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Gene Review

Ins2  -  insulin II

Mus musculus

Synonyms: AA986540, Ins-2, InsII, Insulin-2, Mody, ...
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Disease relevance of Ins2


Psychiatry related information on Ins2


High impact information on Ins2

  • In mice homozygous for a targeted disruption of Neurod, pancreatic islet morphogenesis is abnormal and overt diabetes develops due in part to inadequate expression of the insulin gene (Ins2) [7].
  • Similarly transformed fibroblast L-cells secrete only proinsulin; they do not store it, and their secretion rate is unaffected by secretagogues [8].
  • The stably transformed cell line, AtT-20ins4b/1, stores immunoreactive insulin, proteolytically processes proinsulin to smaller fragments, and on stimulation with secretagogues releases insulin-like material, not proinsulin, into the medium [8].
  • Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells [9].
  • We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta-cell-specific glucokinase and sulfonylurea receptor [10].

Chemical compound and disease context of Ins2


Biological context of Ins2


Anatomical context of Ins2

  • By RT-PCR, they express predominantly Ins2 as opposed to Ins1, as does whole thymus [20].
  • In yolk sacs, only Ins2 transcripts were found [17].
  • These results indicate that this cell line is subject to continuous ER stress and that the Ins2 C96Y mutation induces the expression of ER chaperones through the activation of ATF6 and XBP1 [2].
  • 5. In the brain, comparative analysis of lacZ expression in Ins2(lacZ/+) and Ins2(dta/laZ) mice identified the choroid plexus (CP) as a major Ins2 expression site [21].
  • Isolation and characterization of proinsulin-producing medullary thymic epithelial cell clones [20].

Associations of Ins2 with chemical compounds

  • Clarification of the Ins2 gene sequence: relevance to glucose intolerance in NON/Lt mice [22].
  • This study demonstrates that one of the alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form [4].
  • In insulin-dependent streptozotocin-treated diabetic rats, islet area and number were profoundly reduced; insulin deprivation failed to raise proinsulin mRNA in surviving beta cells above control levels [23].
  • CJC-1131 increased levels of pancreatic proinsulin mRNA transcripts, percent islet area, and the number of bromodeoxyuridine-positive islet cells [24].
  • Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing beta-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca(2+) mobilization, proinsulin content, and insulin gene expression [25].

