1. Parkinson’s disease non-motor subtypes classification in a group of Slovenian patients : actuarial vs. data-driven approachTimotej Petrijan, Jan Zmazek, Marija Menih, 2023, original scientific article Abstract: Background and purpose: The aim of this study was to examine the risk factors, prodromal symptoms, non-motor symptoms (NMS), and motor symptoms (MS) in different Parkinson’s disease (PD) non-motor subtypes, classified using newly established criteria and a data-driven approach.
Methods: A total of 168 patients with idiopathic PD underwent comprehensive NMS and MS examinations. NMS were assessed by the Non-Motor Symptom Scale (NMSS), Montreal Cognitive Assessment (MoCA), Hamilton Depression Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Epworth Sleepiness Scale (ESS), Starkstein Apathy Scale (SAS) and Fatigue Severity Scale (FSS). Motor subtypes were classified based on Stebbins’ method. Patients were classified into groups of three NMS subtypes (cortical, limbic, and brainstem) based on the newly designed inclusion criteria. Further, data-driven clustering was performed as an alternative, statistical learning-based classification approach. The two classification approaches were compared for consistency.
Results: We identified 38 (22.6%) patients with the cortical subtype, 48 (28.6%) with the limbic, and 82 (48.8%) patients with the brainstem NMS PD subtype. Using a data-driven approach, we identified five different clusters. Three corresponded to the cortical, limbic, and brainstem subtypes, while the two additional clusters may have represented patients with early and advanced PD. Pearson chi-square test of independence revealed that a priori classification and cluster membership were significantly related to one another with a large effect size (χ2(8) = 175.001, p < 0.001, Cramer’s V = 0.722). The demographic and clinical profiles differed between NMS subtypes and clusters.
Conclusion: Using the actuarial and clustering approach, marked differences between individual NMS subtypes were found. The newly established criteria have potential as a simplified tool for future clinical research of NMS subtypes of Parkinson’s disease.
Keywords: Parkinson’s disease, non-motor symptoms subtypes, a priori classification, cluster analysis
Published in DKUM: 07.04.2025; Views: 0; Downloads: 9
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3. Mitochondrial dysfunction in pancreatic alpha and beta cells associated with type 2 diabetes mellitusVladimir Grubelnik, Jan Zmazek, Rene Markovič, Marko Gosak, Marko Marhl, 2020, original scientific article Abstract: 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.
Keywords: pancreatic endocrine cells, mathematical model, mitochondrial dysfunction, cellular bioenergetics, diabetes, glucagon, insulin
Published in DKUM: 03.09.2024; Views: 47; Downloads: 16
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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, 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: 162; Downloads: 21
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5. 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, 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: 171; Downloads: 6
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6. Role of cAMP in double switch of glucagon secretionJan 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: 107; Downloads: 15
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7. Modeling the amino acid effect on glucagon secretion from pancreatic alpha cellsJan 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: 169; Downloads: 18
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8. Lipotoxicity in a vicious cycle of pancreatic beta cell exhaustionVladimir 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: 133; Downloads: 16
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9. Računska ocena vpliva znotrajceličnih presnovnih in signalnih poti ter medcelične komunikacije na izločanje glukagona in inzulina : doktorska disertacijaJan Zmazek, 2022, doctoral dissertation Abstract: Doktorska disertacija proučuje fiziološke lastnosti celic alfa in beta z uporabo matematičnega modeliranja, omrežnih znanosti in drugih sodobnih biofizikalnih pristopov. V prvem delu disertacije predstavimo matematični model presnove in hormonskega izločanja obeh tipov celic. Rezultati modela kažejo, da je oksidacija maščobnih kislin odgovorna za visoko bazalno nastajanje ATP, medtem ko je od glukoze odvisno zvišanje koncentracije ATP posledica anaerobnih (glikolitskih) značilnosti celice alfa in aerobnih (mitohondrijskih) značilnosti celice beta. Motnje v glikolitski in mitohondrijski presnovi kritično vplivajo na pravilno izločanje hormonov obeh vrst celic. Model celice alfa je nadalje dopolnjen z od cAMP odvisno signalno potjo, ki jo uravnava presnovna aktivnost ali vezava zunajceličnih signalov na membranske receptorje. Glede na modelsko napoved je znižanje znotrajceličnega pH med visoko presnovno aktivnostjo ključnega pomena za znižanje znotrajcelične koncentracije cAMP ob stimulaciji z visoko koncentracijo plazemske glukoze. Modelirana je tudi stimulacija celic alfa z aminokislinami, in sicer tako, da se modelski rezultati ujemajo z eksperimentalnimi opažanji, da obrok mešanih hranil močno poveča izločanje glukagona. Drugi del disertacije predstavlja analizo eksperimentalno pridobljenih kalcijevih signalov iz celic beta v Langerhansovih otočkih. Predstavljena metodologija obdelave podatkov vključuje ekstrahiranje presnovno aktivirane počasne in električno aktivirane hitre komponente, binarizacijo ali diskretizacijo signalov, detekcijo nizkokakovostnih signalov in izgradnjo funkcionalnih mrež. Počasna in hitra oscilatorna komponenta sta med seboj povezani, pri čemer je frekvenca hitrih oscilacij največja okoli vrhov počasnih oscilacij. To vedenje je bolj izrazito pri stimulaciji s fiziološko koncentracijo glukoze kakor pri suprafiziološki koncentraciji. Za obe komponenti so zgrajene funkcionalne mreže, njihova analiza pa kaže na večjo lokalno gručavost in segregacijo mrež hitre komponente ter večjo globalno povezanost počasne komponente. Analiza večplastnih mrež kaže na šibko povezavo med hitro in počasno plastjo, kar nakazuje na to, da različni sinhronizacijski mehanizmi oblikujejo kolektivno aktivnost v otočkih.
Keywords: celica beta, celica alfa, modeliranje, presnova, cAMP, aminokisline, kalcij, medcelične mreže
Published in DKUM: 17.01.2023; Views: 615; Downloads: 108
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