·10 Growth disturbance (pancreas?) CDC123/CAMK1D region Cell-division-cycle 123 homologue, calcium or calmodulin-dependent protein kinase D Possibly related to cell-cycle regulation 1·11 Cell-cycle disturbance (pancreas?) TSPAN8 Tetraspanin 8 Cell-surface glycoprotein (expressed in pancreas, liver, and colon carcinomas) 1·09 Unknown THADA Thyroid-adenoma-associated gene Possibly involved in apoptosis 1·15 Unknown (apoptosis pancreatic β cells?) ADAMTS9 ADAM metallopeptidase with thrombospondin type 1 motif 9 Involved in cleavage of proteoglycans (muscle, pancreas) 1·09 Unknown NOTCH2 Notch homologue 2 Transmembrane receptor of embryonic pancreatic ductal cells 1·13 Disturbed β-cell development? Open table in a new tab