| First Author | Shyr ZA | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 6952 |
| PubMed ID | 31061431 | Mgi Jnum | J:279031 |
| Mgi Id | MGI:6357424 | Doi | 10.1038/s41598-019-43452-8 |
| Citation | Shyr ZA, et al. (2019) The role of membrane excitability in pancreatic beta-cell glucotoxicity. Sci Rep 9(1):6952 |
| abstractText | Persistent hyperglycemia is causally associated with pancreatic beta-cell dysfunction and loss of pancreatic insulin. Glucose normally enhances beta-cell excitability through inhibition of KATP channels, opening of voltage-dependent calcium channels, increased [Ca(2+)]i, which triggers insulin secretion. Glucose-dependent excitability is lost in islets from KATP-knockout (KATP-KO) mice, in which beta-cells are permanently hyperexcited, [Ca(2+)]i, is chronically elevated and insulin is constantly secreted. Mouse models of human neonatal diabetes in which KATP gain-of-function mutations are expressed in beta-cells (KATP-GOF) also lose the link between glucose metabolism and excitation-induced insulin secretion, but in this case KATP-GOF beta-cells are chronically underexcited, with permanently low [Ca(2+)]i and lack of glucose-dependent insulin secretion. We used KATP-GOF and KATP-KO islets to examine the role of altered-excitability in glucotoxicity. Wild-type islets showed rapid loss of insulin content when chronically incubated in high-glucose, an effect that was reversed by subsequently switching to low glucose media. In contrast, hyperexcitable KATP-KO islets lost insulin content in both low- and high-glucose, while underexcitable KATP-GOF islets maintained insulin content in both conditions. Loss of insulin content in chronic excitability was replicated by pharmacological inhibition of KATP by glibenclamide, The effects of hyperexcitable and underexcitable islets on glucotoxicity observed in in vivo animal models are directly opposite to the effects observed in vitro: we clearly demonstrate here that in vitro, hyperexcitability is detrimental to islets whereas underexcitability is protective. |
