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: 44; Prenosov: 2
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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: 43; Prenosov: 2
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3. Endogenous social distancing and its underappreciated impact on the epidemic curveMarko Gosak, Moritz U. G. Kraemer, Heinrich H. Nax, Matjaž Perc, Bary S. R. Pradelski, 2021, izvirni znanstveni članek Opis: Social distancing is an efective strategy to mitigate the impact of infectious diseases. If sick or healthy, or both, predominantly socially distance, the epidemic curve fattens. Contact reductions may occur for diferent reasons during a pandemic including health-related mobility loss (severity of symptoms), duty of care for a member of a high-risk group, and forced quarantine. Other decisions to reduce contacts are of a more voluntary nature. In particular, sick people reduce contacts consciously to avoid infecting others, and healthy individuals reduce contacts in order to stay healthy. We use game theory to formalize the interaction of voluntary social distancing in a partially infected population. This improves the behavioral micro-foundations of epidemiological models, and predicts diferential social distancing rates dependent on health status. The model's key predictions in terms of comparative statics are derived, which concern changes and interactions between social distancing behaviors of sick and healthy. We ft the relevant parameters for endogenous social distancing to an epidemiological model with evidence from infuenza waves to provide a benchmark for an epidemic curve with endogenous social distancing. Our results suggest that spreading similar in peak and case numbers to what partial immobilization of the population produces, yet quicker to pass, could occur endogenously. Going forward, eventual social distancing orders and lockdown policies should be benchmarked against more realistic epidemic models that take endogenous social distancing into account, rather than be driven by static, and therefore unrealistic, estimates for social mixing that intrinsically overestimate spreading.
Ključne besede: COVID-19, pandemic, disease dynamics, exponential growth, virality
Objavljeno v DKUM: 14.08.2024; Ogledov: 120; Prenosov: 3
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4. pH-dependence of glucose- dependent activity of beta cell networks in acute mouse pancreatic tissue sliceSandra Postić, Marko Gosak, Wen-Hao Tsai, Johannes Pfabe, Srdjan Sarikas, Andraž Stožer, Dean Korošak, Shi-Bing Yang, Marjan Rupnik, 2022, izvirni znanstveni članek Opis: Extracellular pH has the potential to affect various aspects of the pancreatic beta cell function. To explain this effect, a number of mechanisms was proposed involving both extracellular and intracellular targets and pathways. Here, we focus on reassessing the influence of extracellular pH on glucose-dependent beta cell activation and collective activity in physiological conditions. To this end we employed mouse pancreatic tissue slices to perform high-temporally resolved functional imaging of cytosolic Ca2+ oscillations. We investigated the effect of either physiological H+ excess or depletion on the activation properties as well as on the collective activity of beta cell in an islet. Our results indicate that lowered pH invokes activation of a subset of beta cells in substimulatory glucose concentrations, enhances the average activity of beta cells, and alters the beta cell network properties in an islet. The enhanced average activity of beta cells was determined indirectly utilizing cytosolic Ca2+ imaging, while direct measuring of insulin secretion confirmed that this enhanced activity is accompanied by a higher insulin release. Furthermore, reduced functional connectivity and higher functional segregation at lower pH, both signs of a reduced intercellular communication, do not necessary result in an impaired insulin release.
Ključne besede: insulin secretion, membrane excitability, potassium channels, beta cell network, collective activity, calcium waves, pancreatic islets, pH-dependence
Objavljeno v DKUM: 01.07.2024; Ogledov: 137; Prenosov: 3
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5. Determinants of collective failure in excitable networksUroš Barać, Matjaž Perc, Marko Gosak, 2023, izvirni znanstveni članek Opis: We study collective failures in biologically realistic networks that consist of coupled excitable units. The networks have broad-scale degree distribution, high modularity, and small-world properties, while the excitable dynamics is determined by the paradigmatic FitzHugh–Nagumo model. We consider different coupling strengths, bifurcation distances, and various aging scenarios as potential culprits of collective failure. We find that for intermediate coupling strengths, the network remains globally active the longest if the high-degree nodes are first targets for inactivation. This agrees well with previously published results, which showed that oscillatory networks can be highly fragile to the targeted inactivation of low-degree nodes, especially under weak coupling. However, we also show that the most efficient strategy to enact collective failure does not only non-monotonically depend on the coupling strength, but it also depends on the distance from the bifurcation point to the oscillatory behavior of individual excitable units. Altogether, we provide a comprehensive account of determinants of collective failure in excitable networks, and we hope this will prove useful for better understanding breakdowns in systems that are subject to such dynamics.
