Andraz Stozer

• MD, PhD
• Professor (Assistant) at University of Maribor

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...

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and huma...

Oscillatory electrical activity is regarded as a hallmark of the pancreatic beta cell glucose-dependent excitability pattern. Electrophysiologically recorded membrane potential oscillations in beta cells are associated with in-phase oscillatory cytosolic calcium activity ([Ca(2+)]i) measured with fluorescent probes. Recent high spatial and temporal...

We propose a network representation of electrically coupled beta cells in islets of Langerhans. Beta cells are functionally connected on the basis of correlations between calcium dynamics of individual cells, obtained by means of confocal laser-scanning calcium imaging in islets from acute mouse pancreas tissue slices. Obtained functional networks...

In endocrine cells within islets of Langerhans calcium ions couple cell stimulation to hormone secretion. Since the advent of modern fluorimetry, numerous in vitro studies employing primarily isolated mouse islets have investigated the effects of various secretagogues on cytoplasmic calcium, predominantly in insulin-secreting beta cells. Due to tec...

Arginine vasopressin (AVP) is well known for regulating fluid volume, osmotic balance, and vascular tone. Its role in the regulation of pancreatic α and β cell function has been reported, yet its effects are not fully understood, particularly regarding its interaction with plasma glucose levels. The osmotic and volume challenges posed by hyper- and...

Acute pancreatitis (AP) is a sudden inflammation of the exocrine part of the pancreas, resulting in self-digestion and destruction of exocrine tissue. The intricate relationship between exocrine and endocrine functions is pivotal, as damage to acinar cells can affect endocrine cell function and vice versa. However, our understanding of these intera...

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...

Calcium signals in pancreatic beta-cells collectives show a sharp transition from uncorrelated to correlated state resembling a phase transition as the slowly increasing glucose concentration crosses the tipping point. However, the exact nature or the order of this phase transition is not well understood. Using confocal microscopy to record the col...

Calcium signals in pancreatic β cell collectives show a sharp transition from uncorrelated to correlated state resembling a phase transition as the slowly increasing glucose concentration crosses the tipping point. However, the exact nature or the order of this phase transition is not well understood. Using confocal microscopy to record the collect...

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...

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...

Mouse models of diet-induced type 2 diabetes mellitus provide powerful tools for studying the structural and physiological changes that are related to the disease progression. In this study, diabetic-like glucose dysregulation was induced in mice by feeding them a western diet, and light and transmission electron microscopy were used to study the u...

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...

Zakon o ohranitvi energije velja za človeško telo enako kot za druge kompleksne sisteme. Energija se sprejema s hrano in pijačo in porablja s fizičnim delom in toploto. Razlika med vnosom in porabo povzroči v telesu pozitivno bilanco energije, kar dolgoročno pomeni povečanje zalog triacilglicerola v adipocitih. Obstajajo številni dokazi, da vnos en...

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...

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 incomplet...

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...

Beta cell dysfunction has long been thought to be at the root of type 2 diabetes pathogenesis; however, a bi-hormonal model of the disease appears to be more realistic. Alpha cells play a significant role in glucose homeostasis due to their communication with other cells within the islets of Langerhans and tissues like the liver through glucagon ac...

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...

Presented with sensory challenges, living cells employ extensive noisy, fluctuating signaling and communication among themselves to compute a physiologically proper response. Using coupled stochastic oscillators model, we propose that biological computation mechanism undertaken by insulin secreting beta-cells consists of a combination of dual intra...

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...

The release of peptide hormones is predominantly regulated by a transient increase in cytosolic Ca ²⁺ concentration ([Ca ²⁺ ] c ). To trigger exocytosis, Ca ²⁺ ions enter the cytosol from intracellular Ca ²⁺ stores or from the extracellular space. The molecular events of late stages of exocytosis, and their dependence on [Ca ²⁺ ] c , were extensive...

Adrenaline inhibits insulin secretion from pancreatic beta cells to allow an organism to cover immediate energy needs by unlocking internal nutrient reserves. The stimulation of α2-adrenergic receptors on the plasma membrane of beta cells reduces their excitability and insulin secretion mostly through diminished cAMP production and downstream desen...

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...

Determining the viability of cells is fraught with many uncertainties. It is often difficult to determine whether a cell is still alive, approaching the point of no return, or dead. Today, there are many methods for determining cell viability. Most rely on an indirect determination of cell death (metabolism, molecular transport, and leakage, to nam...

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...

Presented with sensory challenges, living cells employ extensive noisy, fluctuating signalling and communication among themselves to compute a physiologically proper response which often results in symmetry breaking. We propose, based on the results of a coupled stochastics oscillators model that biological computation mechanism undertaken by insul...

