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Taurine promotes insulin synthesis by enhancing Isl-1 expression through miR-7a/RAF1/ERK1/2 pathway

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Abstract

It has been well established that the circulating taurine affects the insulin synthesis in pancreatic islet β-cells, whereas miR-7a and LIM-homeodomain transcription factor Isl-1 are important intracellular factors regulating insulin transcription and synthesis. However, it still remains unknown whether taurine regulates insulin synthesis by affecting miR‐7a and/or Isl-1 expressions in mouse pancreatic islet β-cells. The present study was thus proposed to identify the effects of taurine on the expressions of miR‐7a and/or Isl-1 and their relations to insulin synthesis in mouse pancreatic islet β-cells by using miR-7a2 knockout (KO) and taurine transporter (TauT) KO mouse models and the related in vitro experiments. The results demonstrated that taurine supplement significantly decreased the pancreas miR-7a expression, but sharply upregulated the pancreas Isl-1 and insulin expressions, and serum insulin levels. However, the enhanced effects of taurine on Isl-1 expression and insulin synthesis were mitigated in the TauT KO and miR-7a2 KO mice. In addition, our results confirmed that taurine markedly increased pancreas RAF1 and ERK1/2 expressions. Collectively, the present study firstly demonstrates that taurine regulates insulin synthesis through TauT/miR-7a/RAF1/ERK1/2/Isl-1 signaling pathway, which are crucial for our understanding the mechanisms of taurine affecting insulin synthesis, and also potential for establishing the therapeutic strategies for diabetes and the diseases related to metabolism.

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Data supporting this study are included within the article and supporting materials.

References

  • Bravo-Egana V, Rosero S, Molano RD, Pileggi A, Ricordi C, Domínguez-Bendala J, Pastori RL (2008) Quantitative differential expression analysis reveals miR-7 as major islet microRNA. Biochem Biophys Res Commun 366:922–926

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Fu R, Cui Y, Li YS, Pan JR, Liu JL, Luo HS, Yin JD, Li DF, Cui S (2013) LIM-homeodomain transcription factor Isl-1 mediates the effect of leptin on insulin secretion in mice. J Biol Chem 288:12395–12405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Fu R, Cui Y, Pan J, Li Y, Zhang X, Evans S, Cui S, Liu J (2014a) LIM-homeodomain transcription factor Isl-1 mediates kisspeptin’s effect on insulin secretion in mice. Mol Endocrinol (Baltimore, Md) 28:1276–1290

    Article  Google Scholar 

  • Chen J, Fu R, Cui Y, Pan J, Li Y, Zhang X, Evans SM, Cui S, Liu J (2014b) LIM-homeodomain transcription factor Isl-1 mediates kisspeptin’s effect on insulin secretion in mice. Mol Endocrinol 28:1276–1290

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen X, Sebastian BM, Tang H, McMullen MM, Axhemi A, Jacobsen DW, Nagy LE (2009) Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology 49:1554–1562

    Article  CAS  PubMed  Google Scholar 

  • Dixon G, Nolan J, McClenaghan N, Flatt P, Newsholme P (2003) A comparative study of amino acid consumption by rat islet cells and the clonal beta-cell line BRIN-BD11 - the functional significance of L-alanine. J Endocrinol 179:447–454

    Article  CAS  PubMed  Google Scholar 

  • Du A, Hunter C, Murray J, Noble D, Cai C, Evans S, Stein R, May C (2009) Islet-1 is required for the maturation, proliferation, and survival of the endocrine pancreas. Diabetes 58:2059–2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ediger BN, Du A, Liu J, Hunter CS, Walp ER, Schug J, Kaestner KH, Stein R, Stoffers DA, May CL (2014) Islet-1 is essential for pancreatic β-cell function. Diabetes 63:4206–4217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El Mesallamy H, El-Demerdash E, Hammad L, El Magdoub H (2010) Effect of taurine supplementation on hyperhomocysteinemia and markers of oxidative stress in high fructose diet induced insulin resistance. Diabetol Metab Syndr 2:46

    Article  PubMed  PubMed Central  Google Scholar 

  • Fu R, Liu J, Fan J, Li R, Li D, Yin J, Cui S (2012) Novel evidence that testosterone promotes cell proliferation and differentiation via G protein-coupled receptors in the rat L6 skeletal muscle myoblast cell line. J Cell Physiol 227:98–107

