Marko Gosak

• Doctor of Philosophy
• Assoc. prof. at University of Maribor

While the islet β-cells were traditionally viewed as a singular functional entity, findings of 1970s and up until recent years, reveal that individual β-cells differ in their calcium dynamics and insulin secretion, forming distinct subpopulations that together maintain glucose homeostasis. However, the underlying mechanisms driving functional β-cel...

Background The crucial steps in beta cell stimulus‐secretion coupling upon stimulation with glucose are oscillatory changes in metabolism, membrane potential, intracellular calcium concentration, and exocytosis. The changes in membrane potential consist of bursts of spikes, with silent phases between them being dominated by membrane repolarization...

Ca2+ ions play a central role in the stimulus-secretion coupling cascade of pancreatic beta cells. The use of confocal microscopy in conjunction with the acute pancreas tissue slice technique offers valuable insights into changes in the intracellular calcium concentration following stimulation by secretagogues. This allows the study of beta cells o...

When individual oscillators age and become inactive, the collective dynamics of coupled oscillators is often affected as well. Depending on the fraction of inactive oscillators or cascading failures that percolate from crucial information exchange points, the critical shift toward macroscopic inactivity in coupled oscillator networks is known as th...

Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect of metabolic homeostasis. Despite the inherent heterogeneity and multimodal activity of individual cells, intercellular coupling acts as a homogenizing force, enabling coordinated responses through the propagation of intercellular waves. Disrupt...

Tight control of beta cell stimulus-secretion coupling is crucial for maintaining homeostasis of energy-rich nutrients. While glucose serves as a primary regulator of this process, incretins augment beta cell function, partly by enhancing cytosolic [Ca²⁺] dynamics. However, the details of how precisely they affect beta cell recruitment during activ...

Pancreatic beta cells are coupled excitable oscillators that synchronize their activity via different communication pathways. Their oscillatory activity manifests itself on multiple timescales and consists of bursting electrical activity, subsequent oscillations in the intracellular Ca2+, as well as oscillations in metabolism and exocytosis. The co...

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 o...

Hyperbolic networks have high clustering, short average path lengths, and community structure, which are all properties that are commonly associated with social networks. As such, these networks constitute the perfect playing ground for probing factors that may affect public cooperation in realistic scenarios. And although much is already known abo...

Pancreatic beta cells are coupled excitable oscillators that synchronize their activity via different communication pathways. Their oscillatory activity manifests itself on multiple timescales and consists of bursting electrical activity, subsequent oscillations in the intracellular Ca2+, as well as oscillations in metabolism and exocytosis. The co...

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...

Islets of Langerhans operate as multicellular networks in which several hundred beta cells work in synchrony to produce secretory pulses of insulin, a hormone crucial for controlling metabolic homeostasis. Their collective rhythmic activity is facilitated by gap junctional coupling and affected by their functional heterogeneity, but the details of...

Pancreatic islets are highly interconnected structures that produce pulses of insulin and other hormones, maintaining normal homeostasis of glucose and other nutrients. Normal stimulus-secretion and intercellular coupling are essential to regulated secretory responses and these hallmarks are known to be altered in diabetes. In the present study, we...

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 a...

Our core body temperature is held around 37∘\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$37~^\circ$$\end{document}C by an effective internal thermoregulatory system....

Islets of Langerhans are multicellular microorgans located in the pancreas that play a central role in whole-body energy homeostasis. Through secretion of insulin and other hormones they regulate postprandial storage and interprandial usage of energy-rich nutrients. In these clusters of hormone-secreting endocrine cells, intricate cell-cell communi...

The physiology and pathophysiology of the exocrine pancreas are in close connection to changes in intra-cellular Ca²⁺ concentration. Most of our knowledge is based on in vitro experiments on acinar cells or acini enzymatically isolated from their surroundings, which can alter their structure, physiology, and limit our understanding. Due to these li...

The firing patterns of neuronal populations often exhibit emergent collective oscillations, which can display substantial regularity even though the dynamics of individual elements is very stochastic. One of the many phenomena that is often studied in this context is coherence resonance, where additional noise leads to improved regularity of spikin...

