Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation
Complex genetic determinants contribute to an inherent susceptibility of type 2 diabetes, characterized by insulin resistance, a dysfunction and loss of insulin-producing beta-cells. We compared the islet expression profile and the genome of two obese mouse strains that react differently when receiving a caloric enriched diet. One mouse (B6-ob/ob) is able to compensate by increasing the beta-cell mass, whereas the other (NZO) develops hyperglycemia due to beta-cells loss. Focusing on differentially expressed genes that are located in susceptibility locus for diabetes and obesity on chromosome 1 we found 6 genes to be only expressed in islets of the diabetes-resistant mouse and one to be exclusively present in islets of the diabetes-prone mouse. Among these, the overexpression of 3 genes (Lefty1, Apoa2, and Pcp4l1) increased and that of Ifi202b decreased the division of primary islet cells. In summary, our data provide new insights into genes inducing or inhibiting islet size and thereby participate in the pathogenesis of type 2 diabetes.
Vyšlo v časopise:
Identification of Four Mouse Diabetes Candidate Genes Altering β-Cell Proliferation. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005506
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1005506
Souhrn
Complex genetic determinants contribute to an inherent susceptibility of type 2 diabetes, characterized by insulin resistance, a dysfunction and loss of insulin-producing beta-cells. We compared the islet expression profile and the genome of two obese mouse strains that react differently when receiving a caloric enriched diet. One mouse (B6-ob/ob) is able to compensate by increasing the beta-cell mass, whereas the other (NZO) develops hyperglycemia due to beta-cells loss. Focusing on differentially expressed genes that are located in susceptibility locus for diabetes and obesity on chromosome 1 we found 6 genes to be only expressed in islets of the diabetes-resistant mouse and one to be exclusively present in islets of the diabetes-prone mouse. Among these, the overexpression of 3 genes (Lefty1, Apoa2, and Pcp4l1) increased and that of Ifi202b decreased the division of primary islet cells. In summary, our data provide new insights into genes inducing or inhibiting islet size and thereby participate in the pathogenesis of type 2 diabetes.
Zdroje
1. DeFronzo RA (2010) Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 53: 1270–1287. doi: 10.1007/s00125-010-1684-1 20361178
2. Coleman DL (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14: 141–148. 350680
3. Leiter EH (2002) Mice with targeted gene disruptions or gene insertions for diabetes research: problems, pitfalls, and potential solutions. Diabetologia 45: 296–308. 11914735
4. Chadt A, Leicht K, Deshmukh A, Jiang LQ, Scherneck S, et al. (2008) Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nature genetics 40: 1354–1359. doi: 10.1038/ng.244 18931681
5. Vogel H, Scherneck S, Kanzleiter T, Benz V, Kluge R, et al. (2012) Loss of function of Ifi202b by a microdeletion on chromosome 1 of C57BL/6J mice suppresses 11beta-hydroxysteroid dehydrogenase type 1 expression and development of obesity. Human molecular genetics 21: 3845–3857. doi: 10.1093/hmg/dds213 22692684
6. Scherneck S, Nestler M, Vogel H, Bluher M, Block MD, et al. (2009) Positional cloning of zinc finger domain transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL. PLoS genetics 5: e1000541. doi: 10.1371/journal.pgen.1000541 19578398
7. Meyre D, Farge M, Lecoeur C, Proenca C, Durand E, et al. (2008) R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population. Human molecular genetics 17: 1798–1802. doi: 10.1093/hmg/ddn070 18325908
8. Stone S, Abkevich V, Russell DL, Riley R, Timms K, et al. (2006) TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. Human molecular genetics 15: 2709–2720. 16893906
9. Jurgens HS, Schurmann A, Kluge R, Ortmann S, Klaus S, et al. (2006) Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice. Physiological genomics 25: 234–241. 16614459
10. Kluth O, Mirhashemi F, Scherneck S, Kaiser D, Kluge R, et al. (2011) Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure. Diabetologia 54: 605–616. doi: 10.1007/s00125-010-1973-8 21107520
11. Mirhashemi F, Kluth O, Scherneck S, Vogel H, Kluge R, et al. (2008) High-fat, carbohydrate-free diet markedly aggravates obesity but prevents beta-cell loss and diabetes in the obese, diabetes-susceptible db/db strain. Obesity facts 1: 292–297. doi: 10.1159/000176064 20054191
12. Kluth O, Matzke D, Schulze G, Schwenk RW, Joost HG, et al. (2014) Differential transcriptome analysis of diabetes-resistant and-sensitive mouse islets reveals significant overlap with human diabetes susceptibility genes. Diabetes 63: 4230–4238. doi: 10.2337/db14-0425 25053586