    Article  CAS  PubMed  Google Scholar 

  • Gosmain Y, Katz L, Masson M, Cheyssac C, Poisson C, Philippe J (2012) Pax6 is crucial for β-cell function, insulin biosynthesis, and glucose-induced insulin secretion. Mol Endocrinol (Baltimore, Md) 26:696–709

    Article  CAS  Google Scholar 

  • Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, Robertson RP, Powers AC, Stein R (2013) Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Invest 123:3305–3316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haber C, Lam T, Yu Z, Gupta N, Goh T, Bogdanovic E, Giacca A, Fantus I (2003) N-Acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol Endocrinol Metab 285:E744-753

    Article  CAS  PubMed  Google Scholar 

  • Han J, Bae J, Kim S, Lee H, Jang B, Lee I, Cho C, Lim J, Suh S, Kwon T et al (2004) Taurine increases glucose sensitivity of UCP2-overexpressing beta-cells by ameliorating mitochondrial metabolism. Am J Physiol Endocrinol Metab 287:E1008-1018

    Article  CAS  PubMed  Google Scholar 

  • Holland AM, Hale MA, Kagami H, Hammer RE, MacDonald RJ (2002) Experimental control of pancreatic development and maintenance. Proc Natl Acad Sci U S A 99:12236–12241

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Hsu PD, Scott DA, Weinstein JA, Ran FA, Konermann S, Agarwala V, Li Y, Fine EJ, Wu X, Shalem O et al (2013) DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol 31:827–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Chu K, Nemoz-Gaillard E, Elberg D, Tsai M (2002) Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice. Mol Endocrinol (Baltimore, Md) 16:541–551

    CAS  Google Scholar 

  • Huxtable R (1992) Physiological actions of taurine. Physiol Rev 72:101–163

    Article  CAS  PubMed  Google Scholar 

  • Inam-U-Llah, Piao F, Aadil R, Suleman R, Li K, Zhang M, Wu P, Shahbaz M, Ahmed Z (2018) Ameliorative effects of taurine against diabetes: a review. Amino Acids 50:487–502

  • Ito T, Kimura Y, Uozumi Y, Takai M, Muraoka S, Matsuda T, Ueki K, Yoshiyama M, Ikawa M, Okabe M et al (2008) Taurine depletion caused by knocking out the taurine transporter gene leads to cardiomyopathy with cardiac atrophy. J Mol Cell Cardiol 44:927–937

    Article  CAS  PubMed  Google Scholar 

  • Ito T, Yoshikawa N, Ito H, Schaffer S (2015) Impact of taurine depletion on glucose control and insulin secretion in mice. J Pharmacol Sci 129:59–64

    Article  CAS  PubMed  Google Scholar 

  • Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H et al (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422:173–176

    Article  CAS  PubMed  ADS  Google Scholar 

  • Kaniuk N, Kiraly M, Bates H, Vranic M, Volchuk A, Brumell J (2007) Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes 56:930–939

    Article  CAS  PubMed  Google Scholar 

  • Karlsson O, Thor S, Norberg T, Ohlsson H, Edlund T (1990) Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain. Nature 344:879–882

    Article  CAS  PubMed  ADS  Google Scholar 

  • Kredo-Russo S, Mandelbaum AD, Ness A, Alon I, Lennox KA, Behlke MA, Hornstein E (2012) Pancreas-enriched miRNA refines endocrine cell differentiation. Development 139:3021–3031

    Article  CAS  PubMed  Google Scholar 

  • Kulakowski EC, Maturo J (1984) Hypoglycemic properties of taurine: not mediated by enhanced insulin release. Biochem Pharmacol 33:2835–2838

    Article  CAS  PubMed  Google Scholar 

  • Lambert I, Kristensen D, Holm J, Mortensen O (2015) Physiological role of taurine–from organism to organelle. Acta Physiol (oxf) 213:191–212

    Article  CAS  PubMed  Google Scholar 

  • Latreille M, Hausser J, Stützer I, Zhang Q, Hastoy B, Gargani S, Kerr-Conte J, Pattou F, Zavolan M, Esguerra J et al (2014) MicroRNA-7a regulates pancreatic β cell function. J Clin Investig 124:2722–2735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leonard J, Peers B, Johnson T, Ferreri K, Lee S, Montminy MR (1993) Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. Mol Endocrinol 7:1275–1283

