Horm Metab Res 2007; 39(5): 336-340
DOI: 10.1055/s-2007-976538
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Alterations of Pancreatic Beta-cell Mass and Islet Number due to Ins2-controlled Expression of Cre Recombinase: RIP-Cre Revisited; Part 2

D. Pomplun 1 , 2 [] , S. Florian 1 [] , T. Schulz 1 , 2 , A. F. H. Pfeiffer 1 , M. Ristow 1 , 2
  • 1German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
  • 2Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena, Germany
Further Information

Publication History

received 30. 10. 2006

accepted 18. 12. 2006

Publication Date:
29 May 2007 (online)

Abstract

Tissue-specific disruption of genes by targeted expression of Cre recombinase in insulin-producing cells has been widely used to explore pathways involved in regulation of pancreatic beta-cell mass. One particular line of transgenic mice [B6.Cg-Tg(Ins2-cre)25Mgn/J], commonly called RIP-Cre, in which the expression of Cre recombinase is controlled by a short fragment of the rat insulin II gene promoter has been used on at least 20 genes in at least 27 studies. In the majority of these studies (15 out of 27) inactivation of the gene of interest was associated with alterations in islet architecture, islet mass, or pancreatic insulin content. We have tested the hypothesis that genomic integration or expression of Cre recombinase alone causes alterations of beta-cell mass by quantifying islet number and mass in RIP-Cre mice. We have observed a significant hypoplasia of beta-cells in young RIP-Cre mice, and a significant hyperplasia of islets in older RIP-Cre animals. These findings suggest that glucose intolerance and impaired insulin secretion previously described for younger RIP-Cre mice might be caused by transgene-associated islet hypoplasia, and that hyperplasia in older mice might reflect a compensatory response to transgene-related glucose intolerance.

