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The role of anaplerotic metabolism of glucose and glutamine in insulin secretion : a model approach
Vladimir Grubelnik, Jan Zmazek, Marko Gosak, Marko Marhl, 2024, original scientific article

Abstract: 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.
Keywords: mathematical models, pancreatic beta cell, pyruvate-malate cycle
Published in DKUM: 06.06.2024; Views: 71; Downloads: 1
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Assessing different temporal scales of calcium dynamics in networks of beta cell populations
Jan Zmazek, Maša Skelin, Rene Markovič, Jurij Dolenšek, Marko Marhl, Andraž Stožer, Marko Gosak, 2021, original scientific article

Abstract: Beta cells within the pancreatic islets of Langerhans respond to stimulation with coherent oscillations of membrane potential and intracellular calcium concentration that presumably drive the pulsatile exocytosis of insulin. Their rhythmic activity is multimodal, resulting from networked feedback interactions of various oscillatory subsystems, such as the glycolytic, mitochondrial, and electrical/calcium components.How these oscillatory modules interact and affect the collective cellular activity, which is a prerequisite for proper hormone release, is incompletely understood. In the present work, we combined advanced confocal Ca2+ imaging in fresh mouse pancreas tissue slices with time series analysis and network science approaches to unveil the glucosedependent characteristics of different oscillatory components on both the intra- and inter-cellular level. Our results reveal an interrelationship between the metabolically driven low-frequency component and the electrically driven high-frequency component, with the latter exhibiting the highest bursting rates around the peaks of the slow component and the lowest around the nadirs. Moreover, the activity, as well as the average synchronicity of the fast component, considerably increased with increasing stimulatory glucose concentration, whereas the stimulation level did not affect any of these parameters in the slow component domain. Remarkably, in both dynamical components, the average correlation decreased similarly with intercellular distance, which implies that intercellular communication affects the synchronicity of both types of oscillations. To explore the intra-islet synchronization patterns in more detail, we constructed functional connectivity maps. The subsequent comparison of network characteristics of different oscillatory components showed more locally clustered and segregated networks of fast oscillatory activity, while the slow oscillations were more global, resulting in several long-range connections and a more cohesive structure. Besides the structural differences, we found a relatively weak relationship between the fast and slow network layer, which suggests that different synchronization mechanisms shape the collective cellular activity in islets, a finding which has to be kept in mind in future studies employing different oscillations for constructing networks.
Keywords: islets of Langerhans, beta cell network, calcium oscillations, multimodal activity analysis, confocal imaging, functional connectivity, multiplex network
Published in DKUM: 06.06.2024; Views: 67; Downloads: 4
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Role of cAMP in double switch of glucagon secretion
Jan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2021, original scientific article

Abstract: 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.
Keywords: pancreatic alpha cell, glucagon, cAMP, mathematical model, diabetes, cellular bioenergetics
Published in DKUM: 06.06.2024; Views: 28; Downloads: 0
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Modeling the amino acid effect on glucagon secretion from pancreatic alpha cells
Jan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2022, original scientific article

Abstract: 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.
Keywords: diabetes, hormone secretion, glucose, amino acid, cAMP
Published in DKUM: 21.05.2024; Views: 101; Downloads: 2
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Age-related changes in lipid and glucose levels associated with drug use and mortality : an observational study
Rene Markovič, Vladimir Grubelnik, Helena Blažun Vošner, Peter Kokol, Matej Završnik, Karmen Janša, Marjeta Zupet, Jernej Završnik, Marko Marhl, 2022, original scientific article

Abstract: 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.
Keywords: diabetes, metabolic syndrome, hematological data, aging
Published in DKUM: 21.05.2024; Views: 91; Downloads: 1
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Lipotoxicity in a vicious cycle of pancreatic beta cell exhaustion
Vladimir Grubelnik, Jan Zmazek, Matej Završnik, Marko Marhl, 2022, original scientific article

