The UPS in Diabetes and Obesity

Overview

Journal BMC Biochem

Publisher Biomed Central

Specialty Biochemistry

Date 2008 Nov 26

PMID 19007436

Citations 31

Authors

Simon S Wing

Affiliations

Soon will be listed here.

Abstract

Type 2 diabetes is caused by defects in both insulin signaling and insulin secretion. Though the role of the ubiquitin proteasome system (UPS) in the pathogenesis of type 2 diabetes remains largely unexplored, the few examples present in the literature are interesting and suggest targets for drug development. Studies indicate that insulin resistance can be induced by stimulating the degradation of important molecules in the insulin signaling pathway, in particular the insulin receptor substrate proteins IRS1, IRS2 and the kinase AKT1 (Akt). In addition, a defect in insulin secretion could occur due to UPS-mediated degradation of IRS2 in the beta-cells of the pancreas. The UPS also appears to be involved in regulating lipid synthesis in adipocytes and lipid production by the liver and could influence the development of obesity. Other possible mechanisms for inducing defects in insulin signaling and secretion remain to be explored, including the role of ubiquitylation in insulin receptor internalization and trafficking. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

Citing Articles

Overexpression of proteasome 26S subunit non-ATPase 6 protein and its clinicopathological significance in intrahepatic cholangiocarcinoma.

Tang Z, Tang Y, Qin K, Li Q, Chen G, Huang Y World J Hepatol. 2024; 16(11):1282-1289.

PMID: 39606161 PMC: 11586755. DOI: 10.4254/wjh.v16.i11.1282.

The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus.

Pan Z, Huang L, Gan Y, Xia Y, Yu W Molecules. 2024; 29(12).

PMID: 38930917 PMC: 11206814. DOI: 10.3390/molecules29122852.

Integrated bioinformatics approach reveals methylation-regulated differentially expressed genes in obesity.

Duarte G, Pellenz F, Crispim D, Assmann T Arch Endocrinol Metab. 2023; 67(4):e000604.

PMID: 37252693 PMC: 10665070. DOI: 10.20945/2359-3997000000604.

Substrate-specific effects of natural genetic variation on proteasome activity.

Collins M, Avery R, Albert F PLoS Genet. 2023; 19(5):e1010734.

PMID: 37126494 PMC: 10174532. DOI: 10.1371/journal.pgen.1010734.

Dysregulation of Gene Expression of Key Signaling Mediators in PBMCs from People with Type 2 Diabetes Mellitus.

Qureshi N, Desousa J, Siddiqui A, Drees B, Morrison D, Qureshi A Int J Mol Sci. 2023; 24(3).

PMID: 36769056 PMC: 9916932. DOI: 10.3390/ijms24032732.

References

MacDonald P, Joseph J, Rorsman P . Glucose-sensing mechanisms in pancreatic beta-cells. Philos Trans R Soc Lond B Biol Sci. 2005; 360(1464):2211-25. PMC: 1569593. DOI: 10.1098/rstb.2005.1762. View

Xu X, Sarikas A, Dias-Santagata D, Dolios G, Lafontant P, Tsai S . The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. Mol Cell. 2008; 30(4):403-14. PMC: 2633441. DOI: 10.1016/j.molcel.2008.03.009. View

Posner B . Regulation of insulin receptor kinase activity by endosomal processes: possible areas for therapeutic intervention. Curr Opin Investig Drugs. 2003; 4(4):430-4. View

Biddinger S, Kahn C . From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol. 2006; 68:123-58. DOI: 10.1146/annurev.physiol.68.040104.124723. View

Prentice A . The emerging epidemic of obesity in developing countries. Int J Epidemiol. 2005; 35(1):93-9. DOI: 10.1093/ije/dyi272. View

Ogawa T, Furochi H, Mameoka M, Hirasaka K, Onishi Y, Suzue N . Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest. Muscle Nerve. 2006; 34(4):463-9. DOI: 10.1002/mus.20611. View

Trujillo M, Scherer P . Adipose tissue-derived factors: impact on health and disease. Endocr Rev. 2006; 27(7):762-78. DOI: 10.1210/er.2006-0033. View

Fisher E, Zhou M, Mitchell D, Wu X, Omura S, Wang H . The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteasome pathway and involves heat shock protein 70. J Biol Chem. 1997; 272(33):20427-34. DOI: 10.1074/jbc.272.33.20427. View

Sugita H, Fujimoto M, Yasukawa T, Shimizu N, Sugita M, Yasuhara S . Inducible nitric-oxide synthase and NO donor induce insulin receptor substrate-1 degradation in skeletal muscle cells. J Biol Chem. 2005; 280(14):14203-11. DOI: 10.1074/jbc.M411226200. View

10.

Tanti J, Gremeaux T, Van Obberghen E, Le Marchand-Brustel Y . Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J Biol Chem. 1994; 269(8):6051-7. View

11.

Satoh S, Nishimura H, Clark A, Kozka I, Vannucci S, Simpson I . Use of bismannose photolabel to elucidate insulin-regulated GLUT4 subcellular trafficking kinetics in rat adipose cells. Evidence that exocytosis is a critical site of hormone action. J Biol Chem. 1993; 268(24):17820-9. View

12.

Briaud I, Dickson L, Lingohr M, McCuaig J, Lawrence J, Rhodes C . Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells. J Biol Chem. 2004; 280(3):2282-93. DOI: 10.1074/jbc.M412179200. View

13.

Tiao G, Hobler S, Wang J, Meyer T, Luchette F, Fischer J . Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle. J Clin Invest. 1997; 99(2):163-8. PMC: 507782. DOI: 10.1172/JCI119143. View

14.

Lee Y, White M . Insulin receptor substrate proteins and diabetes. Arch Pharm Res. 2004; 27(4):361-70. DOI: 10.1007/BF02980074. View

15.

Zimmet P, Alberti K, Shaw J . Global and societal implications of the diabetes epidemic. Nature. 2001; 414(6865):782-7. DOI: 10.1038/414782a. View

16.

Saltiel A, Kahn C . Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414(6865):799-806. DOI: 10.1038/414799a. View

17.

Krook A, Brueton L, ORahilly S . Homozygous nonsense mutation in the insulin receptor gene in infant with leprechaunism. Lancet. 1993; 342(8866):277-8. DOI: 10.1016/0140-6736(93)91820-c. View

18.

James D, Strube M, Mueckler M . Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature. 1989; 338(6210):83-7. DOI: 10.1038/338083a0. View

19.

Hicke L, Dunn R . Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol. 2003; 19:141-72. DOI: 10.1146/annurev.cellbio.19.110701.154617. View

20.

Schreyer S, Wilson D, LeBoeuf R . C57BL/6 mice fed high fat diets as models for diabetes-accelerated atherosclerosis. Atherosclerosis. 1998; 136(1):17-24. DOI: 10.1016/s0021-9150(97)00165-2. View