Enzymatic interactions of Ins2


Regulatory relationships of Ins2


Other interactions of Ins2


Analytical, diagnostic and therapeutic context of Ins2


  1. Compensatory responses in mice carrying a null mutation for Ins1 or Ins2. Leroux, L., Desbois, P., Lamotte, L., Duvillié, B., Cordonnier, N., Jackerott, M., Jami, J., Bucchini, D., Joshi, R.L. Diabetes (2001) [Pubmed]
  2. The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2+/Akita pancreatic beta cells. Nozaki, J., Kubota, H., Yoshida, H., Naitoh, M., Goji, J., Yoshinaga, T., Mori, K., Koizumi, A., Nagata, K. Genes Cells (2004) [Pubmed]
  3. Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7. Jones, J.M., Meisler, M.H., Seldin, M.F., Lee, B.K., Eicher, E.M. Genomics (1992) [Pubmed]
  4. A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. Wang, J., Takeuchi, T., Tanaka, S., Kubo, S.K., Kayo, T., Lu, D., Takata, K., Koizumi, A., Izumi, T. J. Clin. Invest. (1999) [Pubmed]
  5. Transgenic insulin (B:9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout. Jasinski, J.M., Yu, L., Nakayama, M., Li, M.M., Lipes, M.A., Eisenbarth, G.S., Liu, E. Diabetes (2006) [Pubmed]
  6. Localisation of presenilin 2 in human and rodent pancreatic islet beta-cells; Met239Val presenilin 2 variant is not associated with diabetes in man. Jaikaran, E.T., Marcon, G., Levesque, L., George-Hyslop, P.S., Fraser, P.E., Clark, A. J. Cell. Sci. (1999) [Pubmed]
  7. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Malecki, M.T., Jhala, U.S., Antonellis, A., Fields, L., Doria, A., Orban, T., Saad, M., Warram, J.H., Montminy, M., Krolewski, A.S. Nat. Genet. (1999) [Pubmed]
  8. Expressing a human proinsulin cDNA in a mouse ACTH-secreting cell. Intracellular storage, proteolytic processing, and secretion on stimulation. Moore, H.P., Walker, M.D., Lee, F., Kelly, R.B. Cell (1983) [Pubmed]
  9. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Scheuner, D., Mierde, D.V., Song, B., Flamez, D., Creemers, J.W., Tsukamoto, K., Ribick, M., Schuit, F.C., Kaufman, R.J. Nat. Med. (2005) [Pubmed]
  10. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Kojima, H., Fujimiya, M., Matsumura, K., Younan, P., Imaeda, H., Maeda, M., Chan, L. Nat. Med. (2003) [Pubmed]
  11. Extrapancreatic insulin-producing cells in multiple organs in diabetes. Kojima, H., Fujimiya, M., Matsumura, K., Nakahara, T., Hara, M., Chan, L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  12. The fusion of bone-marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy. Terashima, T., Kojima, H., Fujimiya, M., Matsumura, K., Oi, J., Hara, M., Kashiwagi, A., Kimura, H., Yasuda, H., Chan, L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Loss of ganciclovir sensitivity by exclusion of thymidine kinase gene from transplanted proinsulin-producing fibroblasts as a gene therapy model for diabetes. Yoshimoto, K., Murakami, R., Moritani, M., Ohta, M., Iwahana, H., Nakauchi, H., Itakura, M. Gene Ther. (1996) [Pubmed]
  14. Proinsulin C-peptide rapidly stimulates mitogen-activated protein kinases in Swiss 3T3 fibroblasts: requirement of protein kinase C, phosphoinositide 3-kinase and pertussis toxin-sensitive G-protein. Kitamura, T., Kimura, K., Jung, B.D., Makondo, K., Okamoto, S., Cañas, X., Sakane, N., Yoshida, T., Saito, M. Biochem. J. (2001) [Pubmed]
  15. PPAR-gamma overexpression suppresses glucose-induced proinsulin biosynthesis and insulin release synergistically with pioglitazone in MIN6 cells. Nakamichi, Y., Kikuta, T., Ito, E., Ohara-Imaizumi, M., Nishiwaki, C., Ishida, H., Nagamatsu, S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  16. The mouse H19 locus mediates a transition between imprinted and non-imprinted DNA replication patterns. Greally, J.M., Starr, D.J., Hwang, S., Song, L., Jaarola, M., Zemel, S. Hum. Mol. Genet. (1998) [Pubmed]
  17. Tissue- and developmental stage-specific imprinting of the mouse proinsulin gene, Ins2. Deltour, L., Montagutelli, X., Guenet, J.L., Jami, J., Páldi, A. Dev. Biol. (1995) [Pubmed]
  18. Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to beta-cell hyperplasia in mutant mice lacking insulin. Duvillié, B., Currie, C., Chrones, T., Bucchini, D., Jami, J., Joshi, R.L., Hill, D.J. Endocrinology (2002) [Pubmed]
  19. Imprinting at the mouse Ins2 locus: evidence for cis- and trans-allelic interactions. Duvillié, B., Bucchini, D., Tang, T., Jami, J., Pàldi, A. Genomics (1998) [Pubmed]
