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1.
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: 78; Downloads: 1
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2.
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: 73; Downloads: 4
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3.
Human beta cell functional adaptation and dysfunction in insulin resistance and its reversibility
Maša Skelin, Jan Kopecky, Jurij Dolenšek, Andraž Stožer, 2023, other scientific articles

Abstract: Background: Beta cells play a key role in the pathophysiology of diabetes since their functional adaptation is able to maintain euglycemia in the face of insulin resistance, and beta cell decompensation or dysfunction is a necessary condition for full-blown type 2 diabetes (T2D). The mechanisms behind compensation and decompensation are incompletely understood, especially for human beta cells, and even less is known about influences of chronic kidney disease (CKD) or immunosupressive therapy after transplantation on these processes and the development of posttransplant diabetes. Summary: During compensation, beta cell sensitivity to glucose becomes left-shifted, i.e., their sensitivity to stimulation increases, and this is accompanied by enhanced signals along the stimulus-secretion coupling cascade from membrane depolarization to intracellular calcium and the most distal insulin secretion dynamics. There is currently no clear evidence regarding changes in intercellular coupling during this stage of disease progression. During decompensation, intracellular stimulus-secretion coupling remains enhanced to some extent at low or basal glucose concentrations but seems to become unable to generate effective signals to stimulate insulin secretion at high or otherwise stimulatory glucose concentrations. Additionally, intercellular coupling becomes disrupted, lowering the number of cells that contribute to secretion. During progression of CKD, beta cells also seem to drift from a compensatory left-shift to failure, and immunosupressants can further impair beta cell function following kidney transplantation. Key Messages: Beta cell stimulus-secretion coupling is enhanced in compensated insulin resistance. With worsening insulin resistance, both intra- and intercellular coupling become disrupted. CKD can progressively disrupt beta cell function, but further studies are needed, especially regarding changes in intercellular coupling.
Keywords: human beta cell, functional adaptation, dysfunction, insulin resistance
Published in DKUM: 15.04.2024; Views: 121; Downloads: 10
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4.
Membrane potential and calcium dynamics in beta cells from mouse pancreas tissue slices : theory, experimentation, and analysis
Jurij Dolenšek, Denis Špelič, Maša Skelin, Borut Žalik, Marko Gosak, Marjan Rupnik, Andraž Stožer, 2015, review article

Abstract: Beta cells in the pancreatic islets of Langerhans are precise biological sensors for glucose and play a central role in balancing the organism between catabolic and anabolic needs. A hallmark of the beta cell response to glucose are oscillatory changes of membrane potential that are tightly coupled with oscillatory changes in intracellular calcium concentration which, in turn, elicit oscillations of insulin secretion. Both membrane potential and calcium changes spread from one beta cell to the other in a wave-like manner. In order to assess the properties of the abovementioned responses to physiological and pathological stimuli, the main challenge remains how to effectively measure membrane potential and calcium changes at the same time with high spatial and temporal resolution, and also in as many cells as possible. To date, the most wide-spread approach has employed the electrophysiological patch-clamp method to monitor membrane potential changes. Inherently, this technique has many advantages, such as a direct contact with the cell and a high temporal resolution. However, it allows one to assess information from a single cell only. In some instances, this technique has been used in conjunction with CCD camera-based imaging, offering the opportunity to simultaneously monitor membrane potential and calcium changes, but not in the same cells and not with a reliable cellular or subcellular spatial resolution. Recently, a novel family of highly-sensitive membrane potential reporter dyes in combination with high temporal and spatial confocal calcium imaging allows for simultaneously detecting membrane potential and calcium changes in many cells at a time. Since the signals yielded from both types of reporter dyes are inherently noisy, we have developed complex methods of data denoising that permit for visualization and pixel-wise analysis of signals. Combining the experimental approach of high-resolution imaging with the advanced analysis of noisy data enables novel physiological insights and reassessment of current concepts in unprecedented detail.
Keywords: calcium sensors, membrane potential sensors, calcium imaging, membrane potential imaging, beta cell, pancreas, denoising, patch-clamp
Published in DKUM: 22.06.2017; Views: 1581; Downloads: 212
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5.
Exocytosis of insulin in vivo maturation of mouse endocrine pancreas
Aldo Rozzo, Tiziana Meneghel-Rozzo, Saška Lipovšek Delakorda, Shi-Bing Yang, Marjan Rupnik, 2009, published scientific conference contribution

Abstract: The aim of this study was to define when an insulin-positive cell becomes functional in vivo and starts to exocytose insulin in a regulated nutrient-dependent manner. Insulin-positive cells appear in embryonic life (midgestation) and complete their maturation, presumably around birth. In order to work with embryonic and newborn endocrine pancreas, we used organotypic slices. The mouse embryonic pancreas slices show high basal insulin release that is not further elevated by high glucose levels. Despite the presence of functional voltage-activated ion channels, the cells are not electrically active in the presence of secretagogues. At birth, the high basalinsulin release drops and, after postnatal day 2, the insulin-positive cells show both adult-like bursting electrical activity and hormone release induced by high glucose levels. These properties allowed us to define them as beta cells. Despite the apparent stability of the transcription factor profile reported in insulin-positive cells during late-embryonic life, functional beta cells appear only 2 days after birth.
Keywords: cell biology, insulin release, embrios, newborn, beta-cell maturation, developing pancreas
Published in DKUM: 07.06.2012; Views: 1502; Downloads: 28
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