20.500.12556/DKUM-88676 Lipotoxicity in a vicious cycle of pancreatic beta cell exhaustion Hyperlipidemia is a common metabolic disorder in modern society and may precede hyperglycemia and diabetes by several years. Exactly how disorders of lipid and glucose metabolism are related is still a mystery in many respects. We analyze the effects of hyperlipidemia, particularly free fatty acids, on pancreatic beta cells and insulin secretion. We have developed a computational model to quantitatively estimate the effects of specific metabolic pathways on insulin secretion and to assess the effects of short- and long-term exposure of beta cells to elevated concentrations of free fatty acids. We show that the major trigger for insulin secretion is the anaplerotic pathway via the phosphoenolpyruvate cycle, which is affected by free fatty acids via uncoupling protein 2 and proton leak and is particularly destructive in long-term chronic exposure to free fatty acids, leading to increased insulin secretion at low blood glucose and inadequate insulin secretion at high blood glucose. This results in beta cells remaining highly active in the “resting” state at low glucose and being unable to respond to anaplerotic signals at high pyruvate levels, as is the case with high blood glucose. The observed fatty-acid-induced disruption of anaplerotic pathways makes sense in the context of the physiological role of insulin as one of the major anabolic hormones. diabetes insulin secretion lipids PEP cycle uncoupling proteins mitochondrial dysfunction mitohondrijska disfunkcija diabetes izločanje inzulina proteini mitohondrijska disfunkcija sladkorna bolezen true true true MDPI Angleški jezik Slovenski jezik Članek v reviji 2024-05-18 03:18:56 2024-05-20 09:50:22 2024-05-21 03:37:08 0000-00-00 00:00:00 2022 0 0 str. 1-16 iss. 7 Vol. 10 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2022-05-09 2022-07-05 2022-07-07 577.35:616.151 114930947 10.3390/biomedicines10071627 2227-9059 https://www.mdpi.com/2227-9059/10/7/1627 1 9a0bd509-14b4-11ef-a567-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=179449 RAZ_Grubelnik_Vladimir_2022.pdf RAZ_Grubelnik_Vladimir_2022.pdf 1 2D5204D7C3039216BAE449BF9E220331 b6cef7dd87d5ff40b722dfddad414e941eb61154b5561981b3bf7231ed64797b 6fe3aeeb-167d-11ef-a997-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=179473 Fakulteta za naravoslovje in matematiko Pedagoška fakulteta 0 0 0