| First Author | Jiang S | Year | 2016 |
| Journal | J Pathol | Volume | 238 |
| Issue | 1 | Pages | 109-19 |
| PubMed ID | 26434932 | Mgi Jnum | J:227776 |
| Mgi Id | MGI:5702796 | Doi | 10.1002/path.4652 |
| Citation | Jiang S, et al. (2016) GGPPS-mediated Rab27A geranylgeranylation regulates beta cell dysfunction during type 2 diabetes development by affecting insulin granule docked pool formation. J Pathol 238(1):109-19 |
| abstractText | Loss of first-phase insulin secretion associated with beta cell dysfunction is an independent predictor of type 2 diabetes mellitus (T2DM) onset. Here we found that a critical enzyme involved in protein prenylation, geranylgeranyl pyrophosphate synthase (GGPPS), is required to maintain first-phase insulin secretion. GGPPS shows a biphasic expression pattern in islets of db/db mice during the progression of T2DM: GGPPS is increased during the insulin compensatory period, followed by a decrease during beta cell dysfunction. Ggpps deletion in beta cells results in typical T2DM beta cell dysfunction, with blunted glucose-stimulated insulin secretion and consequent insulin secretion insufficiency. However, the number and size of islets and insulin biosynthesis are unaltered. Transmission electron microscopy shows a reduced number of insulin granules adjacent to the cellular membrane, suggesting a defect in docked granule pool formation, while the reserve pool is unaffected. Ggpps ablation depletes GGPP and impairs Rab27A geranylgeranylation, which is responsible for the docked pool deficiency in Ggpps-null mice. Moreover, GGPPS re-expression or GGPP administration restore glucose-stimulated insulin secretion in Ggpps-null islets. These results suggest that GGPPS-controlled protein geranylgeranylation, which regulates formation of the insulin granule docked pool, is critical for beta cell function and insulin release during the development of T2DM. |
