| First Author | Fan F | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 32 | PubMed ID | 34362840 |
| Mgi Jnum | J:309549 | Mgi Id | MGI:6758474 |
| Doi | 10.1073/pnas.2021764118 | Citation | Fan F, et al. (2021) Dynamin deficiency causes insulin secretion failure and hyperglycemia. Proc Natl Acad Sci U S A 118(32):e2021764118 |
| abstractText | Pancreatic beta cells operate with a high rate of membrane recycling for insulin secretion, yet endocytosis in these cells is not fully understood. We investigate this process in mature mouse beta cells by genetically deleting dynamin GTPase, the membrane fission machinery essential for clathrin-mediated endocytosis. Unexpectedly, the mice lacking all three dynamin genes (DNM1, DNM2, DNM3) in their beta cells are viable, and their beta cells still contain numerous insulin granules. Endocytosis in these beta cells is severely impaired, resulting in abnormal endocytic intermediates on the plasma membrane. Although insulin granules are abundant, their release upon glucose stimulation is blunted in both the first and second phases, leading to hyperglycemia and glucose intolerance in mice. Dynamin triple deletion impairs insulin granule exocytosis and decreases intracellular Ca(2+) responses and granule docking. The docking defect is correlated with reduced expression of Munc13-1 and RIM1 and reorganization of cortical F-actin in beta cells. Collectively, these findings uncover the role of dynamin in dense-core vesicle endocytosis and secretory capacity. Insulin secretion deficiency in the absence of dynamin-mediated endocytosis highlights the risk of impaired membrane trafficking in endocrine failure and diabetes pathogenesis. |