    CAS  PubMed  Google Scholar 

  • Leonard J, Serup P, Gonzalez G, Edlund T, Montminy M (1992) The LIM family transcription factor Isl-1 requires cAMP response element binding protein to promote somatostatin expression in pancreatic islet cells. Proc Natl Acad Sci U S A 89:6247–6251

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Li JF, Norville JE, Aach J, McCormack M, Zhang D, Bush J, Church GM, Sheen J (2013) Multiplex and homologous recombination-mediated genome editing in Arabidopsis and Nicotiana benthamiana using guide RNA and Cas9. Nat Biotechnol 31:688–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li L, Zhang J, Lu C, Wang B, Guo J, Zhang H, Cui S (2022) MicroRNA-7a2 contributes to estrogen synthesis and is modulated by FSH via the JNK signaling pathway in ovarian granulosa cells. Int J Mol Sci 23(15):8565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H, Zhang D, Zhou Y, Cui S (2021) MicroRNA-7a inhibits Isl1 expression to regulate insulin secretion by targeting Raf1 and Mapkap1 in NIT-1 cells. In Vitro Cell Dev Biol Anim 57:817–824

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka T, Artner I, Henderson E, Means A, Sander M, Stein R (2004) The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc Natl Acad Sci USA 101:2930–2933

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Murakami S, Ono A, Kawasaki A, Takenaga T, Ito T (2018) Taurine attenuates the development of hepatic steatosis through the inhibition of oxidative stress in a model of nonalcoholic fatty liver disease in vivo and in vitro. Amino Acids 50:1279–1288

    Article  CAS  PubMed  Google Scholar 

  • Naya F, Huang H, Qiu Y, Mutoh H, DeMayo F, Leiter A, Tsai M (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 11:2323–2334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolan CJ, Leahy JL, Delghingaro-Augusto V, Moibi J, Soni K, Peyot ML, Fortier M, Guay C, Lamontagne J, Barbeau A et al (2006) Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling. Diabetologia 49:2120–2130

    Article  CAS  PubMed  Google Scholar 

  • Oprescu A, Bikopoulos G, Naassan A, Allister E, Tang C, Park E, Uchino H, Lewis G, Fantus I, Rozakis-Adcock M et al (2007) Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo. Diabetes 56:2927–2937

    Article  CAS  PubMed  Google Scholar 

  • Peschke E (2008) Melatonin, endocrine pancreas and diabetes. J Pineal Res 44:26–40

    Article  CAS  PubMed  Google Scholar 

  • Picinato M, Haber E, Cipolla-Neto J, Curi R, de Oliveira Carvalho C, Carpinelli A (2002) Melatonin inhibits insulin secretion and decreases PKA levels without interfering with glucose metabolism in rat pancreatic islets. J Pineal Res 33:156–160

    Article  CAS  PubMed  Google Scholar 

  • Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS (2006) Regulation of the insulin gene by glucose and fatty acids. J Nutr 136:873–876

    Article  CAS  PubMed  Google Scholar 

  • Ropero A, Fuentes E, Rovira J, Ripoll C, Soria B, Nadal A (1999) Non-genomic actions of 17beta-oestradiol in mouse pancreatic beta-cells are mediated by a cGMP-dependent protein kinase. J Physiol 521(2):397–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ropero A, Soria B, Nadal A (2002) A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas. Mol Endocrinol (Baltimore, Md) 16:497–505

    Article  CAS  Google Scholar 

  • Sakuma T, Nishikawa A, Kume S, Chayama K, Yamamoto T (2014) Multiplex genome engineering in human cells using all-in-one CRISPR/Cas9 vector system. Sci Rep 4:5400

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Sener A, Malaisse WJ (1980) L-Leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase. Nature 288:187–189

    Article  CAS  PubMed  ADS  Google Scholar 

  • Seufert J, Kieffer T, Habener J (1999) Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice. Proc Natl Acad Sci USA 96:674–679

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • So WY, Liu WN, Teo AKK, Rutter GA, Han W (2021) Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis. Sci Transl Med 13:eabb1038