  20. Isolation and characterization of proinsulin-producing medullary thymic epithelial cell clones. Palumbo, M.O., Levi, D., Chentoufi, A.A., Polychronakos, C. Diabetes (2006) [Pubmed]
  21. Knock-in of diphteria toxin A chain gene at Ins2 locus: effects on islet development and localization of Ins2 expression in the brain. Lamotte, L., Jackerott, M., Bucchini, D., Jami, J., Joshi, R.L., Deltour, L. Transgenic Res. (2004) [Pubmed]
  22. Clarification of the Ins2 gene sequence: relevance to glucose intolerance in NON/Lt mice. Pearce, R.B., Peterson, C.M. Mamm. Genome (1996) [Pubmed]
  23. Molecular and cellular responses of islets during perturbations of glucose homeostasis determined by in situ hybridization histochemistry. Chen, L., Komiya, I., Inman, L., McCorkle, K., Alam, T., Unger, R.H. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  24. Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Kim, J.G., Baggio, L.L., Bridon, D.P., Castaigne, J.P., Robitaille, M.F., Jetté, L., Benquet, C., Drucker, D.J. Diabetes (2003) [Pubmed]
  25. SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. Iguchi, H., Ikeda, Y., Okamura, M., Tanaka, T., Urashima, Y., Ohguchi, H., Takayasu, S., Kojima, N., Iwasaki, S., Ohashi, R., Jiang, S., Hasegawa, G., Ioka, R.X., Magoori, K., Sumi, K., Maejima, T., Uchida, A., Naito, M., Osborne, T.F., Yanagisawa, M., Yamamoto, T.T., Kodama, T., Sakai, J. J. Biol. Chem. (2005) [Pubmed]
  26. Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3. Smeekens, S.P., Montag, A.G., Thomas, G., Albiges-Rizo, C., Carroll, R., Benig, M., Phillips, L.A., Martin, S., Ohagi, S., Gardner, P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  27. Murine myeloid leukemia: in vivo suppression by sericystatin A, a proteinase inhibitor from leukocytes. Pavelić, K., Sirotković, M., Kopitar, M., Pavelić, J., Vuk-Pavlović, S. European journal of cancer & clinical oncology. (1983) [Pubmed]
  28. Differential expression and imprinting status of Ins1 and Ins2 genes in extraembryonic tissues of laboratory mice. Deltour, L., Vandamme, J., Jouvenot, Y., Duvillié, B., Kelemen, K., Schaerly, P., Jami, J., Paldi, A. Gene Expr. Patterns (2004) [Pubmed]
  29. Interaction of glucagon-like peptide-I (7-37) and somatostatin-14 on signal transduction and proinsulin gene expression in beta TC-1 cells. Fehmann, H.C., Strowski, M., Göke, B. Metab. Clin. Exp. (1994) [Pubmed]
  30. Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Zhu, X., Orci, L., Carroll, R., Norrbom, C., Ravazzola, M., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  31. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Izumi, T., Yokota-Hashimoto, H., Zhao, S., Wang, J., Halban, P.A., Takeuchi, T. Diabetes (2003) [Pubmed]
  32. Galanin inhibits proinsulin gene expression stimulated by the insulinotropic hormone glucagon-like peptide-I(7-37) in mouse insulinoma beta TC-1 cells. Fehmann, H.C., Habener, J.F. Endocrinology (1992) [Pubmed]
  33. Phenotypic alterations in insulin-deficient mutant mice. Duvillié, B., Cordonnier, N., Deltour, L., Dandoy-Dron, F., Itier, J.M., Monthioux, E., Jami, J., Joshi, R.L., Bucchini, D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  34. Nucleotide sequence of a 28-kb mouse genomic region comprising the imprinted Igf2 gene. Sasaki, H., Shimozaki, K., Zubair, M., Aoki, N., Ohta, K., Hatano, N., Moore, T., Feil, R., Constancia, M., Reik, W., Rotwein, P. DNA Res. (1996) [Pubmed]
  35. Glucagon and insulin from lean rats and genetically obese fatty rats: studies by radioimmunoassay, radioreceptorassay and bioassay. Laburthe, M., Rançon, F., Freychet, P., Rosselin, G. Diabetologia (1975) [Pubmed]
  36. Proinsulin/insulin is synthesized locally and prevents caspase- and cathepsin-mediated cell death in the embryonic mouse retina. Valenciano, A.I., Corrochano, S., de Pablo, F., de la Villa, P., de la Rosa, E.J. J. Neurochem. (2006) [Pubmed]
  37. Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic beta-cells via transcriptional activation. Ueda, K., Kawano, J., Takeda, K., Yujiri, T., Tanabe, K., Anno, T., Akiyama, M., Nozaki, J., Yoshinaga, T., Koizumi, A., Shinoda, K., Oka, Y., Tanizawa, Y. Eur. J. Endocrinol. (2005) [Pubmed]
  38. Insulin production by engineered muscle cells. Gros, L., Riu, E., Montoliu, L., Ontiveros, M., Lebrigand, L., Bosch, F. Hum. Gene Ther. (1999) [Pubmed]
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