Reactive oxygen species (ROS) are critical mediators of cellular signaling that regulate metabolic homeostasis, including lipid uptake, synthesis, and storage. NADPH oxidase 4 (NOX4), a significant enzymatic source of ROS, has been identified as a redox-sensitive regulator of glucose and lipid metabolism. However, its contribution to sex-specific metabolic regulation remains poorly defined. This study compared how NOX4 knock-out (NOX4 KO) shifted systemic and tissue-specific metabolic phenotypes between male and female mice fed with a high-fat diet (HFD) for 20-weeks. We observed that male NOX4 mice on HFD exhibited reduced adiposity, diminished liver lipid accumulation, and improved glucose and insulin tolerance compared to male WT mice on HFD. In contrast, female NOX4 KO mice developed increased adiposity and lipid accumulation in peripheral adipose depots, accompanied by impaired glucose tolerance. Gene expression profiling in skeletal muscle and liver revealed distinct, sex-specific patterns of changes in genes related to lipid uptake, synthesis, and storage, possibly implicating differential activation of PPAR signaling pathways supportive of in vivo data. These findings identify NOX4 as a central regulator of sexually dimorphic lipid metabolism, acting through redox-sensitive transcriptional networks to shape divergent metabolic responses to HFD.

• MeSH
• adipozita MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• glukosa metabolismus   MeSH
• inzulinová rezistence MeSH
• játra metabolismus   MeSH
• kosterní svaly metabolismus   MeSH
• metabolismus lipidů genetika   MeSH
• myši knockoutované MeSH
• myši MeSH
• NADPH-oxidasa 4 * nedostatek   genetika   metabolismus   MeSH
• oxidace-redukce MeSH
• pohlavní dimorfismus MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glukosa MeSH
• NADPH-oxidasa 4 * MeSH
• Nox4 protein, mouse MeSH Prohlížeč
• reaktivní formy kyslíku MeSH

In the diagnostics of diabetes, specific targeting of drugs (e.g., liraglutide) to insulin-deficient β-cells with their simultaneous noninvasive imaging is currently needed. In this report, liraglutide (LGL)-conjugated poly(methyl vinyl ether-alt-maleic acid) (PMVEMA)-coated core-shell NaYF4:Yb,Er,Fe@NaYF4:Nd upconversion nanoparticles (CS-UCNPs) have been developed, thoroughly physicochemically characterized, and evaluated in vivo. Novel codoping of Fe2+, Yb3+, and Er3+ ions in the host NaYF4 induced upconversion emission in the red region at both 980 and 808 nm excitation, making the particles suitable for deep-tissue imaging. Surface functionalization with PMVEMA provided colloidal stability and facilitated covalent conjugation with LGL, enabling targeted binding to GLP-1 receptors on pancreatic β-cells, increasing glucose-stimulated insulin secretion from isolated Langerhans islets. Biocompatibility of CS-UCNP@PMVEMA-LGL nanoparticles was confirmed by the trypan blue dye exclusion assay. When the fluorescent dye Flamma was conjugated to the nanoparticles, in vivo fluorescence imaging revealed significantly enhanced accumulation of CS-UCNP@PMVEMA-LGL-Flamma nanoparticles in the pancreas 24 h after intramuscular injection compared with intravenous administration, with luminescence intensity approximately doubled. The improved pancreatic targeting efficiency was attributed to enhanced binding to GLP-1 receptors. Confocal microscopy and elemental analysis confirmed receptor-mediated uptake of the nanoparticles by internalization and their localization within pancreatic β-cells. These findings highlight the potential of CS-UCNP@PMVEMA-LGL nanoparticles as biocompatible targetable imaging agents with future applications in pancreatic diagnostics.

• Klíčová slova
• Flamma, diabetes, liraglutide, nanoparticles, poly(methyl vinyl ether-alt-maleic acid), theranostics, upconversion,
• MeSH
• beta-buňky metabolismus   účinky léků   MeSH
• experimentální diabetes mellitus * farmakoterapie   diagnostické zobrazování   MeSH
• fluoridy MeSH
• inzulin metabolismus   MeSH
• lidé MeSH
• liraglutid * chemie   farmakologie   MeSH
• maleáty * chemie   MeSH
• myši MeSH
• nanočástice * chemie   MeSH
• polyvinyly chemie   MeSH
• teranostická nanomedicína * metody   MeSH
• ytrium MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fluoridy MeSH
• inzulin MeSH
• liraglutid * MeSH
• maleáty * MeSH
• polyvinyly MeSH
• sodium yttriumtetrafluoride MeSH Prohlížeč
• ytrium MeSH

We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H2O2, providing: i) mitochondria-to-plasma-membrane redox signaling, closing KATP-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H2O2-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA2γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA2γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H2O2-monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K+-channels open, and diminishing cytosolic [Ca2+]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS.