Abstract: 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.
Keywords: diabetes, insulin secretion, lipids, PEP cycle, uncoupling proteins, mitochondrial dysfunction
Published in DKUM: 20.05.2024; Views: 66; Downloads: 2
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Self-organization of enzyme-catalyzed reactions studied by the maximum entropy production principle
Andrej Dobovišek, Marko Vitas, Tina Blaževič, Rene Markovič, Marko Marhl, Aleš Fajmut, 2023, original scientific article

Abstract: The self-organization of open reaction systems is closely related to specific mechanisms that allow the export of internally generated entropy from systems to their environment. According to the second law of thermodynamics, systems with effective entropy export to the environment are better internally organized. Therefore, they are in thermodynamic states with low entropy. In this context, we study how self-organization in enzymatic reactions depends on their kinetic reaction mechanisms. Enzymatic reactions in an open system are considered to operate in a non-equilibrium steady state, which is achieved by satisfying the principle of maximum entropy production (MEPP). The latter is a general theoretical framework for our theoretical analysis. Detailed theoretical studies and comparisons of the linear irreversible kinetic schemes of an enzyme reaction in two and three states are performed. In both cases, in the optimal and statistically most probable thermodynamic steady state, a diffusion-limited flux is predicted by MEPP. Several thermodynamic quantities and enzymatic kinetic parameters, such as the entropy production rate, the Shannon information entropy, reaction stability, sensitivity, and specificity constants, are predicted. Our results show that the optimal enzyme performance may strongly depend on the number of reaction steps when linear reaction mechanisms are considered. Simple reaction mechanisms with a smaller number of intermediate reaction steps could be better organized internally and could allow fast and stable catalysis. These could be features of the evolutionary mechanisms of highly specialized enzymes.
Keywords: enzymes, kinetic data analysis, steady state, self-organization, maximum entropy production
Published in DKUM: 08.05.2024; Views: 151; Downloads: 8
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Dinamika enodimenzionalnih sistemov
Vladimir Grubelnik, Marko Marhl, 2024, reviewed university, higher education or higher vocational education textbook

Abstract: 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.
Keywords: dinamika sistemov, povratne zanke, stabilnostna analiza, bifurkacije, logistična mapa, kaos
Published in DKUM: 13.02.2024; Views: 279; Downloads: 22
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Vpliv meteoroloških pojavov na astronomska opazovanja objektov sončnega sistema na razredni stopnji : magistrsko delo
Vera Homšak, 2023, master's thesis

Abstract: V magistrski nalogi so predstavljeni priprava na astronomsko opazovanje z upoštevanjem vplivov meteoroloških pojavov ter didaktični pripomočki oz. modeli, ki jih učitelj lahko uporabi pri predstavitvi te teme učencem razrednega pouka. V teoretičnem delu je težišče na astronomiji kot vedi in deloma na nastanku vesolja, posvetimo pa se tudi predstavitvi objektov v sončnem sistemu in pripravljanju na opazovanje. Dotaknemo se še meteorologije kot vede in meteoroloških pojavov ter njihovega vpliva na astronomsko opazovanje objektov našega Osončja. Obe obravnavani vedi sta med seboj tesno povezani, kar mora upoštevati tudi učitelj pri obravnavi teh tem, še zlasti pri pripravi na astronomsko opazovanje na razredni stopnji, pa tudi v preostalih razredih osnovne šole. V nalogi se nato posvetimo pregledu učnih vsebin s področja astronomije in meteorologije iz učnega načrta za osnovno šolo, tako za redni pouk od 1. do 9. razreda kot tudi za izbirni predmet v 3. vzgojno-izobraževalnem obdobju. Sledi praktični del zaključne naloge, v katerem so predstavljene štiri astronomske aktivnosti. Vse štiri aktivnosti smo izvedli z učenci 5. razreda, ki so bili naključno izbrani in razvrščeni v dve skupini. Vse izbrane in izvedene aktivnosti spodbujajo učence h globljemu spoznavanju te zanimive znanosti in k boljši predstavi o našem Osončju.
Keywords: astronomija, meteorologija, sončni sistem, opazovanje objektov sončnega sistema, osnovna šola
Published in DKUM: 21.06.2023; Views: 453; Downloads: 79
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