Insulin resistance in key target organs and beta cell dysfunction due to gluco- and lipotoxicity, are the two main factors driving type 2 diabetes mellitus pathogenesis. Recently, it has been suggested that ectopic fat deposition in the pancreas, named non-alcoholic fatty pancreas disease, occurs in metabolic syndrome, and may play an etiological r...

Although mice are a very instrumental model in islet beta cell research, possible phenotypic differences between strains and substrains are largely neglected in the scientific community. In this study, we show important phenotypic differences in beta cell responses to glucose between C57BL/6J, C57BL/6N, and NMRI mice, i.e., the three most commonly...

Information and Communication Technology (ICT) is a commonly used concept in schools, implemented in laboratory work in the form of various digital devices. We evaluated the ICT implementation in cardiovascular physiology in Slovenian primary school education. Surprisingly, we showed a relatively low acceptance rate in biology classes: only 42.8 %...

Although mice are a very instrumental model in islet beta cell research, possible phenotypic differences between strains and substrains are largely neglected in the scientific community. In this study, we show important phenotypic differences in beta cell responses to glucose between NMRI, C57BL/6J, and C57BL/6N mice, i.e., the three most commonly...

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...

Purpose: Urinary incontinence is highly prevalent in both women and men. Urodynamic testing is essential for diagnosis, but a gap exists in the usefulness of simple assessments that do not provide sufficient data, and devices that provide the necessary data, but are used primarily in clinics and clinical trials. This study considered the existing m...

β cells are biologically essential for humans and other vertebrates. Because their functionality arises from cell-cell interactions, they are also a model system for collective organization among cells. There are currently two contradictory pictures of this organization: the hub-cell idea pointing at leaders who coordinate the others, and the elect...

The ethical constraints and shortcomings of animal models, combined with the demand to study disease pathogenesis under controlled conditions, are giving rise to a new field at the interface of tissue engineering and pathophysiology, which focuses on the development of in vitro models of disease. In vitro models are defined as synthetic experimenta...

Anatomical proximity and functional correlations between the exocrine and endocrine pancreas warrant reciprocal effects between the two parts. Inflammatory diseases of the exocrine pancreas, such as acute or chronic pancreatitis, or the presence of cystic fibrosis disrupt endocrine function, resulting in diabetes of the exocrine pancreas. Although...

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...

Cholinergic innervation in the pancreas controls both the release of digestive enzymes to support the intestinal digestion and absorption, as well as insulin release to promote nutrient use in the cells of the body. The effects of muscarinic receptor stimulation are described in detail for endocrine beta cells and exocrine acinar cells separately....

Dextromethorphan (DXM) acts as cough suppressant via its central action. Cell-protective effects of this drug have been reported in peripheral tissues, making DXM potentially useful for treatment of several common human diseases, such as type 2 diabetes mellitus (T2DM). Pancreatic islets are among the peripheral tissues that positively respond to D...

Cholinergic innervation in pancreas controls both the release of digestive enzymes to support the intestinal digestion and absorption, as well as insulin release to promote nutrient use in the cells of the body. The effects of muscarinic receptor stimulation are described in detail for endocrine beta cells and exocrine acinar cells separately. Here...

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...

Knjiga Izbrana poglavja iz fiziologije za študente medicine z navodili za vaje so strukturirana tako, da študent skozi prvi dve poglavji osvoji fiziologijo vzdražnih celic. Sledijo poglavja, ki obravnavajo fiziologijo nekaterih notranjih organov. Več poglavij je namenjenih kardiovaskularni fiziologiji, kjer študent usvoji koncepte arterijskega prit...

Objective Insulin release from pancreatic beta cells is driven by cytosolic [Ca ²⁺ ] c oscillations of several different time scales that are primarily attributed to plasma membrane ion channel activity. However, the majority of past studies have been performed at supraphysiological glucose concentrations above 10 mM using electrophysiologic approa...

The acute mouse pancreatic tissue slice is a unique in situ preparation with preserved intercellular communication and tissue architecture that entails significantly fewer preparation-induced changes than isolated islets, acini, ducts, or dispersed cells described in typical in vitro studies. By combining the acute pancreatic tissue slice with live...

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...

Želja po razvoju tkivnih nadomestkov, potrebe po preučevanju mehanizmov bolezni v kontroliranih pogojih, pomanjkljivosti živalskih modelov in etične omejitve so bile povod za razvoj področja naprednih modelov in vitro. Te definiramo kot alternativne eksperimentalne sisteme, ki z uporabo modernih tehnik tkivnega inženirstva in aditivne proizvodnje p...