Technological advances in imaging techniques and biometric data acquisition have enabled us to apply methods of network science to study the morphology and structural design of organelles, organs, and tissues, as well as the coordinated interactions among them that yield a healthy physiology at the level of whole organisms. We here review research...

Pancreatic islets are highly interconnected structures that produce pulses of insulin and other hormones, maintaining normal homeostasis of glucose and other nutrients. Normal stimulus-secretion and intercellular coupling are essential to regulated secretory responses and these hallmarks are known to be altered in diabetes. In the present study, we...

Thermoregulation constitutes one of the most important homeostatic systems of the human body. The human thermoregulatory system is highly complex and intertwined with other regulatory homeostatic systems. Different evolutionary adaptations have evolved to ensure a well-regulated body temperature, encompassing simple behavioural (e.g., seeking shelt...

Many details of glucose-stimulated intracellular calcium changes in beta cells during activation, activity, and deactivation, as well as their concentration-dependence, remain to be analyzed. Classical physiological experiments indicated that in islets, functional differences between individual cells are largely attenuated, but recent findings sugg...

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibi...

We propose and study an epidemiological model on a social network that takes into account heterogeneity of the population and different vaccination strategies. In particular, we study how the COVID-19 epidemics evolves and how it is contained by different vaccination scenarios by taking into account data showing that older people, as well as indivi...

NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cell...

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibi...

Calcium imaging is a very powerful approach to determine the role that Ca2+ ions play in living cells and enables the analysis of spatiotemporal Ca2+ dynamics in vitro, in situ, and in vivo. Various physiological processes, from exocytosis and contraction to gene expression, depend on intracellular Ca2+ and defects in Ca2+ signaling can lead to sev...

Beta cells couple stimulation by glucose with insulin secretion and impairments in this coupling play a central role in diabetes mellitus. To clarify the effect of cAMP and the role of Epac2A in intracellular calcium signals and intercellular coupling, we performed functional multicellular calcium imaging in beta cells in mouse pancreas tissue slic...

Ca²⁺ homeostasis and signaling disturbances are associated with lens pathophysiology and are involved in cataract formation. Here, we explored the spatiotemporal changes in Ca²⁺ signaling in lens epithelial cells (LECs) upon local mechanical stimulation, to better understand the LECs’ intercellular communication and its association with cataractoge...

Community lockdowns and travel restrictions are commonly employed to decelerate epidemic spreading.We here use a stochastic susceptible-infectious-recovered model on different social networks to determine when and to what degree such lockdowns are likely to be effective. Our research shows that community lockdowns are effective only if the links ou...

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...

Understanding the evolution of cooperation in structured populations remains one of the fundamental challenges of the 21st century, with far-reaching implications for the wellbeing of modern human societies. Studies over the past two decades showed that the structure of the network of contacts plays a crucial role in determining whether cooperation...

Social distancing is an effective strategy to mitigate the impact of infectious diseases. If sick or healthy, or both, predominantly socially distance, the epidemic curve flattens. Contact reductions may occur for different reasons during a pandemic including health-related mobility loss (severity of symptoms), duty of care for a member of a high-r...

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...

Thermoregulation plays a vital role in homeostasis. Many species of animals as well as humans have evolved various physiological mechanisms for body temperature control, which are characteristically flexible and enable a fine‐tuned spatial and temporal regulation of body temperature in different environmental conditions and circumstances. Human bei...

The human brain is increasingly seen as a dynamic neural system, the function of which relies on a diverse set of connections between brain regions. To assess these complex dynamical interactions, formalism of complex networks was suggested as one of the most promising tools to offer new insight into the brain's structural and functional organizati...

If interaction partners in social dilemma games are not selected randomly from the population but are instead determined by a network of contacts, it has far reaching consequences for the evolutionary dynamics. Selecting partners randomly leads to a well-mixed population, where pattern formation is essentially impossible. This rules out important m...