Ključne besede: collective behavior, excitable media, complex network, neuronal dynamics
Objavljeno v DKUM: 10.06.2024; Ogledov: 158; Prenosov: 14
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6. 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: 157; Prenosov: 6
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7. Assessing different temporal scales of calcium dynamics in networks of beta cell populationsJan Zmazek, Maša Skelin, Rene Markovič, Jurij Dolenšek, Marko Marhl, Andraž Stožer, Marko Gosak, 2021, izvirni znanstveni članek Opis: 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.
Ključne besede: islets of Langerhans, beta cell network, calcium oscillations, multimodal activity analysis, confocal imaging, functional connectivity, multiplex network
Objavljeno v DKUM: 06.06.2024; Ogledov: 166; Prenosov: 5
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8. Vpliv mešanja in kompleksnih interakcij na razvoj sodelovanja v igri javnih dobrin : doktorska disertacija po skandinavskem modeluMaja Duh, 2024, doktorska disertacija Opis: Razumevanje razvoja sodelovanja med posamezniki, ki so v osnovi sebični, je eden najpomembnejših izzivov današnjega časa, ki vzbuja zanimanje raziskovalcev iz različnih področij. V ta namen znanstveniki integrirajo evolucijsko teorijo iger z naprednimi metodami s področja znanosti o omrežjih in metodami statistične fizike. V doktorski disertaciji smo s pomočjo takega interdisciplinarnega pristopa raziskali, kako različni tipi mobilnosti oziroma mešanj igralcev na različnih interakcijskih mrežah vplivajo na evolucijo in promocijo sodelovanja v igri javnih dobrin. V ta namen smo raziskovalno delo razdelili v štiri sklope. V prvem delu smo pokazali, da uvedba mešanja igralcev v igri javnih dobrin na regularnem omrežju omogoči prehod iz stanja sistema vpetega v prostorsko mrežo v stanje dobro mešane populacije, kjer struktura interakcijske mreže več nima bistvenega pomena na evolucijsko dinamiko. Izkaže se, da je v primeru mešanja najbližjih sosedov za to potrebna večja frekvenca mešanja kot pri mešanju naključnih igralcev. Nadalje smo pokazali, da oba načina mešanja zavirata evolucijski uspeh kooperatorjev. V nadaljevanju smo raziskavo razširili na področje kompleksnih omrežij, ki podajajo realnejši opis interakcij med posamezniki. V drugem delu doktorske disertacije smo tako igro javnih dobrin postavili na naključno omrežje, vpeto v hiperbolični prostor in v model vključili asortativno in disasortativno mešanje igralcev. Ugotovili smo, da oba tipa mešanja zavirata razvoj sodelovanja ne glede na arhitekturo omrežja, a je vpliv disasortativnega mešanja večji v primerjavi z asortativnim mešanjem. Naslednji tip interakcijske mreže, s katerim se še boljše opišemo realne interakcije, so večplastna soodvisna omrežja, ki smo jih v raziskave vključili v naših naslednjih dveh raziskavah. Soodvisnost med dvema omrežjema smo vpeljali s koristnostno funkcijo in pokazali, da lahko parameter pristranskosti učinkovito vpliva na raven sodelovanja. Pokazali smo, da asortativne medmrežne povezave med dvema skalno neodvisnima omrežjema spodbujajo kooperacijo v igri javnih dobrin v nekoliko večji meri kot naključne in disasortativne povezave. V zadnjem sklopu raziskav smo prišli do presenetljivih zaključkov. Rezultati mešanja na dvoplastnem soodvisnem omrežju, kjer posamezna plast predstavlja naključno omrežje, vpeto v hiperbolični prostor, kažejo, da lahko mešanje znotraj posamezne plasti omrežja, kjer je sodelovanje prvotno uspešno, močno oslabi evolucijsko uspešnost kooperatorjev na tej plasti, medtem ko jo za določene vrednosti normaliziranega sinergijskega faktorja spodbuja sodelovanje na drugi plasti omrežja. Rezultati doktorske disertacije predstavljajo pomemben prispevek k znanstvenemu raziskovanju na področju razumevanja razvoja in vzdrževanja sodelovanja, s poudarkom na uporabi evolucijske teorije iger, kompleksnih omrežij in mobilnosti igralcev.
