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: 4
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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: 8
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3. Cardiovascular comorbidities in COVID-19 : comprehensive analysis of key topicsRene Markovič, Luka Ternar, Tim Trstenjak, Marko Marhl, Vladimir Grubelnik, 2024, izvirni znanstveni članek Ključne besede: hypertension, hyperglycemia, embolism, thrombosis, heart failure, vascular disease
Objavljeno v DKUM: 22.08.2024; Ogledov: 53; Prenosov: 10
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4. The role of anaplerotic metabolism of glucose and glutamine in insulin secretion : a model approachVladimir Grubelnik, Jan Zmazek, Marko Gosak, Marko Marhl, 2024, izvirni znanstveni članek Opis: We propose a detailed computational beta cell model that emphasizes the role of anaplerotic metabolism under glucose and glucose-glutamine stimulation. This model goes beyond the traditional focus on mitochondrial oxidative phosphorylation and ATP-sensitive K+ channels, highlighting the predominant generation of ATP from phosphoenolpyruvate in the vicinity of KATP channels. It also underlines the modulatory role of H2O2 as a signaling molecule in the first phase of glucose-stimulated insulin secretion. In the second phase, the model emphasizes the critical role of anaplerotic pathways, activated by glucose stimulation via pyruvate carboxylase and by glutamine via glutamate dehydrogenase. It particularly focuses on the production of NADPH and glutamate as key enhancers of insulin secretion. The predictions of the model are consistent with empirical data, highlighting the complex interplay of metabolic pathways and emphasizing the primary role of glucose and the facilitating role of glutamine in insulin secretion. By delineating these crucial metabolic pathways, the model provides valuable insights into potential therapeutic targets for diabetes.
Ključne besede: mathematical models, pancreatic beta cell, pyruvate-malate cycle
Objavljeno v DKUM: 06.06.2024; Ogledov: 162; Prenosov: 7
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5. 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: 11
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6. Modeling the amino acid effect on glucagon secretion from pancreatic alpha cellsJan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2022, izvirni znanstveni članek Opis: Type 2 Diabetes Mellitus (T2DM) is a burdensome problem in modern society, and intensive research is focused on better understanding the underlying cellular mechanisms of hormone secretion for blood glucose regulation. T2DM is a bi-hormonal disease, and in addition to 100 years of increasing knowledge about the importance of insulin, the second hormone glucagon, secreted by pancreatic alpha cells, is becoming increasingly important. We have developed a mathematical model for glucagon secretion that incorporates all major metabolic processes of glucose, fatty acids, and glutamine as the most abundant postprandial amino acid in blood. In addition, we consider cAMP signaling in alpha cells. The model predictions quantitatively estimate the relative importance of specific metabolic and signaling pathways and particularly emphasize the important role of glutamine in promoting glucagon secretion, which is in good agreement with known experimental data.
Ključne besede: diabetes, hormone secretion, glucose, amino acid, cAMP
Objavljeno v DKUM: 21.05.2024; Ogledov: 169; Prenosov: 13
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7. Age-related changes in lipid and glucose levels associated with drug use and mortality : an observational studyRene Markovič, Vladimir Grubelnik, Helena Blažun Vošner, Peter Kokol, Matej Završnik, Karmen Janša, Marjeta Zupet, Jernej Završnik, Marko Marhl, 2022, izvirni znanstveni članek Opis: Background: The pathogenesis of type 2 diabetes mellitus is complex and still unclear in some details. The main feature of diabetes mellitus is high serum glucose, and the question arises of whether there are other statistically observable dysregulations in laboratory measurements before the state of hyperglycemia becomes severe. In the present study, we aim to examine glucose and lipid profiles in the context of age, sex, medication use, and mortality. Methods: We conducted an observational study by analyzing laboratory data from 506,083 anonymized laboratory tests from 63,606 different patients performed by a regional laboratory in Slovenia between 2008 and 2019. Laboratory data-based results were evaluated in the context of medication use and mortality. The medication use database contains anonymized records of 1,632,441 patients from 2013 to 2018, and mortality data were obtained for the entire Slovenian population. Results: We show that the highest percentage of the population with elevated glucose levels occurs approximately 20 years later than the highest percentage with lipid dysregulation. Remarkably, two distinct inflection points were observed in these laboratory results. The first inflection point occurs at ages 55 to 59 years, corresponding to the greatest increase in medication use, and the second coincides with the sharp increase in mortality at ages 75 to 79 years. Conclusions: Our results suggest that medications and mortality are important factors affecting population statistics and must be considered when studying metabolic disorders such as dyslipidemia and hyperglycemia using laboratory data.
Ključne besede: diabetes, metabolic syndrome, hematological data, aging
Objavljeno v DKUM: 21.05.2024; Ogledov: 204; Prenosov: 11
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8. Lipotoxicity in a vicious cycle of pancreatic beta cell exhaustionVladimir Grubelnik, Jan Zmazek, Matej Završnik, Marko Marhl, 2022, izvirni znanstveni članek Opis: 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.
Ključne besede: diabetes, insulin secretion, lipids, PEP cycle, uncoupling proteins, mitochondrial dysfunction
Objavljeno v DKUM: 20.05.2024; Ogledov: 133; Prenosov: 8
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9. Profiling of patients with type 2 diabetes based on medication adherence dataRene Markovič, Vladimir Grubelnik, Tadej Završnik, Helena Blažun Vošner, Peter Kokol, Matjaž Perc, Marko Marhl, Matej Završnik, Jernej Završnik, 2023, izvirni znanstveni članek Ključne besede: diabetes, data analysis, public health, statistics
Objavljeno v DKUM: 09.05.2024; Ogledov: 196; Prenosov: 8
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10. Dinamika enodimenzionalnih sistemovVladimir Grubelnik, Marko Marhl, 2024, univerzitetni, visokošolski ali višješolski učbenik z recenzijo Opis: Učbenik obravnava enodimenzionalne dinamične sisteme z elementarnim pristopom. Cilj je študentom omogočiti boljše razumevanje temeljnih načel dinamike sistemov, kot so določitev stacionarnih stanj, stabilnostna analiza, bifurkacije in dolgoročno obnašanje sistemov. Učbenik je zasnovan predvsem za študente fizike, vendar je uporaben tudi za druge smeri, kjer je matematično modeliranje dinamičnih sistemov del učnega načrta. Vsebinski sklopi učbenika zajemajo osnovne značilnosti dinamičnih sistemov, geometrijski pristop reševanja enodimenzionalnih sistemov, tokove na krožnici, bifurkacije in njihove značilnosti, enodimenzionalne preslikave (mape) ter številne primere enodimenzionalnih sistemov v fiziki, biologiji in kemiji. Primeri so izbrani tako, da študentom pomagajo razvijati intuicijo za dinamiko bolj kompleksnih več dimenzionalnih sistemov, s katerimi se soočajo v vsakdanjem življenju.
Ključne besede: dinamika sistemov, povratne zanke, stabilnostna analiza, bifurkacije, logistična mapa, kaos
Objavljeno v DKUM: 13.02.2024; Ogledov: 368; Prenosov: 40
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