13. Vogel H, Nestler M, Ruschendorf F, Block MD, Tischer S, et al. (2009) Characterization of Nob3, a major quantitative trait locus for obesity and hyperglycemia on mouse chromosome 1. Physiological genomics 38: 226–232. doi: 10.1152/physiolgenomics.00011.2009 19470805
14. Hasstedt SJ, Chu WS, Das SK, Wang H, Elbein SC (2008) Type 2 diabetes susceptibility genes on chromosome 1q21-24. Annals of human genetics 72: 163–169. doi: 10.1111/j.1469-1809.2007.00416.x 18269685
15. Staiger H, Bohm A, Scheler M, Berti L, Machann J, et al. (2013) Common genetic variation in the human FNDC5 locus, encoding the novel muscle-derived 'browning' factor irisin, determines insulin sensitivity. PloS one 8: e61903. doi: 10.1371/journal.pone.0061903 23637927
16. Clarke CJ, Hii LL, Bolden JE, Johnstone RW (2010) Inducible activation of IFI 16 results in suppression of telomerase activity, growth suppression and induction of cellular senescence. Journal of cellular biochemistry 109: 103–112. doi: 10.1002/jcb.22386 19885868
17. Chen C, Shen MM (2004) Two modes by which Lefty proteins inhibit nodal signaling. Current biology: CB 14: 618–624. 15062104
18. Cheng SK, Olale F, Brivanlou AH, Schier AF (2004) Lefty blocks a subset of TGFbeta signals by antagonizing EGF-CFC coreceptors. PLoS biology 2: E30. 14966532
19. Hamada H, Meno C, Watanabe D, Saijoh Y (2002) Establishment of vertebrate left-right asymmetry. Nature reviews Genetics 3: 103–113. 11836504
20. Zhang YQ, Sterling L, Stotland A, Hua H, Kritzik M, et al. (2008) Nodal and lefty signaling regulates the growth of pancreatic cells. Developmental dynamics: an official publication of the American Association of Anatomists 237: 1255–1267.
21. Millet C, Zhang YE (2007) Roles of Smad3 in TGF-beta signaling during carcinogenesis. Critical reviews in eukaryotic gene expression 17: 281–293. 17725494
22. Ray D, Terao Y, Nimbalkar D, Chu LH, Donzelli M, et al. (2005) Transforming growth factor beta facilitates beta-TrCP-mediated degradation of Cdc25A in a Smad3-dependent manner. Molecular and cellular biology 25: 3338–3347. 15798217
23. Fang G, Yu H, Kirschner MW (1998) Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Molecular cell 2: 163–171. 9734353
24. Glotzer M, Murray AW, Kirschner MW (1991) Cyclin is degraded by the ubiquitin pathway. Nature 349: 132–138. 1846030
25. Johnson DG, Walker CL (1999) Cyclins and cell cycle checkpoints. Annual review of pharmacology and toxicology 39: 295–312. 10331086
26. Rozen-Zvi B, Hayashida T, Hubchak SC, Hanna C, Platanias LC, et al. (2013) TGF-beta/Smad3 activates mammalian target of rapamycin complex-1 to promote collagen production by increasing HIF-1alpha expression. American journal of physiology Renal physiology 305: F485–494. doi: 10.1152/ajprenal.00215.2013 23761672
27. Verrecchia F, Mauviel A (2002) Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. The Journal of investigative dermatology 118: 211–215. 11841535
28. Duesing K, Charpentier G, Marre M, Tichet J, Hercberg S, et al. (2009) Evaluating the association of common APOA2 variants with type 2 diabetes. BMC medical genetics 10: 13. doi: 10.1186/1471-2350-10-13 19216768
29. Bulfone A, Caccioppoli C, Pardini C, Faedo A, Martinez S, et al. (2004) Pcp4l1, a novel gene encoding a Pcp4-like polypeptide, is expressed in specific domains of the developing brain. Gene expression patterns: GEP 4: 297–301. 15053978
30. Morgan MA, Morgan JI (2012) Pcp4l1 contains an auto-inhibitory element that prevents its IQ motif from binding to calmodulin. Journal of neurochemistry 121: 843–851. doi: 10.1111/j.1471-4159.2012.07745.x 22458599
31. Gotoh M, Ohzato H, Dono K, Kawai M, Yamamoto H, et al. (1990) Successful islet isolation from preserved rat pancreas following pancreatic ductal collagenase at the time of harvesting. Hormone and metabolic research Supplement series 25: 1–4.
32. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408. 11846609
33. Tsukiyama S, Matsushita M, Matsumoto S, Morita T, Kobayashi S, et al. (2006) Transduction of exogenous constitutively activated Stat3 into dispersed islets induces proliferation of rat pancreatic beta-cells. Tissue engineering 12: 131–140. 16499450
34. Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes care 22: 1462–1470. 10480510
35. Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome biology 11: R106. doi: 10.1186/gb-2010-11-10-r106 20979621
36. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26: 139–140. doi: 10.1093/bioinformatics/btp616 19910308
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2015 Číslo 9
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Arabidopsis AtPLC2 Is a Primary Phosphoinositide-Specific Phospholipase C in Phosphoinositide Metabolism and the Endoplasmic Reticulum Stress Response
- Bridges Meristem and Organ Primordia Boundaries through , , and during Flower Development in
- KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome
- The Chromatin Protein DUET/MMD1 Controls Expression of the Meiotic Gene during Male Meiosis in