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Opis: 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 communication is essential for proper function. Electrical coupling between the insulin-secreting beta cells through gap junctions composed of connexin36 is particularly important, as it provides the required, most important, basis for coordinated responses of the beta cell population. The increasing evidence that gap-junctional communication and its modulation are vital to well-regulated secretion of insulin has stimulated immense interest in how subpopulations of heterogeneous beta cells are functionally arranged throughout the islets and how they mediate intercellular signals. In the last decade, several novel techniques have been proposed to assess cooperation between cells in islets, including the prosperous combination of multicellular imaging and network science. In the present contribution, we review recent advances related to the application of complex network approaches to uncover the functional connectivity patterns among cells within the islets. We first provide an accessible introduction to the basic principles of network theory, enumerating the measures characterizing the intercellular interactions and quantifying the functional integration and segregation of a multicellular system. Then we describe methodological approaches to construct functional beta cell networks, point out possible pitfalls, and specify the functional implications of beta cell network examinations. We continue by highlighting the recent findings obtained through advanced multicellular imaging techniques supported by network-based analyses, giving special emphasis to the current developments in both mouse and human islets, as well as outlining challenges offered by the multilayer network formalism in exploring the collective activity of islet cell populations. Finally, we emphasize that the combination of these imaging techniques and network-based analyses does not only represent an innovative concept that can be used to describe and interpret the physiology of islets, but also provides fertile ground for delineating normal from pathological function and for quantifying the changes in islet communication networks associated with the development of diabetes mellitus.
Ključne besede: pancreatic islets, beta cells, calcium imaging, intercellular communication, functional networks, multilayer networks
Objavljeno v DKUM: 20.12.2024; Ogledov: 0; Prenosov: 3
Celotno besedilo (14,78 MB)
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Opis: 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 inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus-secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca2+ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans.
Ključne besede: cAMP, beta cells, stimulus-secretion coupling, intercellular coupling, PKA, Epac2A
Objavljeno v DKUM: 16.10.2024; Ogledov: 0; Prenosov: 4
Celotno besedilo (19,95 MB)
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Opis: 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 used strains. High-resolution multicellular confocal imaging of beta cells in acute pancreas tissue slices was used to measure and quantitatively compare the calcium dynamics in response to a wide range of glucose concentrations. Strain- and substrain-specific features were found in all three phases of beta cell responses to glucose: a shift in the dose-response curve characterizing the delay to activation and deactivation in response to stimulus onset and termination, respectively, and distinct concentration-encoding principles during the plateau phase in terms of frequency, duration, and active time changes with increasing glucose concentrations. Our results underline the significance of carefully choosing and reporting the strain to enable comparison and increase reproducibility, emphasize the importance of analyzing a number of different beta cell physiological parameters characterizing the response to glucose, and provide a valuable standard for future studies on beta cell calcium dynamics in health and disease in tissue slices.
Ključne besede: beta cell, mouse models, calcium imaging, glucose-dependence, tissue slice
Objavljeno v DKUM: 15.07.2024; Ogledov: 148; Prenosov: 22
Celotno besedilo (4,45 MB)
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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: 193; Prenosov: 14
Celotno besedilo (12,03 MB)
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Opis: The accumulation of oxidative damage to DNA and other biomolecules plays an important role in the etiology of aging and age-related diseases such as type 2 diabetes mellitus (T2D), atherosclerosis, and neurodegenerative disorders. Mitochondrial DNA (mtDNA) is especially sensitive to oxidative stress. Mitochondrial dysfunction resulting from the accumulation of mtDNA damage impairs normal cellular function and leads to a bioenergetic crisis that accelerates aging and associated diseases. Age-related mitochondrial dysfunction decreases ATP production, which directly affects insulin secretion by pancreatic beta cells and triggers the gradual development of the chronic metabolic dysfunction that characterizes T2D. At the same time, decreased glucose oxidation in skeletal muscle due to mitochondrial damage leads to prolonged postprandial blood glucose rise, which further worsens glucose homeostasis. ROS are not only highly reactive by-products of mitochondrial respiration capable of oxidizing DNA, proteins, and lipids but can also function as signaling and effector molecules in cell membranes mediating signal transduction and inflammation. Mitochondrial uncoupling proteins (UCPs) located in the inner mitochondrial membrane of various tissues can be activated by ROS to protect cells from mitochondrial damage. Mitochondrial UCPs facilitate the reflux of protons from the mitochondrial intermembrane space into the matrix, thereby dissipating the proton gradient required for oxidative phosphorylation. There are five known isoforms (UCP1-UCP5) of mitochondrial UCPs. UCP1 can indirectly reduce ROS formation by increasing glutathione levels, thermogenesis, and energy expenditure. In contrast, UCP2 and UCP3 regulate fatty acid metabolism and insulin secretion by beta cells and modulate insulin sensitivity. Understanding the functions of UCPs may play a critical role in developing pharmacological strategies to combat T2D. This review summarizes the current knowledge on the protective role of various UCP homologs against age-related oxidative stress in T2D.
Ključne besede: uncoupling proteins, reactive oxygen species, aging, age-related diseases, diabetes
Objavljeno v DKUM: 23.08.2023; Ogledov: 467; Prenosov: 38
Celotno besedilo (1,14 MB)
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