References

  • 1 Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.  J Biol Chem. 1999;  274 305-315
  • 2 Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, O’Connell PJ, Gonzalez FJ, Kahn CR. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes.  Cell. 2005;  122 337-349
  • 3 Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, Obermuller S, Olofsson CS, Salehi A, Wendt A, Klugbauer N, Wollheim CB, Rorsman P, Hofmann F. Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice.  Embo J. 2003;  22 3844-3854
  • 4 Dai C, Huh CG, Thorgeirsson SS, Liu Y. Beta-cell-specific ablation of the hepatocyte growth factor receptor results in reduced islet size, impaired insulin secretion, and glucose intolerance.  Am J Pathol. 2005;  167 429-436
  • 5 Roccisana J, Reddy V, Vasavada RC, Gonzalez-Pertusa JA, Magnuson MA, Garcia-Ocana A. Targeted inactivation of hepatocyte growth factor receptor c-met in beta-cells leads to defective insulin secretion and GLUT-2 downregulation without alteration of beta-cell mass.  Diabetes. 2005;  54 2090-2102
  • 6 Bardoux P, Zhang P, Flamez D, Perilhou A, Lavin TA, Tanti JF, Hellemans K, Gomas E, Godard C, Andreelli F, Buccheri MA, Kahn A, Le Marchand-Brustel Y, Burcelin R, Schuit F, Vasseur-Cognet M. Essential role of chicken ovalbumin upstream promoter-transcription factor II in insulin secretion and insulin sensitivity revealed by conditional gene knockout.  Diabetes. 2005;  54 1357-1363
  • 7 Sund NJ, Vatamaniuk MZ, Casey M, Ang SL, Magnuson MA, Stoffers DA, Matschinsky FM, Kaestner KH. Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia.  Genes Dev. 2001;  15 1706-1715
  • 8 Ristow M, Mulder H, Pomplun D, Schulz TJ, Müller-Schmehl K, Krause A, Fex M, Puccio H, Müller J, Isken F, Spranger J, Müller-Wieland D, Magnuson MA, Möhlig M, Koenig M, Pfeiffer AFH. Frataxin-deficiency in pancreatic islets causes diabetes due to loss of beta-cell mass.  J Clin Invest. 2003;  112 527-534
  • 9 Gesina E, Tronche F, Herrera P, Duchene B, Tales W, Czernichow P, Breant B. Dissecting the role of glucocorticoids on pancreas development.  Diabetes. 2004;  53 2322-2329
  • 10 Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, Rhoads DB. Selective deletion of the Hnf1beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release.  Endocrinology. 2004;  145 3941-3949
  • 11 Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, Duncan SA, Kaestner KH. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.  J Clin Invest. 2005;  115 1006-1015
  • 12 Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, Fukui K, Nammo T, Yoneda K, Inoue Y, Sladek FM, Magnuson MA, Kasai H, Miyagawa J, Gonzalez FJ, Shimomura I. Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells.  J Biol Chem. 2006;  281 5246-5257
  • 13 Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA, Kahn CR. Beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.  Nat Genet. 2002;  31 111-115
  • 14 Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes.  Cell. 1999;  96 329-339
  • 15 Ueki K, Okada T, Hu J, Liew CW, Assmann A, Dahlgren GM, Peters JL, Shackman JG, Zhang M, Artner I, Satin LS, Stein R, Holzenberger M, Kennedy RT, Kahn CR, Kulkarni RN. Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes.  Nat Genet. 2006;  38 583-588
  • 16 Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes.  J Clin Invest. 2004;  114 908-916
  • 17 Kubota N, Terauchi Y, Tobe K, Yano W, Suzuki R, Ueki K, Takamoto I, Satoh H, Maki T, Kubota T, Moroi M, Okada-Iwabu M, Ezaki O, Nagai R, Ueta Y, Kadowaki T, Noda T. Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus.  J Clin Invest. 2004;  114 917-927
  • 18 Choudhury AI, Heffron H, Smith MA, Al-Qassab H, Xu AW, Selman C, Simmgen M, Clements M, Claret M, Maccoll G, Bedford DC, Hisadome K, Diakonov I, Moosajee V, Bell JD, Speakman JR, Batterham RL, Barsh GS, Ashford ML, Withers DJ. The role of insulin receptor substrate 2 in hypothalamic and beta cell function.  J Clin Invest. 2005;  115 940-950
  • 19 Crabtree JS, Scacheri PC, Ward JM, McNally SR, Swain GP, Montagna C, Hager JH, Hanahan D, Edlund H, Magnuson MA, Garrett-Beal L, Burns AL, Ried T, Chandrasekharappa SC, Marx SJ, Spiegel AM, Collins FS. Of mice and MEN1: insulinomas in a conditional mouse knockout.  Mol Cell Biol. 2003;  23 6075-6085
  • 20 Biondi CA, Gartside MG, Waring P, Loffler KA, Stark MS, Magnuson MA, Kay GF, Hayward NK. Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues.  Mol Cell Biol. 2004;  24 3125-3131
  • 21 Hashimoto N, Kido Y, Uchida T, Asahara S, Shigeyama Y, Matsuda T, Takeda A, Tsuchihashi D, Nishizawa A, Ogawa W, Fujimoto Y, Okamura H, Arden KC, Herrera PL, Noda T, Kasuga M. Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass.  Nat Genet. 2006;  38 589-593
  • 22 Hashimoto N, Kido Y, Uchida T, Matsuda T, Suzuki K, Inoue H, Matsumoto M, Ogawa W, Maeda S, Fujihara H, Ueta Y, Uchiyama Y, Akimoto K, Ohno S, Noda T, Kasuga M. PKClambda regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic beta cells.  J Clin Invest. 2005;  115 138-145
  • 23 Rosen ED, Kulkarni RN, Sarraf P, Ozcan U, Okada T, Hsu CH, Eisenman D, Magnuson MA, Gonzalez FJ, Kahn CR, Spiegelman BM. Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis.  Mol Cell Biol. 2003;  23 7222-7229
  • 24 Stiles BL, Kuralwalla-Martinez C, Guo W, Gregorian C, Wang Y, Tian J, Magnuson MA, Wu H. Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes.  Mol Cell Biol. 2006;  26 2772-2781
  • 25 Gorogawa S, Fujitani Y, Kaneto H, Hazama Y, Watada H, Miyamoto Y, Takeda K, Akira S, Magnuson MA, Yamasaki Y, Kajimoto Y, Hori M. Insulin secretory defects and impaired islet architecture in pancreatic beta-cell-specific STAT3 knockout mice.  Biochem Biophys Res Commun. 2004;  319 1159-1170
  • 26 Cui Y, Huang L, Elefteriou F, Yang G, Shelton JM, Giles JE, Oz OK, Pourbahrami T, Lu CY, Richardson JA, Karsenty G, Li C. Essential role of STAT3 in body weight and glucose homeostasis.  Mol Cell Biol. 2004;  24 258-269
  • 27 Wang XP, Yang J, Norman MA, Magnusson J, DeMayo FJ, Brunicardi FC. SSTR5 ablation in islet results in alterations in glucose homeostasis in mice.  FEBS Lett. 2005;  579 3107-3114
  • 28 Silva JP, Kohler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, Larsson NG. Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes.  Nat Genet. 2000;  26 336-340
  • 29 Lee JY, Ristow M, Lin X, White MF, Magnuson MA, Hennighausen L. RIP-Cre revisited: evidence for impairments of pancreatic beta-cell function.  J Biol Chem. 2006;  281 2649-2653
  • 30 Reaven EP, Gold G, Walker W, Reaven GM. Effect of variations in islet size and shape on glucose-stimulated insulin secretion.  Horm Metab Res. 1981;  13 673-674
  • 31 Mahler RJ. The hyperplastic pancreatic islet as the cause of insulin resistance in obesity.  Horm Metab Res. 1974;  4 172-174
  • 32 Gapp DA, Leiter EH, Coleman DL, Schwizer RW. Temporal changes in pancreatic islet composition in C57BL/6J-db/db (diabetes) mice.  Diabetologia. 1983;  25 439-443
  • 33 Hull RL, Kodama K, Utzschneider KM, Carr DB, Prigeon RL, Kahn SE. Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation.  Diabetologia. 2005;  48 1350-1358
  • 34 Herrera PL. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages.  Development. 2000;  127 2317-2322
  • 35 Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes.  Genes Dev. 1998;  12 1763-1768

1 These authors contributed equally to this work.

Correspondence

M. Ristow

Department of Human Nutrition

Institute of Nutrition

University of Jena

Dornburger Strasse 29

07743 Jena

Germany

Phone: +49/3641/949 63 0

Fax: +49/3641/949 63 2

Email: michael.ristow@mristow.org