Significance: Glucose-induced lipid metabolism is essential for preserving functional β-cells, and its disruption is linked to type 2 diabetes (T2D) development. Lipids are an integral part of the cells playing an indispensable role as structural components, energy storage molecules, and signals. Recent Advances: Glucose presence significantly impacts lipid metabolism in β-cells, where fatty acids are primarily synthesized de novo and/or are transported from the bloodstream. This process is regulated by the glycerolipid/free fatty acid cycle, which includes lipogenic and lipolytic reactions producing metabolic coupling factors crucial for insulin secretion. Disrupted lipid metabolism involving oxidative stress and inflammation is a hallmark of T2D. Critical Issues: Lipid metabolism in β-cells is complex involving multiple simultaneous processes. Exact compartmentalization and quantification of lipid metabolism and its intermediates, especially in response to glucose or chronic hyperglycemia, are essential. Current research often uses non-physiological conditions, which may not accurately reflect in vivo situations. Future Directions: Identifying and quantifying individual steps and their signaling, including redox, within the complex fatty acid and lipid metabolic pathways as well as the metabolites formed during acute versus chronic glucose stimulation, will uncover the detailed mechanisms of glucose-stimulated insulin secretion. This knowledge is crucial for understanding T2D pathogenesis and identifying pharmacological targets to prevent this disease. Antioxid. Redox Signal. 41, 865-889.
OBJECTIVE: Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health. METHODS: We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells. RESULTS: Glucose stimulation significantly increases ROS levels in β-cells, leading to targeted reversible oxidation of proteins involved in key metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, pyruvate metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum (ER), and insulin secretion. Furthermore, the glucose-induced increase in reversible cysteine oxidation correlates with the presence of other post-translational modifications, including acetylation and phosphorylation. CONCLUSIONS: Proper functioning of pancreatic β-cell metabolism relies on fine-tuned regulation, achieved through a sophisticated system of diverse post-translational modifications that modulate protein functions. Our findings demonstrate that glucose induces the production of ROS in pancreatic β-cells, leading to targeted reversible oxidative modifications of proteins. Furthermore, protein activity is modulated by acetylation and phosphorylation, highlighting the complexity of the regulatory mechanisms in β-cell function.
- MeSH
- beta-buňky * metabolismus účinky léků MeSH
- fyziologická adaptace fyziologie MeSH
- glukosa * metabolismus MeSH
- lidé MeSH
- myši MeSH
- oxidace-redukce * MeSH
- posttranslační úpravy proteinů MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- sekrece inzulinu účinky léků fyziologie MeSH
- signální transdukce * fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants.
- MeSH
- beta-buňky * účinky léků metabolismus MeSH
- buněčné linie MeSH
- homeostáza * účinky léků MeSH
- inzulin * metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- organofosfáty toxicita MeSH
- organofosforové sloučeniny * toxicita MeSH
- proinsulin metabolismus MeSH
- retardanty hoření * toxicita MeSH
- sekrece inzulinu účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- studie VERIFY, studie INTERVAL,
- MeSH
- beta-buňky účinky léků MeSH
- diabetes mellitus 2. typu * komplikace MeSH
- inhibitory dipeptidylpeptidasy 4 farmakologie terapeutické užití MeSH
- inzulin MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- metformin MeSH
- randomizované kontrolované studie jako téma MeSH
- vildagliptin * aplikace a dávkování terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- aplikace intralymfatická, studie DIAGNODE-2,
- MeSH
- beta-buňky účinky léků MeSH
- C-peptid fyziologie MeSH
- diabetes mellitus 1. typu * imunologie MeSH
- glutamát dekarboxyláza * terapeutické užití MeSH
- lidé MeSH
- randomizované kontrolované studie jako téma metody MeSH
- vitamin D MeSH
- Check Tag
- lidé 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.
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
Gliminy reprezentují novou možnost léčby diabetu 2. typu. Korigují činnost mitochondrií, což může ovlivnit sekreci inzulinu i jeho účinek v periferních tkáních. Prvním představitelem této skupiny je imeglimin. Efekt imegliminu na redukci glykovaného hemoglobinu je srovnatelný s metforminem, gliptiny, thiazolidindiony či glifloziny. Je vhodné jej kombinovat s ostatními antidiabetiky a lze ho úspěšně použít i u nemocných léčených inzulinem. Má minimum nežádoucích účinků včetně nízkého rizika rozvoje hypoglykemií. Lék je zatím komerčně dostupný jen v Japonsku.
Glimins represent a new treatment option for type 2 diabetes. They correct the activity of mitochondria, which can affect the secretion of insulin and its effect in peripheral tissues. The first representative of this group is imeglimin. The effect of imeglimin on reducing glycated hemoglobin is comparable to metformin, gliptins, thiazolidinediones or gliflozins. It is advisable to combine it with other antidiabetics and it can also be used successfully in patients treated with insulin. Imeglimin has a minimum of side effects, including a low risk of developing hypoglycemia. The drug is currently only commercially available in Japan.
- Klíčová slova
- Glimini, imeglimin,
- MeSH
- beta-buňky účinky léků MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- mitochondrie * fyziologie patologie MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS: In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS: Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS: Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).
- MeSH
- antigeny CD3 antagonisté a inhibitory imunologie MeSH
- beta-buňky účinky léků imunologie MeSH
- C-peptid analýza MeSH
- diabetes mellitus 1. typu * diagnóza imunologie terapie MeSH
- dítě MeSH
- dvojitá slepá metoda MeSH
- humanizované monoklonální protilátky * škodlivé účinky farmakologie terapeutické užití MeSH
- hypoglykemika aplikace a dávkování terapeutické užití MeSH
- inzulin aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- mladiství MeSH
- progrese nemoci MeSH
- T-lymfocyty účinky léků imunologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
