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Diabetologia
Published in: Diabetologia 7/2007

01-07-2007 | Article

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

Authors: S. Calderari, M.-N. Gangnerau, M. Thibault, M.-J. Meile, N. Kassis, C. Alvarez, B. Portha, P. Serradas

Published in: Diabetologia | Issue 7/2007

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Abstract

Aims/hypothesis

The Goto–Kakizaki (GK) rat is a spontaneous model of type 2 diabetes. Defective beta cell mass detectable in late fetal age precedes the onset of hyperglycaemia. Our hypothesis was that an embryonic IGF production deficiency might be involved in beta cell mass anomaly in the diabetic GK rat. To test this, we evaluated during pancreatic organogenesis: (1) the beta cell development in GK rats on embryonic day (E) 13.5 and E18.5; (2) IGF2 and IGF1 receptor (IGF1R) pancreatic protein production on E13.5 and E18.5; (3) the in vitro development of GK pancreatic rudiment on E13.5; and (4) the in vitro effect of IGF2 addition on beta cell mass.

Materials and methods

Beta cell quantitative analyses were determined by immunohistochemistry and morphometry. IGF2 and IGF1R pancreatic protein production was evaluated using western blot analyses. Dorsal pancreatic rudiments were dissected on E13.5, separated from surrounding mesenchyme and cultured for 7 days without or with recombinant IGF2.

Results

While beta cell mass was already decreased on E18.5, the differentiation of the first beta cells was in fact normal in E13.5 GK pancreas. Moreover, defective IGF2 and IGF1R protein production was detected in GK pancreatic rudiment as early as E13.5. The isolated GK pancreatic rudiment as maintained in vitro mimics the GK beta cell deficiency observed in vivo. This last approach enabled us to show that GK beta cells were fully responsive to IGF2 as far as their net growth is concerned.