A precise structural organization of epithelial cells is needed for the proper functioning and development of different tissues. The epithelial cell packing mechanism is associated with mechanical interactions between cells that place the tissue in a state with the lowest free energy. In addition, planar cell polarity has been recognized as another...

Many tissues are gap-junction-coupled syncytia that support cell-to-cell communication via propagating calcium waves. This also holds true for pancreatic islets of Langerhans, where several thousand beta cells work in synchrony to ensure proper insulin secretion. Two emerging functional parameters of islet function are the location of wave initiato...

Morphological and anatomical characteristics of the posterior intercostal arteries have revived interest in their branching networks. Collateral supply between intercostal spaces is extensive due to anastomoses, although the data about the quantitative description of the branching networks in the existing literature are rather limited. The presence...

Many details of glucose-stimulated intracellular calcium changes in beta cells during activation, activity and deactivation, as well as their concentration-dependence, remain to be described. Classical physiological experiments indicated that in islets functional differences between individual cells are largely attenuated, but recent findings sugge...

We present a mathematical model of the energy-driven metabolic switch for glucagon and insulin secretion from pancreatic alpha and beta cells, respectively. The energy status related to hormone secretion is studied for various glucose concentrations. Additionally, the physiological response is studied with regards to the presence of other metabolit...

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...

Research at the interface of statistical physics, evolutionary game theory, and network science has in the past two decades significantly improved our understanding of cooperation in structured populations. We know that networks with broad-scale degree distributions favor the emergence of robust cooperative clusters, and that temporal networks migh...

Signatures of criticality, such as power law scaling of observables, have been empirically found in a plethora of real-life settings, including biological systems. The presence of critical states is believed to have many functional advantages and is associated with optimal operational abilities. Typically, critical dynamics arises in the proximity...

Research at the interface of statistical physics, evolutionary game theory, and network science has in the past two decades significantly improved our understanding of cooperation in structured populations. We know that networks with broad-scale degree distributions favor the emergence of robust cooperative clusters, and that temporal networks migh...

Self-organized critical dynamics is assumed to be an attractive mode of functioning for several real-life systems and entails an emergent activity in which the extent of observables follows a power-law distribution. The hallmarks of criticality have recently been observed in a plethora of biological systems, including beta cell populations within p...

Network science has provided new promising tools for studying the structure and function of various complex systems. In the present contribution we demonstrate how network concepts can be used to describe the collective activity of pancreatic β cell populations in islets of Langerhans. In this microorgan, electrically coupled β cells produce and se...

Understanding energy consumption patterns in the residential sector is of paramount importance for the design of new energy management strategies that are based on innovative information and communication technologies. Smart metering provides considerable opportunities in this respect and allows for the assessment of household characteristics, beha...

Words are the building blocks of human communication. They are arranged in sentences in a non-trivial and universal way, which implies the existence of fundamental organizational principles that have shaped language development. One of the fundamental examples is the Zipf’s law, which says that the frequency of word occurrence is roughly an inverse...

A coordinated functioning of beta cells within pancreatic islets is mediated by oscillatory membrane depolarization and subsequent changes in cytoplasmic calcium concentration. While gap junctions allow for intraislet information exchange, beta cells within islets form complex syncytia that are intrinsically nonlinear and highly heterogeneous. To s...

Simulated spatio-temporal activity under constant stimulation with homogeneous coupling. Typical computed [Ca2+]c responses of four different beta cells after switching to stimulatory conditions (upper panel, gray area indicates stimulatory conditions) and binarization of the computed oscillations of all cells (lower panel). The electrical coupling...

Representative animation of computed and binarized spatiotemporal [Ca2+]i activity under constant stimulation with glucose.

Movie of experimentally measured and binarized [Ca2+]i activity under constant stimulation with 8 mM glucose from the onset of glucose increase.

Movie of experimentally measured and binarized [Ca2+]i activity under periodic stimulation with 6-8-6-8-6-8-6 mM glucose.

The course of the simulated oscillatory stimulation protocol. Variations in the glucokinase reaction rate reflect the oscillatory changes in glucose.

