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Diabetes mellitus, noninsulin-dependent; NIDDM

Disease ID:280
Name:Diabetes mellitus, noninsulin-dependent; NIDDM
Associated with:15 targets
1 immuno-relevant ligand
Diabetes mellitus, Type II; T2D | Maturity onset diabetes | Type 2 diabetes mellitus
Database Links
Disease Ontology: DOID:9352
OMIM: 125853


C5a2 receptor
Mutations:  C5a2 receptor is associated with 1 mutation. Click here for details
chemerin receptor 1
References:  6,9
FFA4 receptor
Comments:  FFA4 is a potential drug target in type 2 diabetes mellitus.
References:  14,18
MT2 receptor
Role:  Mutation in the gene MTNR1B are associated with susceptibility to type II diabetes
Mutations:  MT2 receptor is associated with 4 mutation. Click here for details
References:  23
Comments:  KCNJ15 has been identified as a susceptibility gene for diabetes
References:  19
Role:  SNPs in the CACNA1E gene (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) are associated with impairment of beta cell function in patients diagnosed with Type II diabetes
References:  13,16,22
Peroxisome proliferator-activated receptor-γ
Comments:  Mutations in the ligand-binding domain are associated with severe insulin resistance, diabetes mellitus and hypertension
References:  4,7-8,12,15
Hepatocyte nuclear factor-4-α
Comments:  Early onset: Three mutations affecting HNF4 alpha function have been found (asp126tyr; asp126his; arg154gln).
Late onset: Missense mutations have been found in the LBD (arg323his) and the F domain (val393ile), although only the latter has been characterized functionally. Thirteen SNPs in the P2 promoter, three of which are in Pima Indians, have also been associated with this disease, as well as a 7 bp deletion in the Sp1 site of the P1 promoter.
References:  1,10-11,17,20
Mutations:  Hepatocyte nuclear factor-4-α is associated with 5 mutation. Click here for details
AKT serine/threonine kinase 2
Insulin receptor
regulator of G-protein signaling 8
Role:  Mouse studies suggest that Rgs8 is likely to control aspects of islet progenitor cell activation, differentiation and beta-cell expansion in embryos and metabolically stressed adults.
References:  24


Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
Immuno Disease Comments: A Phase 2 clinical candidate predicted to exhibit a useful effect on T2D-associated inflammation.
Clinical Use: A series of Phase 1 and Phase 2 results are reported in entries | View clinical data
Bioactivity Comments: In contrast with ONO6818, an inhibitor that binds covalently to NE, AZD9668 exhibited a more rapid association and dissociation rate, and its interaction with NE was fully reversible. It also generally showed greater specificity than ONO6818 or for NE over other neutrophil-derived serine proteases, particularly Pr-3 and pancreatic elastase [21]. Approximately 90 analogues are listed in a patent [3] where this is example 94, but only limited SAR data is included. | View biological activity


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1. Aguilar-Salinas CA, Reyes-Rodríguez E, Ordóñez-Sánchez ML, Torres MA, Ramírez-Jiménez S, Domínguez-López A, Martínez-Francois JR, Velasco-Pérez ML, Alpizar M, García-García E, Gómez-Pérez F, Rull J, Tusié-Luna MT. (2001) Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population. J Clin Endocrinol Metab, 86 (1): 220-6. [PMID:11232004]

2. Andersson EA, Holst B, Sparsø T, Grarup N, Banasik K, Holmkvist J, Jørgensen T, Borch-Johnsen K, Egerod KL, Lauritzen T et al.. (2010) MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans. Diabetes, 59 (6): 1539-48. [PMID:20200315]

3. Andersson, Marjana et al.. (2007) 2-Pyridone Derivatives As Neutrophil Elastase Inhibitors And Their Use. Patent number: US20070203129. Assignee: AstraZeneca. Priority date: 15/09/2004. Publication date: 30/08/2007.

4. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S. (1999) Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature, 402 (6764): 880-3. [PMID:10622252]

5. Bonnefond A, Clément N, Fawcett K, Yengo L, Vaillant E, Guillaume JL, Dechaume A, Payne F, Roussel R, Czernichow S et al.. (2012) Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet, 44 (3): 297-301. [PMID:22286214]

6. Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, Walder K, Segal D. (2007) Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology, 148 (10): 4687-94. [PMID:17640997]

7. Deeb SS, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. (1998) A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet, 20 (3): 284-7. [PMID:9806549]

8. Desvergne B, Michalik L, Wahli W. (2004) Be fit or be sick: peroxisome proliferator-activated receptors are down the road. Mol Endocrinol, 18 (6): 1321-32. [PMID:15087471]

