| First Author | Burke SJ | Year | 2018 |
| Journal | Mol Metab | Volume | 14 |
| Pages | 95-107 | PubMed ID | 29914854 |
| Mgi Jnum | J:315908 | Mgi Id | MGI:6831867 |
| Doi | 10.1016/j.molmet.2018.06.003 | Citation | Burke SJ, et al. (2018) Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet beta-cell de-differentiation. Mol Metab 14:95-107 |
| abstractText | OBJECTIVE: Pancreatic tissue, and islets in particular, are enriched in expression of the interleukin-1 receptor type I (IL-1R). Because of this enrichment, islet beta-cells are exquisitely sensitive to the IL-1R ligands IL-1alpha and IL-1beta, suggesting that signaling through this pathway regulates health and function of islet beta-cells. METHODS: Herein, we report a targeted deletion of IL-1R in pancreatic tissue (IL-1R(Pdx1-/-)) in C57BL/6J mice and in db/db mice on the C57 genetic background. Islet morphology, beta-cell transcription factor abundance, and expression of the de-differentiation marker Aldh1a3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance tests were used to examine metabolic status of these genetic manipulations. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion. RESULTS: Pancreatic deletion of IL-1R leads to impaired glucose tolerance, a phenotype that is exacerbated by age. Crossing the IL-1R(Pdx1-/-) with db/db mice worsened glucose tolerance without altering body weight. There were no detectable alterations in insulin tolerance between IL-1R(Pdx1-/-) mice and littermate controls. However, glucose-stimulated insulin secretion was reduced in islets isolated from IL-1R(Pdx1-/-) relative to control islets. Insulin output in vivo after a glucose challenge was also markedly reduced in IL-1R(Pdx1-/-) mice when compared with littermate controls. Pancreatic islets from IL-1R(Pdx1-/-) mice displayed elevations in Aldh1a3, a marker of de-differentiation, and reduction in nuclear abundance of the beta-cell transcription factor MafA. Nkx6.1 abundance was unaltered. CONCLUSIONS: There is an important physiological role for pancreatic IL-1R to promote glucose homeostasis by suppressing expression of Aldh1a3, sustaining MafA abundance, and supporting glucose-stimulated insulin secretion in vivo. |