  • Sonksen PH (2001) Insulin, growth hormone and sport. J Endocrinol 170:13–25

    Article  CAS  PubMed  Google Scholar 

  • Sturman JA (1993) Taurine in development. Physiol Rev 73:119–147

    Article  CAS  PubMed  Google Scholar 

  • Suckale J, Solimena M (2008) Pancreas islets in metabolic signaling–focus on the beta-cell. Front Biosci 13:7156–7171

    Article  CAS  PubMed  Google Scholar 

  • Tokunaga H, Yoneda Y, Kuriyama K (1983) Streptozotocin-induced elevation of pancreatic taurine content and suppressive effect of taurine on insulin secretion. Eur J Pharmacol 87:237–243

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, Jaenisch R (2013) One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153:910–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang M, Drucker DJ (1995) The LIM domain homeobox gene isl-1 is a positive regulator of islet cell-specific proglucagon gene transcription. J Biol Chem 270:12646–12652

    Article  CAS  PubMed  Google Scholar 

  • Wang M, Drucker DJ (1996) Activation of amylin gene transcription by LIM domain homeobox gene isl-1. Mol Endocrinol 10:243–251

    CAS  PubMed  Google Scholar 

  • Wen C, Li F, Zhang L, Duan Y, Guo Q, Wang W, He S, Li J, Yin Y (2019) Taurine is involved in energy metabolism in muscles, adipose tissue, and the liver. Mol Nutr Food Res 63:e1800536

    Article  PubMed  Google Scholar 

  • Yokogoshi H, Oda H (2002) Dietary taurine enhances cholesterol degradation and reduces serum and liver cholesterol concentrations in rats fed a high-cholesterol diet. Amino Acids 23:433–439

    Article  CAS  PubMed  Google Scholar 

  • Zhang D, Wang Z, Luo X, Guo H, Qiu G, Gong Y, Gao H, Cui S (2023) Cysteine dioxygenase and taurine are essential for embryo implantation by involving in E(2)-ERα and P(4)-PR signaling in mouse. J Anim Sci Biotechnol 14:6

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  • Zhang F, Sjöholm Å, Zhang Q (2007) Attenuation of insulin secretion by insulin-like growth factor binding protein-1 in pancreatic beta-cells. Biochem Biophys Res Commun 362:152–157

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Gao J, Zhang D, Liu H, Gou K, Cui S (2021) miR-375 acts as a novel factor modulating pituitary prolactin synthesis through Rasd1 and Esr1. J Endocrinol 250:25–35

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Zhou Y, Guo J, Li L, Liu H, Lu C, Jiang Y, Cui S (2022) MicroRNA-7a2 is required for the development of pituitary stem cells. Stem Cells Dev 31:357–368

    Article  CAS  PubMed  Google Scholar 

  • Zhao A, Bornfeldt K, Beavo J (1998) Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Investig 102:869–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimniak P, Little JM, Radominska A, Oelberg DG, Anwer MS, Lester R (1991) Taurine-conjugated bile acids act as Ca2+ ionophores. Biochemistry 30:8598–8604

    Article  CAS  PubMed  Google Scholar 

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Funding

The Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Authors and Affiliations

  1. College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, People’s Republic of China

    Hui Liu, Tongjuan Niu, Guobin Qiu, Sheng Cui & Di Zhang

  2. Institute of Reproduction and Metabolism, Yangzhou University, Yangzhou, 225009, Jiangsu, People’s Republic of China

    Hui Liu, Tongjuan Niu, Guobin Qiu, Sheng Cui & Di Zhang

  3. Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, People’s Republic of China

    Sheng Cui & Di Zhang

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  1. Hui Liu
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  2. Tongjuan Niu
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  5. Di Zhang
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Contributions

Di Zhang and Sheng Cui designed the experiments. Hui Liu, Tongjuan Niu, and Guobin Qiu carried out the overall assays. Hui Liu and Di Zhang analyzed the results and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Di Zhang.

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Liu, H., Niu, T., Qiu, G. et al. Taurine promotes insulin synthesis by enhancing Isl-1 expression through miR-7a/RAF1/ERK1/2 pathway. In Vitro Cell.Dev.Biol.-Animal 60, 23–35 (2024). https://doi.org/10.1007/s11626-023-00835-6

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