Horm Metab Res 2015; 47(01): 56-63
DOI: 10.1055/s-0034-1390427
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Increased Perinatal Remodelling of the Pancreas in Somatostatin-Deficient Mice: Potential Role of Transforming Growth Factor-Beta Signalling in Regulating Beta Cell Growth in Early Life

C. C. Richardson
1   Division of Diabetes and Nutritional Sciences, King’s College London, London, UK
K. To
1   Division of Diabetes and Nutritional Sciences, King’s College London, London, UK
V. L. Foot
1   Division of Diabetes and Nutritional Sciences, King’s College London, London, UK
A. C. Hauge-Evans
1   Division of Diabetes and Nutritional Sciences, King’s College London, London, UK
D. Carmignac
2   Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK
M. R. Christie
1   Division of Diabetes and Nutritional Sciences, King’s College London, London, UK
› Author Affiliations
Further Information

Publication History

received 01 July 2014

accepted 04 September 2014

Publication Date:
28 October 2014 (online)


Early postnatal life is a critical period for development of the endocrine pancreas, involving remodelling of islet cells and maturation of secretory responses. Factors that regulate these processes are undefined. Somatostatin-secreting delta-cells are abundant in the developing pancreas and, because somatostatin inhibits growth, the hormone may regulate islet expansion in early life. The aim of this study was to investigate effects of somatostatin-deficiency on proliferation, apoptosis and pancreas expansion in the first 3 weeks of life in mice. Pancreases from control or somatostatin-knockout mice were analysed for beta cell, alpha cell and pancreatic volumes by morphometry, proliferation by BrdU incorporation and apoptosis by TUNEL labelling. Signalling pathways associated with proliferation and apoptosis were studied by immunohistochemistry and Western blotting. Knockout mice grew normally in the first 3 weeks of life, but had high circulating insulin that normalised by day 21. Beta cell, alpha cell and pancreatic volumes were decreased in knockout mice, accompanied by reduced proliferation and increased apoptosis in the pancreas. Decreased growth was not due to impaired Akt signalling, as Akt phosphorylation and nuclear cyclin-D2 increased in the knockout pancreas. Levels of TGF-β1, a factor implicated in tissue remodelling, together with SMAD phosphorylation through which TGF-β mediates its effects, were increased in the knockout pancreas. Beta cell expansion was impaired in knockout mice, potentially compensating for increased insulin secretion from islets lacking inhibitory effects of somatostatin, and was associated with increased TGF-β1 levels. TGF-β1 may represent an important regulator of beta cell mass in early life.

