20.500.12556/DKUM-90130 Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic ▫$\alpha$▫-cells Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments. diabetes pancreatic alpha cells glucagon mitochondrial dysfunction free fatty acid diabetes alfa celice glukagon mithondrijska disfunkcija proste maščobne kisline true true true Royal Society Publishing Angleški jezik Slovenski jezik Članek v reviji 2024-08-23 04:13:36 2024-09-03 09:09:42 2024-09-04 05:17:47 0000-00-00 00:00:00 2020 0 0 str. 1-17 iss. 1 Vol. 7 2020 0000-00-00 Zaloznikova Objavljeno apc 2019-07-15 2019-12-16 2020-01-22 616.379 25073672 10.1098/rsos.191171 2054-5703 RAZ_Grubelnik_Vladimir_2020.pdf RAZ_Grubelnik_Vladimir_2020.pdf 1 35737F9D5ADEB2C5ECF1A5440AB73BA3 248cdd2561e3694b159851342bb9a08147a32e92c54e3c8b21e15c474db74125 4f0bf64d-69c3-11ef-af22-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=184159 https://doi.org/10.1098/rsos.191171 0 21c754b0-69c3-11ef-af22-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=184158 Fakulteta za elektrotehniko, računalništvo in informatiko Fakulteta za naravoslovje in matematiko Medicinska fakulteta Pedagoška fakulteta 0 0 0