1. Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic ▫$\alpha$▫-cellsVladimir Grubelnik, Rene Markovič, Saška Lipovšek Delakorda, Gerd Leitinger, Marko Gosak, Jurij Dolenšek, Ismael Valladolid-Acebes, Per-Olof Berggren, Andraž Stožer, Matjaž Perc, Marko Marhl, 2020, izvirni znanstveni članek Opis: 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.
Ključne besede: diabetes, pancreatic alpha cells, glucagon, mitochondrial dysfunction, free fatty acid
Objavljeno v DKUM: 03.09.2024; Ogledov: 49; Prenosov: 6
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2. Mitochondrial dysfunction in pancreatic alpha and beta cells associated with type 2 diabetes mellitusVladimir Grubelnik, Jan Zmazek, Rene Markovič, Marko Gosak, Marko Marhl, 2020, izvirni znanstveni članek Opis: Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30-40% reduction in alpha cells' mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases.
Ključne besede: pancreatic endocrine cells, mathematical model, mitochondrial dysfunction, cellular bioenergetics, diabetes, glucagon, insulin
Objavljeno v DKUM: 03.09.2024; Ogledov: 47; Prenosov: 16
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3. Role of cAMP in double switch of glucagon secretionJan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2021, izvirni znanstveni članek Opis: Glucose metabolism plays a crucial role in modulating glucagon secretion in pancreatic alpha cells. However, the downstream effects of glucose metabolism and the activated signaling pathways influencing glucagon granule exocytosis are still obscure. We developed a computational alpha cell model, implementing metabolic pathways of glucose and free fatty acids (FFA) catabolism and an intrinsically activated cAMP signaling pathway. According to the model predictions, increased catabolic activity is able to suppress the cAMP signaling pathway, reducing exocytosis in a Ca2+ -dependent and Ca2+ independent manner. The effect is synergistic to the pathway involving ATPdependent closure of KATP channels and consequent reduction of Ca2+. We analyze the contribution
of each pathway to glucagon secretion and show that both play decisive roles, providing a kind of "secure double switch". The cAMP-driven signaling switch plays a dominant role, while the ATP-driven metabolic switch is less favored. The ratio is approximately 60:40, according to the most recent experimental evidence.
Ključne besede: pancreatic alpha cell, glucagon, cAMP, mathematical model, diabetes, cellular bioenergetics
Objavljeno v DKUM: 06.06.2024; Ogledov: 107; Prenosov: 15
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