β cells are biologically essential for humans and other vertebrates. Because their functionality arises from cell-cell interactions, they are also a model system for collective organization among cells. There are currently two contradictory pictures of this organization: the hub-cell idea pointing at leaders who coordinate the others, and the elect...

Since December 2019, SARS-CoV-2 infections have altered many aspects of our societies. Citizens were faced with circumstances to which even experts and scientists did not yet know the answers and were applying the scientific method to make daily steps of progress towards better understanding the threat and how to contain it. Within a year, several...

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...

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...

Extreme or unaccustomed eccentric exercise can cause exercise-induced muscle damage, characterized by structural changes involving sarcomere, cytoskeletal, and membrane damage, with an increased permeability of sarcolemma for proteins. From a functional point of view, disrupted force transmission, altered calcium homeostasis, disruption of excitati...

Residing in the islets of Langerhans in the pancreas, β-cells contribute to glucose homeostasis by managing the body's insulin supply. Although it has been acknowledged that healthy β-cells engage in heavy cell-to-cell communication to perform their homeostatic function, the exact role and effects of such communication remain partly understood. We...

The World Health Organization declared the coronavirus disease 2019 a pandemic on March 11th, pointing to the over 118,000 cases in over 110 countries and territories around the world at that time. At the time of writing this manuscript, the number of confirmed cases has been surging rapidly past the half-million mark, emphasizing the sustained ris...

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...

Article Open Access Published: 14 February 2020 A Novel in situ Approach to Studying Detrusor Smooth Muscle Cells in Mice Tamara Serdinšek, Saša Lipovšek, Gerd Leitinger, Igor But, Andraž Stožer & Jurij Dolenšek Scientific Reports volume 10, Article number: 2685 (2020) Cite this article Abstract The aim of our study was to develop a novel approac...

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...

The Centers for Disease Control and Prevention (CDC) provides extensive data that indicate our need for drugs to maintain human population health. Despite the substantial availability of drugs on the market, many patients lack specific drugs. New drugs are required to tackle this issue. Moreover, we need more reliable models for testing drug toxici...

Residing in the islets of Langerhans in the pancreas, beta cells contribute to glucose homeostasis by managing the body's insulin supply. A circulating hypothesis has been that healthy beta cells heavily engage in cell-to-cell communication to perform their homeostatic function. We provide strong evidence in favor of this hypothesis in the form of...

Introduction: The tissue slice technique offers several benefits compared to isolated cells and cell clusters that help us understand the (patho)physiology of several organs in situ. The most prominent features are preserved architecture and function, with intact homotypic and heterotypic interactions between cells in slices. In the pancreas, this...

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...

3D printed bioscaffolds from polysaccharide materials hold a huge promise in tissue engineering applications, especially in regard to in vitro culturing of pancreatic cells, which require cell-ECM mimicking interactions in all spatial dimensions to remain viable for longer times. Material features, surface characteristics and the physical nature of...

This study describes a novel approach to solve the surgical site infection (SSI) classification problem. Feature engineering has traditionally been one of the most important steps in solving complex classification problems, especially in cases with temporal data. The described novel approach is based on abstraction of temporal data recorded in thre...

Background: Beta cells are central in the pathophysiology of diabetes, since their functional adaptation maintains euglycemia in insulin-resistant individuals and beta cell dysfunction is required for the clinical picture of frank diabetes. The pathophysiological mechanisms driving compensation and decompensation are incompletely understood and li...

Background Multimorbidity presents an increasingly common problem in older population, and is tightly related to polypharmacy, i.e., concurrent use of multiple medications by one individual. Detecting polypharmacy from drug prescription records is not only related to multimorbidity, but can also point at incorrect use of medicines. In this work, we...

HYPOTHESIS / AIMS OF STUDY Physiology of the detrusor muscle is very complex, as smooth muscle cells (SMC) of detrusor are part of several receptor and signalling pathways. Moreover, detrusor muscle undergoes a series of functional and morphologic changes under influence of different pathophysiological conditions such as bladder outlet obstruction....

Introduction: Near-infrared spectroscopy (NIRS) enables continuous monitoring of regional oximetry (rSO2). The aim of this study was to describe dynamics of regional cerebral oximetry levels during out of hospital cardiac arrest (OHCA) resuscitation, specifically around the time of restoration of spontaneous circulation (ROSC). Methods: This pro...

Aim: To develop and validate a simplified screening test for undiagnosed Type 2 diabetes mellitus and impaired fasting glucose for the Slovenian population (SloRisk) to be used in the general population. Methods: Data on 11 391 people were collected from the electronic health records of comprehensive medical examinations in five Slovenian health...

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...