Coupling in the multicellular beta cell model. (A) A typical structure of the intercellular network of beta cells. (B) The corresponding degree distribution. The beta cell network is quite homogeneous with a mean degree around 6. (C) The distribution of the electrical coupling coefficient. The coupling strength is rather heterogeneous and follows a...

Mathematical model and parameter values for beta cells.

Representative animation of computed and binarized spatiotemporal [Ca2+]i activity under periodic stimulation with glucose.

SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic β cells. The protein exists as two alternatively spliced isoforms, SNAP-25a and SNAP-25b, differing in 9 out of 206 amino acids, yet their specific roles in pancreatic β cells remain unclear. We explored the effect of SNAP-25b-deficiency o...

Network science is today established as a backbone for description of structure and function of various physical, chemical, biological, technological, and social systems. Here we review recent advances in the study of complex biological systems that were inspired and enabled by methods of network science. First, we present research highlights rangi...

Quantitative analysis of the vascular network anatomy is critical for the understanding of the vasculature structure and function. In this study, we have combined microcomputed tomography (microCT) and computational analysis to provide quantitative three-dimensional geometrical and topological characterization of the normal kidney vasculature, and...

Vasculature segmentation and reconstruction workflow. The flowchart shows the sequential order in which individual subroutines are arranged in our computational protocol in order to segment out the vascular structure and to reconstruct it. Used abbreviation are SO for the Strahler order, SOp for the parent vessel Strahler order, SOd for the daughte...

Global scale parameter analysis. (PDF)

In this work we investigated how modifications of the Ca2+ homeostasis in anterior lens epithelial cells (LECs) are associated with different types of cataract (cortical or nuclear) and how the progression of the cataract (mild or moderate) affects the Ca2+ signaling. We systematically analyzed different aspects of intra- and inter-cellular Ca2+ si...

Analysis of Ca2+ signals in individual LECs with respect to spontaneous activity. Comparison of: A normalized individual activation times, [Δtact,i]norm, and B deactivation times, [Δtdeact,i]norm, between spontaneously active and non-active cells. In the normalization process all values were divided by the average Δtact or Δtdeact in the given LC i...

Spatio-temporal organization of spontaneously active LECs in a characteristic LC. A Positions of LECs with marked spontaneously active cells (black rings, 29 of total 200 cells) in the LC. Positions of 6 spontaneously active LECs, for which traces are presented in the B panel (colored black rings). B Temporal traces of the normalized [Ca2+]i dynami...

Analysis of the activation speeds, SA, (A) and the deactivation speeds, SDA, (B) with regard to spontaneous activity. The one-way ANOVA test did not detect significant differences between the two groups of LCs, i.e. the group with spontaneously active LECs and the group without. The results indicate that the spontaneous activity does not have a sig...

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...

Self-sustained oscillatory dynamics is a motion along a stable limit cycle in the phase space, and it arises in a wide variety of mechanical, electrical, and biological systems. Typically, oscillations are due to a balance between energy dissipation and generation. Their stability depends on the properties of the attractor, in particular, its dissi...

a r t i c l e i n f o a b s t r a c t Modern theory of networks has been recognized as a very successful methodological concept for the description and analysis of complex systems. However, some complex systems are more complex than others. For instance, several real-life systems are constituted by interdependent subsystems and their elements are s...

Collective beta cell activity in islets of Langerhans is critical for the supply of insulin within an organism. Even though individual beta cells are intrinsically heterogeneous, the presence of intercellular coupling mechanisms ensures coordinated activity and a well-regulated exocytosis of insulin. In order to get a detailed insight into the func...

We study the functional connectivity patterns between beta cells in islets of Langerhans from mouse pancreas tissue slices. We build up the functional networks on the basis of correlations between calcium dynamics of individual cells, which were recorded by means of confocal laser-scanning calcium imaging. The extracted patterns of pairwise interac...

Epithelial tissues are structured and highly organized monolayers of cells with many different tissue-specific functions. Ordering of epithelium cells in living tissues relies on spatially and temporally regulated cell behavior and is of vital importance for their functioning. The underlying mechanisms that govern the development of the tissue arch...