Effects of mutations in the insulin-like growth factor signaling system on embryonic pancreas development and beta-cell compensation to insulin resistance.
Insulin and insulin-like growth factors (IGF) play overlapping and complementary roles in pancreatic beta-cell function and peripheral metabolism. In this study, we have analyzed mice bearing loss-of-function mutations of the insulin/IGF signaling systems. Combined inactivation of insulin receptor (Insr) and Igf1 receptor (Igf1r), but not of either receptor alone, resulted in a 90% decrease in the size of the exocrine pancreas, because of decreased cellular proliferation. In contrast to the findings in the exocrine compartment, endocrine alpha- and beta-cell development was unperturbed. Combined ablation of Igf1 and Igf2, the ligands for these two receptors, resulted in an identical phenotype. We also examined the effect of heterozygous null Igf1r mutations on glucose homeostasis in adult mice. Igf1r haploinsufficiency did not affect insulin action and compensatory beta-cell growth in insulin-resistant mice with combined Insr and Igf1r heterozygous null mutations, resulting in a considerably milder phenotype than combined haploinsufficiency for Insr and its main signaling substrates, Irs1 and Irs2. We conclude that Igf1r and Insr are required for embryonic development of the exocrine but not of the endocrine pancreas and that defects of Igf1r do not alter glucose homeostasis as long as the insulin receptor system remains intact.
Kido
Yoshiaki
Y
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Nakae
Jun
J
Hribal
Marta Letizia
ML
Xuan
Shouhong
S
Efstratiadis
Argiris
A
Accili
Domenico
D
D000818:Animals; D001835:Body Weight; D001973:Bromodeoxyuridine / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D006706:Homeostasis; D015151:Immunoblotting; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007515:Islets of Langerhans / Q000196:embryology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D009132:Muscles / Q000201:enzymology; D009154:Mutation; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D015398:Signal Transduction; D013997:Time Factors
D008024:Ligands; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D001973:Bromodeoxyuridine; D005947:Glucose