Conclusions/interpretation

In diabetic GK rat, defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly. IGF2 supplementation expands the pool of beta cells.
Literature
1.
Goto Y, Kakizaki M, Masaki N (1976) Production of spontaneous diabetic rats by repetition of selective breeding. Tohoku J Exp Med 119:85–90PubMedCrossRef
2.
Portha B, Giroix MH, Serradas P et al (2001) Beta-cell function and viability in the spontaneously diabetic GK rat: information from the GK/Par colony. Diabetes 50 (Suppl 1):S89–S93CrossRefPubMed
3.
Movassat J, Saulnier C, Serradas P, Portha B (1997) Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat. Diabetologia 40:916–925CrossRefPubMed
4.
Serradas P, Gangnerau MN, Giroix MH, Saulnier C, Portha B (1998) Impaired pancreatic beta cell function in the fetal GK rat. Impact of diabetic inheritance. J Clin Invest 101:899–904PubMedCrossRef
5.
Serradas P, Goya L, Lacorne M et al (2002) Fetal insulin-like growth factor-2 production is impaired in the GK rat model of type 2 diabetes. Diabetes 51:392–397CrossRefPubMed
6.
Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3–34CrossRefPubMed
7.
Hill DJ, Petrik J, Arany E (1998) Growth factors and the regulation of fetal growth. Diabetes Care 21(Suppl 2):B60–B69PubMed
8.
Dupont J, Holzenberger M (2003) Biology of insulin-like growth factors in development. Birth Defects Res C Embryo Today 69:257–271CrossRefPubMed
9.
Kulkarni RN (2005) New insights into the roles of insulin/IGF-I in the development and maintenance of beta-cell mass. Rev Endocr Metab Disord 6:199–210CrossRefPubMed
10.
Hill DJ, Hogg J, Petrik J, Arany E, Han VK (1999) Cellular distribution and ontogeny of insulin-like growth factors (IGFs) and IGF binding protein messenger RNAs and peptides in developing rat pancreas. J Endocrinol 160:305–317CrossRefPubMed
11.
Petrik J, Pell JM, Arany E et al (1999) Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia. Endocrinology 140:2353–2363CrossRefPubMed
12.
Martin MA, Serradas P, Ramos S et al (2005) Protein-caloric food restriction affects insulin-like growth factor system in fetal Wistar rat. Endocrinology 146:1364–1371CrossRefPubMed
13.
Kemp DM, Thomas MK, Habener JF (2003) Developmental aspects of the endocrine pancreas. Rev Endocr Metab Disord 4:5–17CrossRefPubMed
14.
Pictet RL, Clark WR, Williams RH, Rutter WJ (1972) An ultrastructural analysis of the developing embryonic pancreas. Dev Biol 29:436–467CrossRefPubMed
15.
Miralles F, Czernichow P, Scharfmann R (1998) Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 125:1017–1024PubMed
16.
Serradas P, Giroix MH, Saulnier C et al (1995) Mitochondrial deoxyribonucleic acid content is specifically decreased in adult, but not fetal, pancreatic islets of the Goto–Kakizaki rat, a genetic model of noninsulin-dependent diabetes. Endocrinology 136:5623–5631CrossRefPubMed
17.
Rivero F, Goya L, Alaez C, Pascual-Leone AM (1995) Effects of undernutrition and diabetes on serum and liver mRNA expression of IGFs and their binding proteins during rat development. J Endocrinol 145:427–440PubMedCrossRef
18.
Rivero F, Goya L, Pascual-Leone AM (1994) Comparison of extraction methods for insulin-like growth factor-binding proteins prior to measurement of insulin-like growth factor-I in undernourished neonatal and adult rat serum. J Endocrinol 140:257–263PubMedCrossRef
19.
Reinecke M, Collet C (1998) The phylogeny of the insulin-like growth factors. Int Rev Cytol 183:1–94PubMedCrossRef
20.
Movassat J, Saulnier C, Portha B (1995) Beta-cell mass depletion precedes the onset of hyperglycaemia in the GK rat, a genetic model of non-insulin-dependent diabetes mellitus. Diabete Metab 21:365–370PubMed
21.
Withers DJ, Burks DJ, Towery HH et al (1999) Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 23:32–40PubMed
22.
Withers DJ, Gutierrez JS, Towery H et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904CrossRefPubMed
23.
Pende M, Kozma SC, Jaquet M et al (2000) Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 408:994–997CrossRefPubMed
24.
Devedjian JC, George M, Casellas A et al (2000) Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes. J Clin Invest 105:731–740PubMedCrossRef
25.
George M, Ayuso E, Casellas A et al (2002) Beta cell expression of IGF-I leads to recovery from type 1 diabetes. J Clin Invest 109:1153–1163CrossRefPubMed
26.
Bernal-Mizrachi E, Wen W, Stahlhut S, Welling CM, Permutt MA (2001) Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest 108:1631–1638CrossRefPubMed
27.
Tuttle RL, Gill NS, Pugh W et al (2001) Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha. Nat Med 7:1133–1137CrossRefPubMed
28.
Kubota N, Terauchi Y, Tobe K et al (2004) Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J Clin Invest 114:917–927CrossRefPubMed
29.
Lu Y, Herrera PL, Guo Y et al (2004) Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. Diabetes 53:3131–3141CrossRefPubMed
30.
Kulkarni RN, Holzenberger M, Shih DQ et al (2002) Beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet 31:111–115PubMed
31.
Xuan S, Kitamura T, Nakae J et al (2002) Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J Clin Invest 110:1011–1019CrossRefPubMed
32.
Ueki K, Okada T, Hu J et al (2006) Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 38:583–588CrossRefPubMed
33.
Bonner-Weir S, Deery D, Leahy JL, Weir GC (1989) Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion. Diabetes 38:49–53CrossRefPubMed
34.
Chick WL, Lauris V, Flewelling JH, Andrews KA, Woodruff JM (1973) Effects of glucose on beta cells in pancreatic monolayer cultures. Endocrinology 92:212–218PubMedCrossRef
35.
Miralles F, Portha B (2001) Early development of beta-cells is impaired in the GK rat model of type 2 diabetes. Diabetes 50(Suppl 1):S84–S88CrossRefPubMed
36.
37.
Cras-Meneur C, Elghazi L, Czernichow P, Scharfmann R (2001) Epidermal growth factor increases undifferentiated pancreatic embryonic cells in vitro: a balance between proliferation and differentiation. Diabetes 50:1571–1579CrossRefPubMed
38.
Elghazi L, Cras-Meneur C, Czernichow P, Scharfmann R (2002) Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation. Proc Natl Acad Sci USA 99:3884–3889CrossRefPubMed
39.
Rachdi L, Marie JC, Scharfmann R (2003) Role for VPAC2 receptor-mediated signals in pancreas development. Diabetes 52:85–92CrossRefPubMed
40.
Vincent AM, Feldman EL (2002) Control of cell survival by IGF signaling pathways. Growth Horm IGF Res 12:193–197CrossRefPubMed
41.
Hill DJ, Strutt B, Arany E et al (2000) Increased and persistent circulating insulin-like growth factor II in neonatal transgenic mice suppresses developmental apoptosis in the pancreatic islets. Endocrinology 141:1151–1157CrossRefPubMed
42.
Hennige AM, Burks DJ, Ozcan U et al (2003) Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest 112:1521–1532CrossRefPubMed
43.
Peruzzi F, Prisco M, Dews M et al (1999) Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol 19:7203–7215PubMed
44.
Metadata
Title
Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes
Authors
S. Calderari
M.-N. Gangnerau
M. Thibault
M.-J. Meile
N. Kassis
C. Alvarez
B. Portha
P. Serradas
Publication date
01-07-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 7/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-007-0676-2

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