• Klíčová slova
• Fatty acid-stimulated insulin secretion, GPR40, Mitochondrial fatty acids, Pancreatic β-cells, Redox signaling, Redox-activated phospholipase iPLA2γ,
• MeSH
• beta-buňky * metabolismus   MeSH
• buněčná membrána * metabolismus   MeSH
• fosfolipasy A2, skupina VI metabolismus   genetika   MeSH
• glukosa metabolismus   MeSH
• inzulin metabolismus   MeSH
• mastné kyseliny * metabolismus   MeSH
• mitochondrie * metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• oxidace-redukce * MeSH
• peroxid vodíku metabolismus   MeSH
• receptory spřažené s G-proteiny MeSH
• sekrece inzulinu * MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Ffar1 protein, mouse MeSH Prohlížeč
• fosfolipasy A2, skupina VI MeSH
• glukosa MeSH
• inzulin MeSH
• mastné kyseliny * MeSH
• peroxid vodíku MeSH
• Pla2g6 protein, mouse MeSH Prohlížeč
• receptory spřažené s G-proteiny MeSH

Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic beta-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state.

• MeSH
• antioxidancia metabolismus   MeSH
• beta-buňky metabolismus   MeSH
• lidé MeSH
• mitochondrie * metabolismus   MeSH
• oxidace-redukce * MeSH
• oxidační stres fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia MeSH

Redox status plays a multifaceted role in the intricate physiology and pathology of pancreatic beta-cells, the pivotal regulators of glucose homeostasis through insulin secretion. They are highly responsive to changes in metabolic cues where reactive oxygen species are part of it, all arising from nutritional intake. These molecules not only serve as crucial signaling intermediates for insulin secretion but also participate in the nuanced heterogeneity observed within the beta-cell population. A central aspect of beta-cell redox biology revolves around the localized production of hydrogen peroxide and the activity of NADPH oxidases which are tightly regulated and serve diverse physiological functions. Pancreatic beta-cells possess a remarkable array of antioxidant defense mechanisms although considered relatively modest compared to other cell types, are efficient in preserving redox balance within the cellular milieu. This intrinsic antioxidant machinery operates in concert with redox-sensitive signaling pathways, forming an elaborate redox relay system essential for beta-cell function and adaptation to changing metabolic demands. Perturbations in redox homeostasis can lead to oxidative stress exacerbating insulin secretion defect being a hallmark of type 2 diabetes. Understanding the interplay between redox signaling, oxidative stress, and beta-cell dysfunction is paramount for developing effective therapeutic strategies aimed at preserving beta-cell health and function in individuals with type 2 diabetes. Thus, unraveling the intricate complexities of beta-cell redox biology presents exciting avenues for advancing our understanding and treatment of metabolic disorders.

• MeSH
• beta-buňky * metabolismus   MeSH
• diabetes mellitus 2. typu metabolismus   MeSH
• homeostáza fyziologie   MeSH
• inzulin metabolismus   MeSH
• lidé MeSH
• oxidace-redukce * MeSH
• oxidační stres * fyziologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• sekrece inzulinu fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inzulin MeSH
• reaktivní formy kyslíku MeSH

Redox signaling from mitochondria (mt) to the cytosol and plasma membrane (PM) has been scarcely reported, such as in the case of hypoxic cell adaptation or (2-oxo-) 2-keto-isocaproate (KIC) β-like-oxidation stimulating insulin secretion in pancreatic β-cells. Mutual redox state influence between mitochondrial major compartments, the matrix and the intracristal space, and the cytosol is therefore derived theoretically in this article to predict possible conditions, when mt-to-cytosol and mt-to-PM signals may occur, as well as conditions in which the cytosolic redox signaling is not overwhelmed by the mitochondrial antioxidant capacity. Possible peroxiredoxin 3 participation in mt-to-cytosol redox signaling is discussed, as well as another specific case, whereby mitochondrial superoxide release is diminished, whereas the matrix MnSOD is activated. As a result, the enhanced conversion to H2O2 allows H2O2 diffusion into the cytosol, where it could be a predominant component of the H2O2 release. In both of these ways, mt-to-cytosol and mt-to-PM signals may be realized. Finally, the use of redox-sensitive probes is discussed, which disturb redox equilibria, and hence add a surplus redox-buffering to the compartment, where they are localized. Specifically, when attempts to quantify net H2O2 fluxes are to be made, this should be taken into account.

