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


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
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.
Calderari
S
S
Laboratory of Physiopathology of Nutrition, UMR CNRS 7059, University of Paris 7, 2 place Jussieu, 75251, Paris Cedex 05, France. sophie.calderari@college-de-france.fr
Gangnerau
M-N
MN
Thibault
M
M
Meile
M-J
MJ
Kassis
N
N
Alvarez
C
C
Portha
B
B
Serradas
P
P
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010179:Pancreas / Q000002:abnormalities / Q000196:embryology*; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1