Ključne besede: evolucijska teorija iger, igra javnih dobrin, sodelovanje, mešanje, kompleksna omrežja, večplastna omrežja, simulacije Monte Carlo
Objavljeno v DKUM: 05.06.2024; Ogledov: 110; Prenosov: 11
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9. The effect of forskolin and the role of Epac2A during activation, activity, and deactivation of beta cell networksMaša Skelin, Jurij Dolenšek, Lidija Križančić Bombek, Viljem Pohorec, Marko Gosak, Marjan Rupnik, Andraž Stožer, 2023, izvirni znanstveni članek Opis: Beta cells couple stimulation by glucose with insulin secretion and impairments in this coupling play a central role in diabetes mellitus. Cyclic adenosine monophosphate (cAMP) amplifies stimulus-secretion coupling via protein kinase A and guanine nucleotide exchange protein 2 (Epac2A). With the present research, we aimed to clarify the influence of cAMP-elevating diterpene forskolin on cytoplasmic calcium dynamics and intercellular network activity, which are two of the crucial elements of normal beta cell stimulus-secretion coupling, and the role of Epac2A under normal and stimulated conditions. To this end, we performed functional multicellular calcium imaging of beta cells in mouse pancreas tissue slices after stimulation with glucose and forskolin in wild-type and Epac2A knock-out mice. Forskolin evoked calcium signals in otherwise substimulatory glucose and beta cells from Epac2A knock-out mice displayed a faster activation. During the plateau phase, beta cells from Epac2A knock-out mice displayed a slightly higher active time in response to glucose compared with wild-type littermates, and stimulation with forskolin increased the active time via an increase in oscillation frequency and a decrease in oscillation duration in both Epac2A knock-out and wild-type mice. Functional network properties during stimulation with glucose did not differ in Epac2A knock-out mice, but the presence of Epac2A was crucial for the protective effect of stimulation with forskolin in preventing a decline in beta cell functional connectivity with time. Finally, stimulation with forskolin prolonged beta cell activity during deactivation, especially in Epac2A knock-out mice.
Ključne besede: pancreas, tissue slices, beta cells, calcium imaging, amplifying pathway, forskolin, Epac2A KO, intercellular network
Objavljeno v DKUM: 27.05.2024; Ogledov: 190; Prenosov: 7
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10. Uporaba večceličnih modelov in mrežnih analiz za preučevanje kolektivne celične dinamike v Langerhansovih otočkih : doktorska disertacija po skandinavskem modeluMarko Šterk, 2024, doktorska disertacija Opis: V doktorski disertaciji smo se osredotočili na pereča vprašanja s področja fiziologije Langerhansovih otočkov, ki igrajo ključno vlogo pri uravnavanju glukozne homeostaze v telesu. Z uporabo inovativnih računalniških tehnik smo analizirali vpliv 3D citoarhitekture otočkov na večcelično dinamiko v opazovani 2D optični rezini, vpliv inhibicije NMDA receptorjev na kolektivno dinamiko celic beta, različne subpopulacije celic beta in njihov vpliv na kolektivno dinamiko ter vpliv metabolne sklopitve celic na kompleksnost funkcionalnih omrežij.
Ugotovili smo, da je pri analizi medceličnih kalcijevih valov treba upoštevati 3D citoarhitekturo Langerhansovih otočkov, saj velik delež medceličnih kalcijevih valov izvira izven opazovane optične rezine, kar vpliva na opazovano hitrost širjenja valovne fronte. Nadalje je naša analiza pokazala, da inhibicija NMDA receptorjev blagodejno vpliva na delovanje posameznih celic beta kakor tudi na njihovo kolektivno dinamiko, kar se odraža v povečani stabilnosti poteka medceličnih kalcijevih valov. Podrobna analiza subpopulacij celic beta je razkrila, da centralne celice in celice, ki sprožajo valove, igrajo ključno vlogo pri širjenju medceličnih valov in sinhronosti celic, kar je izjemnega pomena za zagotavljanje normalne fiziološke funkcije. Naši izsledki kažejo, da ti dve vrsti celic predstavljata različni subpopulaciji, ki se med seboj ne prekrivata. Poleg tega s teoretičnim raziskovanjem mehanizmov sinhronizacije celic beta podrobneje prikazujemo, da je za koordinirano aktivnost celic beta dovolj samo električna sklopitev, vendar dodatna metabolna sklopitev še dodatno okrepi sinhrono delovanje in s tem vpliva na lastnosti pridobljenih funkcionalnih omrežij, zaradi česar so ta bolj podobna tistim, ki jih opazimo v eksperimentih.
Z izvedenimi raziskavami smo prispevali k razumevanju, kako je vzpostavljeno koordinirano delovanje v kolektivih celic beta, kar odpira nove možnosti za razvoj zdravil za sladkorno bolezen tipa 2.
Ključne besede: celice beta, kompleksna omrežja, diabetes tipa 2, večcelični modeli, celična dinamika
Objavljeno v DKUM: 25.04.2024; Ogledov: 314; Prenosov: 27
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