9. Du XY, Leung LL. (2009) Proteolytic regulatory mechanism of chemerin bioactivity. Acta Biochim Biophys Sin (Shanghai), 41 (12): 973-9. [PMID:20011981]

10. Gupta RK, Kaestner KH. (2004) HNF-4alpha: from MODY to late-onset type 2 diabetes. Trends Mol Med, 10 (11): 521-4. [PMID:15519277]

11. Hani EH, Suaud L, Boutin P, Chèvre JC, Durand E, Philippi A, Demenais F, Vionnet N, Furuta H, Velho G, Bell GI, Laine B, Froguel P. (1998) A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Invest, 101 (3): 521-6. [PMID:9449683]

12. Henke BR. (2004) Peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes. J Med Chem, 47 (17): 4118-27. [PMID:15293980]

13. Holmkvist J, Tojjar D, Almgren P, Lyssenko V, Lindgren CM, Isomaa B, Tuomi T, Berglund G, Renström E, Groop L. (2007) Polymorphisms in the gene encoding the voltage-dependent Ca(2+) channel Ca (V)2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion. Diabetologia, 50 (12): 2467-75. [PMID:17934712]

14. Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K et al.. (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature, 483 (7389): 350-4. [PMID:22343897]

15. Kersten S, Desvergne B, Wahli W. (2000) Roles of PPARs in health and disease. Nature, 405 (6785): 421-4. [PMID:10839530]

16. Muller YL, Hanson RL, Zimmerman C, Harper I, Sutherland J, Kobes S, International Type 2 Diabetes 1q Consortium, Knowler WC, Bogardus C, Baier LJ. (2007) Variants in the Ca V 2.3 (alpha 1E) subunit of voltage-activated Ca2+ channels are associated with insulin resistance and type 2 diabetes in Pima Indians. Diabetes, 56 (12): 3089-94. [PMID:17720895]

17. Muller YL, Infante AM, Hanson RL, Love-Gregory L, Knowler W, Bogardus C, Baier LJ. (2005) Variants in hepatocyte nuclear factor 4alpha are modestly associated with type 2 diabetes in Pima Indians. Diabetes, 54 (10): 3035-9. [PMID:16186411]

18. Oh DY, Olefsky JM. (2012) Omega 3 fatty acids and GPR120. Cell Metab, 15 (5): 564-5. [PMID:22560206]

19. Okamoto K, Iwasaki N, Doi K, Noiri E, Iwamoto Y, Uchigata Y, Fujita T, Tokunaga K. (2012) Inhibition of glucose-stimulated insulin secretion by KCNJ15, a newly identified susceptibility gene for type 2 diabetes. Diabetes, 61 (7): 1734-41. [PMID:22566534]

20. Price JA, Fossey SC, Sale MM, Brewer CS, Freedman BI, Wuerth JP, Bowden DW. (2000) Analysis of the HNF4 alpha gene in Caucasian type II diabetic nephropathic patients. Diabetologia, 43 (3): 364-72. [PMID:10768098]

21. Stevens T, Ekholm K, Gränse M, Lindahl M, Kozma V, Jungar C, Ottosson T, Falk-Håkansson H, Churg A, Wright JL et al.. (2011) AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase. J Pharmacol Exp Ther, 339 (1): 313-20. [PMID:21791628]

22. Trombetta M, Bonetti S, Boselli M, Turrini F, Malerba G, Trabetti E, Pignatti P, Bonora E, Bonadonna RC. (2012) CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3. PLoS ONE, 7 (3): e32755. [PMID:22427875]

23. Vaughn J, Wolford JK, Prochazka M, Permana PA. (2000) Genomic structure and expression of human KCNJ9 (Kir3.3/GIRK3). Biochem Biophys Res Commun, 274 (2): 302-9. [PMID:10913335]

24. Villasenor A, Wang ZV, Rivera LB, Ocal O, Asterholm IW, Scherer PE, Brekken RA, Cleaver O, Wilkie TM. (2010) Rgs16 and Rgs8 in embryonic endocrine pancreas and mouse models of diabetes. Dis Model Mech, 3 (9-10): 567-80. [PMID:20616094]

25. Zheng YY, Xie X, Ma YT, Yang YN, Fu ZY, Li XM, Ma X, Chen BD, Liu F. (2012) Relationship between type 2 diabetes mellitus and a novel polymorphism C698T in C5L2 in the Chinese Han population. Endocrine, 41 (2): 296-301. [PMID:22180093]