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- Title
Targeted deletion of Insm2 in mice result in reduced insulin secretion and glucose intolerance.
- Authors
Wang, Lin; Sun, Zhong Sheng; Xiang, Bingwu; Wei, Chi-ju; Wang, Yan; Sun, Kevin; Chen, Guanjie; Lan, Michael S.; Carmona, Gilberto N.; Notkins, Abner L.; Cai, Tao
- Abstract
<bold>Background: </bold>Neurogenin3 (Ngn3) and neurogenic differentiation 1 (NeuroD1), two crucial transcriptional factors involved in human diabetes (OMIM: 601724) and islet development, have been previously found to directly target to the E-boxes of the insulinoma-associated 2 (Insm2) gene promoter, thereby activating the expression of Insm2 in insulin-secretion cells. However, little is known about the function of Insm2 in pancreatic islets and glucose metabolisms.<bold>Methods: </bold>Homozygous Insm2-/- mice were generated by using the CRISPR-Cas9 method. Glucose-stimulated insulin secretion and islet morphology were analyzed by ELISA and immunostainings. Expression levels of Insm2-associated molecules were measured using quantitative RT-PCR and Western blots.<bold>Results: </bold>Fasting blood glucose levels of Insm2-/- mice were higher than wild-type counterparts. Insm2-/- mice also showed reduction in glucose tolerance and insulin/C-peptide levels when compared to the wild-type mice. RT-PCR and Western blot analysis revealed that expression of Insm1 was significantly increased in Insm2-/- mice, suggesting a compensatory response of the homolog gene Insm1. Similarly, transcriptional levels of Ngn3 and NeuroD1 were also increased in Insm2-/- mice. Moreover, Insm2-/- female mice showed a significantly decreased reproductive capacity.<bold>Conclusions: </bold>Our findings suggest that Insm2 is important in glucose-stimulated insulin secretion and is involved in the development pathway of neuroendocrine tissues which are regulated by the transcription factors Ngn3, NeuroD1 and Insm1.
- Subjects
GLUCOSE intolerance; INSULIN separation; NEUROGENIN 3; CRISPRS; POLYMERASE chain reaction
- Publication
Journal of Translational Medicine, 2018, Vol 16, Issue 1, pN.PAG
- ISSN
1479-5876
- Publication type
journal article
- DOI
10.1186/s12967-018-1665-6