Contribution of insulin signaling to the regulation of pancreatic beta-cell mass during the catch-up growth period in a low birth weight mouse model
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Children born with low birth weight have a high risk of developing type 2 diabetes mellitus later in life. In this study, we developed a mouse model for low birth weight induced by maternal caloric restriction and investigated its effects on pancreatic β-cells. At birth, the pancreatic β-cell mass in the restricted diet group (RG) offspring was significantly lower than in the control group (CG) offspring. At 8 weeks of age, the pancreatic β-cell mass was greater in the RG offspring than in the CG offspring. RG offspring showed upregulated expression of insulin receptor substrate 2 in islets at 10 weeks of age. Moreover, the activity of insulin signaling molecules in the pancreatic β-cell mass was increased during the period of catch-up growth during the early stage of life. To investigate the effect of insulin signaling on the regulation of pancreatic β-cell mass, we generated β-cell-specific 3-phosphoinositide-dependent protein kinase 1 (PDK1) heterozygous knockout (βPDK1+/−) mice. We detected delayed catch-up growth in the β-cell mass of βPDK1+/− mice that were undernourished as fetuses. Moreover, the insulin signaling pathway was impaired in the islets of βPDK1+/− mice exposed to fetal undernutrition. These findings indicate that fetal undernutrition affects the regulation of pancreatic β-cell mass through altered insulin signaling.
KeywordsInsulin signaling Pancreatic beta-cell Catch-up growth Fetal undernutrition
We thank M. Nagano and H. Meguro for technical assistance. This work was supported by a grant for CLUSTER from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, to M. Kasuga, a Grant-in-Aid for Creative Scientific Research from MEXT to M. Kasuga (18GS0317), a Grant-in-Aid for Scientific Research from MEXT to Y. Kido (22590981), a Grant-in-Aid for Young Scientists from MEXT to N. Hashimoto (22790863), a Grant from Yamaguchi Endocrine Research Association to N. Hashimoto, and a Danon Institute of Japan Foundation Research Grant to M. Kimura-Koyanagi.
Conflict of interest
The authors declare no conflict of interest.
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