  • References

  • 1 Bonner-Weir S. Perspective: Postnatal pancreatic beta cell growth. Endocrinology 2000; 141: 1926-1929
  • 2 Grill V, Lake W, Freinkel N. Generalized diminution in the response to nutrients as insulin-releasing agents during the early neonatal period in the rat. Diabetes 1981; 30: 56-63
  • 3 Kaung HL. Growth dynamics of pancreatic islet cell populations during fetal and neonatal development of the rat. Dev Dyn 1994; 200: 163-175
  • 4 Vasavada RC, Gonzalet-Pertusa JA, Fujinaka Y, Gonzalet-Pertusa JA, Fujinaka Y, Fiaschi-Taesch N, Cozar-castellano I, Garcia-Ocaña A. Growth factors and beta cell replication. Int J Biochem Cell Biol 2006; 38: 931-950
  • 5 Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 1997; 138: 1736-1741
  • 6 Petrik J, Arany E, McDonald TJ, Hill DJ. Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor. Endocrinology 1998; 139: 2994-3004
  • 7 Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999; 20: 157-198
  • 8 Stefan Y, Grasso S, Perrelet A, Orci L. A quantitative immunofluorescent study of the endocrine cell populations in the developing human pancreas. Diabetes 1983; 32: 293-301
  • 9 Ballian N, Brunicardi FC, Wang XP. Somatostatin and its receptors in the development of the endocrine pancreas. Pancreas 2006; 33: 1-12
  • 10 Hauge-Evans AC, King AJ, Carmignac D, Richardson CC, Robinson ICAF, Low MJ, Christie MR, Persaud SJ, Jones PM. Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 2009; 58: 403-411
  • 11 Brundstedt J, Nielsen JH, Lernmark A. and the Hagedorn Study group . Isolation of islets from mice and rats. In: Methods in Diabetes Research. Laboratory Methods. Larner J, Pohl SL. eds New York: Wiley; 1984. Vol. 1. 245-258
  • 12 Jones PM, Salmon DM, Howell SL. Protein phosphorylation in electrically permeabilized islets of Langerhans. Effects of Ca2+, cyclic AMP, a phorbol ester and noradrenaline. Biochem J 1988; 254: 397-403
  • 13 Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9: 671-675
  • 14 Ruifrok AC, Johnston DA. Quantification of histochemical staining by color deconvolution. Anal Quant Cytol Histol 2001; 23: 291-299
  • 15 Low MJ, Otero-Corchon V, Parlow AF, Ramirez JL, Kumar U, Patel YC, Rubinstein M. Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth. J Clin Invest 2001; 107: 1571-1580
  • 16 Luque RM, Kineman RD. Gender-dependent role of endogenous somatostatin in regulating growth hormone-axis function in mice. Endocrinology 2007; 148: 5998-6006
  • 17 Elghazi L, Weiss AJ, Barker DJ, Callaghan J, Staloch L, Sandgren EP, Gannon M, Adsay VN, Bernal-Mizrachi E. Regulation of pancreas plasticity and malignant transformation by Akt signaling. Gastroenterology 2009; 136: 1091-1103
  • 18 Bernal-Mizrachi E, Wen W, Stahlhut S, Welling CM, Permutt MA. Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest 2001; 108: 1631-1638
  • 19 Fatrai S, Elghazi L, Balcazar N, Cras-Méneur C, Krits I, Kiyokawa H, Bernal-Mizrachi E. Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes 2006; 55: 318-325
  • 20 Duronio V. The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J 2008; 415: 333-344
  • 21 Zhong L, Georgia S, Tschen S-I, Nakayama K, Nakqayama K, Bhushan A. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells. J Clin Invest 2007; 117: 2869-2876
  • 22 Rane SG, Lee JH, Lin HM. Transforming growth factor-beta pathway: role in pancreas development and pancreatic disease. Cytokine Growth Factor Rev 2006; 17: 107-119
  • 23 Rahimi RA, Leof EB. TGF-beta signaling: a tale of two responses. J Cell Biochem 2007; 102: 593-608
  • 24 Kim SK, Hebrok M, Li E, Oh SP, Schrewe H, Harmon EB, Lee JS, Melton DA. Activin receptor patterning of foregut organogenesis. Genes Dev 2000; 14: 1866-1871
  • 25 Kumar M, Jordan N, Melton D, Grapin-Botton A. Signals from lateral plate mesoderm instruct endoderm toward a pancreatic fate. Dev Biol 2003; 259: 109-122
  • 26 Dichmann DS, Yassin H, Serup P. Analysis of pancreatic endocrine development in GDF11-deficient mice. Dev Dyn 2006; 235: 3016-3025
  • 27 Yamaoka T, Idehara C, Yano M, Matsuhita T, Yamada T, Li S, Moritani M, Hata J, Sugino H, Noji S, Itakura M. Hypoplasia of pancreatic islets in transgenic mice expressing activin receptor mutants. J Clin Invest 1998; 102: 294-301
  • 28 Bottinger EP, Jakubczak JL, Roberts ISD, Mumy M, Hemmati P, Bagnali K, Merlino G, Wakefield LM. Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas. EMBO J 1997; 16: 2621-2633
  • 29 Simeone DM, Zhang L, Treutelaar MK, Zhang L, Graziano K, Logson CD, Burant CF. Islet hypertrophy following pancreatic disruption of Smad4 signaling. Am J Physiol Endocrinol Metab 2006; 291: E1305-E1316
  • 30 Miralles F, Battelino T, Czernichow P, Scharfmann R. TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J Cell Biol 1998; 143: 827-836
  • 31 Crisera CA, Maldonato AS, Kadison AS, Li M, Alkasab SL, Longaker MT, Gittes GK. Transforming growth factor-beta 1 in the developing mouse pancreas: a potential regulator of exocrine differentiation. Differentiation 2000; 65: 255-259