• Klíčová slova
• H2O2 release into intracristal space, MnSOD, cytosolic H2O2 release, matrix H2O2 release, peroxiredoxins, redox buffers, redox signaling from mitochondria, redox-sensitive probes,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cysteine is one of the least abundant but most conserved amino acid residues in proteins, playing a role in their structure, metal binding, catalysis, and redox chemistry. Thiols present in cysteines can be modified by post-translational modifications like sulfenylation, acylation, or glutathionylation, regulating protein activity and function and serving as signals. Their modification depends on their position in the structure, surrounding amino acids, solvent accessibility, pH, etc. The most studied modifications are the redox modifications by reactive oxygen, nitrogen, and sulfur species, leading to reversible changes that serve as cell signals or irreversible changes indicating oxidative stress and cell damage. Selected antioxidants undergoing reversible oxidative modifications like peroxiredoxin-thioredoxin system are involved in a redox-relay signaling that can propagate to target proteins. Cysteine thiols can also be modified by acyl moieties' addition (derived from lipid metabolism), resulting in protein functional modification or changes in protein anchoring in the membrane. In this review, we update the current knowledge on cysteine modifications and their consequences in pancreatic β-cells. Because β-cells exhibit well-balanced redox homeostasis, the redox modifications of cysteines here serve primarily for signaling purposes. Similarly, lipid metabolism provides regulatory intermediates that have been shown to be necessary in addition to redox modifications for proper β-cell function and, in particular, for efficient insulin secretion. On the contrary, the excess of reactive oxygen, nitrogen, and sulfur species and the imbalance of lipids under pathological conditions cause irreversible changes and contribute to oxidative stress leading to cell failure and the development of type 2 diabetes.

• Klíčová slova
• cysteine, pancreatic beta cells, posttranslational modifications, redox signaling, thiol,
• MeSH
• beta-buňky * metabolismus   MeSH
• cystein chemie   MeSH
• diabetes mellitus 2. typu * MeSH
• kyslík MeSH
• lidé MeSH
• signální transdukce MeSH
• sulfhydrylové sloučeniny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cystein MeSH
• kyslík MeSH
• sulfhydrylové sloučeniny MeSH

Pancreatic-β-cell-specifying transcription factor Nkx6.1, indispensable for embryonic development of the pancreatic epithelium and commitment to β-cell lineage, directly controls the expression of a glucose transporter (Glut2), pyruvate carboxylase (Pcx), and genes for insulin processing (endoplasmic reticulum oxidoreductase-1β, Ero1lb; zinc transporter-8, Slc30a8). The Nkx6.1 decline in aging diabetic Goto-Kakizaki rats contributes to β-cell trans-differentiation into δ-cells. Elucidating further Nkx6.1 roles, we studied Nkx6.1 ablation in rat INS-1E cells, prepared by CRISPR/Cas9 gene editing from single colonies. INS-1ENkx6.1-/- cells exhibited unchanged glucose-stimulated insulin secretion (GSIS), moderately decreased phosphorylating/non-phosphorylating respiration ratios at high glucose; unchanged but delayed ATP-elevation responses to glucose; delayed uptake of fluorescent glucose analog, but slightly improved cytosolic Ca2+-oscillations, induced by glucose; despite approximately halved Glut2, Pcx, Ero1lb, and Slc30a8 expression, and reduced nuclear receptors Nr4a1 and Nr4a3. Thus, ATP synthesis was time-compensated, despite the delayed GLUT2-mediated glucose uptake and crippled pyruvate-malate redox shuttle (owing to the PCX-deficiency) in INS-1ENkx6.1-/- cells. Nkx6.1 thus controls the expression of genes that are not essential for acute insulin secretion, the function of which can be compensated for. Considerations that Nkx6.1 deficiency is an ultimate determinant of β-cell pathology beyond cell trans-(de-)differentiation or β-cell identity are not supported by our results.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• beta-buňky * metabolismus   MeSH
• glukosa metabolismus   MeSH
• homeodoménové proteiny * genetika   metabolismus   MeSH
• inzulin * metabolismus   MeSH
• krysa rodu Rattus MeSH
• sekrece inzulinu MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfát MeSH
• glukosa MeSH
• homeodoménové proteiny * MeSH
• inzulin * MeSH
• Nkx6-1 protein, rat MeSH Prohlížeč
• transkripční faktory MeSH

Significance: Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+ homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca2+ influx was found to enhance GSIS, reflecting cytosolic Ca2+ oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+ release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase. Critical Issues: It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+ signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis. Future Directions: Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact and diabetic states. Antioxid. Redox Signal. 36, 920-952.

• Klíčová slova
• ATP-sensitive K+ channel, GLP-1, TRPM channels, branched-chain ketoacid oxidation, fatty acid-stimulated insulin secretion, insulin secretion, mitochondrial Ca2+ transport, pancreatic β-cell metabolism, redox signaling,
• MeSH
• adenosintrifosfát metabolismus   MeSH
• beta-buňky * metabolismus   MeSH
• glukosa metabolismus   MeSH
• inzulin metabolismus   MeSH
• Langerhansovy ostrůvky * metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• NAD metabolismus   MeSH
• NADP metabolismus   MeSH
• sekrece inzulinu MeSH
• sekretagoga metabolismus   MeSH
• vápník metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adenosintrifosfát MeSH
• glukosa MeSH
• inzulin MeSH
• NAD MeSH
• NADP MeSH
• sekretagoga MeSH
• vápník MeSH

Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.

• Klíčová slova
• de/differentiation, inflammation, oxidative stress, pancreatic β-cells, redox homeostasis, redox signaling,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH