| First Author | Alejandro EU | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 8 | Pages | 2150-2162 |
| PubMed ID | 28546423 | Mgi Jnum | J:252107 |
| Mgi Id | MGI:5924725 | Doi | 10.2337/db16-1349 |
| Citation | Alejandro EU, et al. (2017) Overexpression of Kinase-Dead mTOR Impairs Glucose Homeostasis by Regulating Insulin Secretion and Not beta-Cell Mass. Diabetes 66(8):2150-2162 |
| abstractText | Regulation of glucose homeostasis by insulin depends on beta-cell growth and function. Nutrients and growth factor stimuli converge on the conserved protein kinase mechanistic target of rapamycin (mTOR), existing in two complexes, mTORC1 and mTORC2. To understand the functional relevance of mTOR enzymatic activity in beta-cell development and glucose homeostasis, we generated mice overexpressing either one or two copies of a kinase-dead mTOR mutant (KD-mTOR) transgene exclusively in beta-cells. We examined glucose homeostasis and beta-cell function of these mice fed a control chow or high-fat diet. Mice with two copies of the transgene [RIPCre;KD-mTOR (Homozygous)] develop glucose intolerance due to a defect in beta-cell function without alterations in beta-cell mass with control chow. Islets from RIPCre;KD-mTOR (Homozygous) mice showed reduced mTORC1 and mTORC2 signaling along with transcripts and protein levels of Pdx-1. Islets with reduced mTORC2 signaling in their beta-cells (RIPCre;Rictorfl/fl) also showed reduced Pdx-1. When challenged with a high-fat diet, mice carrying one copy of KD-mTOR mutant transgene developed glucose intolerance and beta-cell insulin secretion defect but showed no changes in beta-cell mass. These findings suggest that the mTOR-mediated signaling pathway is not essential to beta-cell growth but is involved in regulating beta-cell function in normal and diabetogenic conditions. |
