1. The role of cAMP in beta cell stimulus-secretion and intercellular couplingAndraž Stožer, Eva Paradiž, Viljem Pohorec, Jurij Dolenšek, Lidija Križančić Bombek, Marko Gosak, Maša Skelin, 2021, pregledni znanstveni članek 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
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2. Physiological levels of adrenaline fail to stop pancreatic beta cell activity at unphysiologically high glucose levelsNastja Sluga, Lidija Križančić Bombek, Jasmina Kerčmar, Srdjan Sarikas, Sandra Postić, Johannes Pfabe, Maša Skelin, Dean Korošak, Andraž Stožer, Marjan Rupnik, 2022, izvirni znanstveni članek Opis: 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 desensitization of late step(s) of exocytotic machinery to cytosolic Ca2+ concentration ([Ca2+]c). In most studies unphysiologically high adrenaline concentrations have been used to evaluate the role of adrenergic stimulation in pancreatic endocrine cells. Here we report the effect of physiological adrenaline levels on [Ca2+]c dynamics in beta cell collectives in mice pancreatic tissue slice preparation. We used confocal microscopy with a high spatial and temporal resolution to evaluate glucose-stimulated [Ca2+]c events and their sensitivity to adrenaline. We investigated glucose concentrations from 8-20 mM to assess the concentration of adrenaline that completely abolishes [Ca2+]c events. We show that 8 mM glucose stimulation of beta cell collectives is readily inhibited by the concentration of adrenaline available under physiological conditions, and that sequent stimulation with 12 mM glucose or forskolin in high nM range overrides this inhibition. Accordingly, 12 mM glucose stimulation required at least an order of magnitude higher adrenaline concentration above the physiological level to inhibit the activity. To conclude, higher glucose concentrations stimulate beta cell activity in a non-linear manner and beyond levels that could be inhibited with physiologically available plasma adrenaline concentration.
Ključne besede: adrenaline, islets, beta cells, cAMP, concentration dependency, [Ca2+]c oscillations, forskolin
Objavljeno v DKUM: 04.07.2024; Ogledov: 155; Prenosov: 10
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3. Role of cAMP in double switch of glucagon secretionJan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2021, izvirni znanstveni članek Opis: 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.
Ključne besede: pancreatic alpha cell, glucagon, cAMP, mathematical model, diabetes, cellular bioenergetics
Objavljeno v DKUM: 06.06.2024; Ogledov: 107; Prenosov: 11
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4. Modeling the amino acid effect on glucagon secretion from pancreatic alpha cellsJan Zmazek, Vladimir Grubelnik, Rene Markovič, Marko Marhl, 2022, izvirni znanstveni članek Opis: 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.
Ključne besede: diabetes, hormone secretion, glucose, amino acid, cAMP
Objavljeno v DKUM: 21.05.2024; Ogledov: 169; Prenosov: 13
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5. Računska ocena vpliva znotrajceličnih presnovnih in signalnih poti ter medcelične komunikacije na izločanje glukagona in inzulina : doktorska disertacijaJan Zmazek, 2022, doktorska disertacija Opis: 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.
Ključne besede: celica beta, celica alfa, modeliranje, presnova, cAMP, aminokisline, kalcij, medcelične mreže
Objavljeno v DKUM: 17.01.2023; Ogledov: 615; Prenosov: 90
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6. IZRAEL MED LETI 1967 IN 1979Jernej Tomec, 2016, diplomsko delo Opis: Na Bližnjem vzhodu je bilo obdobje med leti 1967 in 1979 eno najturbulentnejših. Meje Izraela in njegovih sosed so se hitro spreminjale zaradi treh vojn: »šestdnevne«, iz katere je Izrael izšel kot zmagovalec; »vojne izčrpavanja«; »jomkipurske vojne«, kjer je Izrael utrpel znatne izgube,
a se je rešil najhujšega. Začele so se teroristične akcije, ki so vplivale na ves svet. Najodmevnejši sta bili masaker na OI v Münchnu in osvoboditev talcev v Ugandi. Pod vplivom ameriškega predsednika Jimmyja Carterja je v Camp Davidu nastal sporazum med Izraelom in Egiptom. Izrael je dosegal vojaško premoč zaradi dobre strategije, smiselno izboljšanega orožja, izurjene vojske in pametne izrabe podnebja. Arabske države so dosegale vojne uspehe s hitrim urjenjem vojske in z inovacijami. Mednarodni terorizem je treba jemati resno. Sporazum v Camp Davidu je utrl pot poznejšemu izraelskemu sporazumu s Palestinci.
Ključne besede: Bližnji vzhod, Izrael, Egipt, Sirija, vojne, zračni napadi, izgube, terorizem, operacije, Camp David
Objavljeno v DKUM: 13.06.2016; Ogledov: 1790; Prenosov: 218
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