Preptin, a 34-amino acid peptide derived from pro-IGF2, is believed to influence various physiological processes, including insulin secretion and the regulation of bone metabolism. Despite its recognized involvement, the precise physiological role of preptin remains enigmatic. To address this knowledge gap, we synthesized 16 analogs of preptin, spanning a spectrum from full-length forms to fragments, and conducted comprehensive comparative activity evaluations alongside native human, mouse and rat preptin. Our study aimed to elucidate the physiological role of preptin. Contrary to previous indications of broad biological activity, our thorough analyses across diverse cell types revealed no significant biological activity associated with preptin or its analogs. This suggests that the associations of preptin with various diseases or tissue-specific abundance fluctuations may be influenced by factors beyond preptin itself, such as higher levels of IGF2 or IGF2 proforms present in tissues. In conclusion, our findings challenge the conventional notion of preptin as an isolated biologically active molecule and underscore the complexity of its interactions within biological systems. Rather than acting independently, the observed effects of preptin may arise from experimental conditions, elevated preptin concentrations, or interactions with related molecules such as IGF2.

• MeSH
• insulinu podobný růstový faktor II * metabolismus   MeSH
• inzulin metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• peptidové fragmenty metabolismus   MeSH
• proteinové prekurzory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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

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.

• 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

Acid-β-glucosidase (GCase, EC3.2.1.45), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the GBA1 gene. Biallelic mutations in GBA1 cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous GBA1 mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme® ) is produced for use in enzyme replacement therapy for GD and is largely successful in relieving disease symptoms, except for the neurological symptoms observed in a subset of patients. As a first step toward developing an alternative to the recombinant human enzymes used to treat GD, we applied the PROSS stability-design algorithm to generate GCase variants with enhanced stability. One of the designs, containing 55 mutations compared to wild-type human GCase, exhibits improved secretion and thermal stability. Furthermore, the design has higher enzymatic activity than the clinically used human enzyme when incorporated into an AAV vector, resulting in a larger decrease in the accumulation of lipid substrates in cultured cells. Based on stability-design calculations, we also developed a machine learning-based approach to distinguish benign from deleterious (i.e., disease-causing) GBA1 mutations. This approach gave remarkably accurate predictions of the enzymatic activity of single-nucleotide polymorphisms in the GBA1 gene that are not currently associated with GD or PD. This latter approach could be applied to other diseases to determine risk factors in patients carrying rare mutations.

• MeSH
• celulasy * genetika   MeSH
• Gaucherova nemoc * farmakoterapie   genetika   MeSH
• heterozygot MeSH
• lidé MeSH
• mutace MeSH
• Parkinsonova nemoc * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Hypovitaminóza D vitaminu - deficit a insuficience, je globální zdravotní problém, který se dotýká více než miliardy dětí a dospělých. Optimální hladina vitaminu D hraje esenciální roli v regulaci kalciového a fosfátového metabolismu a je nezbytná nejen pro správný kostní metabolismus, ale má i jiné funkce v organismu, jako je vliv na funkci svalů, stimulaci diferenciace buněk, sekreci inzulinu a stimulaci imunitního systému. Hypovitaminóza D vitaminu pak bývá spojena nejen s poruchou kostního metabolismu, ale i s výskytem kardiovaskulárních onemocnění, arteriální hypertenze, dyslipidemie, diabetu mellitu II. typu, nádorových onemocnění, depresí, demencí, psychiatrických onemocnění a dalších. Hypovitaminóza D je také jedním z možných faktorů komplikovaného průběhu nemoci covid-19. Článek shrnuje poslední poznatky o jeho suplementaci.

Vitamin D hypovitaminosis - deficiency and insufficiency - is a global health problem that affects more than a billion children and adults. The optimal level of vitamin D plays an essential role in the regulation of calcium and phosphate metabolism and is necessary not only for proper bone metabolism, but also has other functions in the body, such as influencing muscle function, stimulating cell differentiation, insulin secretion and stimulating the immune system. Hypovitaminosis of vitamin D is then associated not only with a disorder of bone metabolism, but also with the occurrence of cardiovascular diseases, arterial hypertension, dyslipidemia, diabetes mellitus type II, cancer, depression, dementia, psychiatric diseases and others. Hypovitaminosis D is also one of the factors in the complicated course of the disease covid 19. The article summarizes the latest findings on its supplementation.

• MeSH
• lidé MeSH
• nedostatek vitaminu D farmakoterapie   MeSH
• rizikové faktory MeSH
• vitamin D * aplikace a dávkování   metabolismus   MeSH
• Check Tag
• lidé MeSH

The aim of this study was to evaluate the impact of diabetes mellitus type 2 (DM2) on the male endocrine system of Zucker Diabetic Fatty (ZDF) rats. Sexually mature ZDF rats were divided to a lean (control) and obese group, and had diabetes confirmed by blood tests. For the in vivo experiment, fasting blood was collected to obtain blood plasma. In case of the in vitro experiments, testicular fragments were cultured for 24 h, and the culture medium was collected. The concentrations of testosterone (T), androstenedione (A4), dehydroepiandrosterone (DHEA-S), estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were quantified in the blood plasma and the medium by the ELISA method, while cholesterol (CHOL) was assessed spectrophotometrically. A significant decline of T (36.31 %), A4 (25.11 %) and FSH (26.99 %) as well as a significant increase of CHOL and E2 (36.17 %) was observed in the blood plasma of obese ZDF rats in comparison to the control. Under in vitro conditions, a significant decrease of FSH (23.35 %) accompanied by an increase of E2 was observed in the obese group compared to the control. In the case of CHOL, LH, T, DHEA and A4 no significant differences were observed. Our results suggest that except for FSH and E2 all steroid biomolecules were synthetized normally by the testicular tissue, however a dramatic endocrine disturbance was observed at the system level. We may conclude that DM2 has negative effects on systemic hormone secretion and these alterations are more pronounced in combination with obesity.

• MeSH
• dehydroepiandrosteron MeSH
• diabetes mellitus 2. typu * MeSH
• estradiol MeSH
• folikuly stimulující hormon MeSH
• krysa rodu rattus MeSH
• luteinizační hormon * MeSH
• obezita MeSH
• potkani Zucker MeSH
• testosteron MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Chrousosův syndrom je generalizovaná rezistence na glukokortikoidy. Je vyvolána poruchou genu NR3C1, který kóduje humánní receptory pro glukokortikoidy. Klinicky se vyznačuje celou řadou pestrých příznaků od téměř asymptomatického průběhu až po případy výrazných důsledků zvýšené mineralokortikoidní aktivity a nadbytku androgenů. Vedle hyperandrogenemie, nápadné zejména u žen, je častým výsledkem hypertenze v důsledku působení mineralokortikoidů. Laboratorním obrazem – vysokou exkrecí volného kortizolu močí a často vyšším ACTH – je blízký nálezům u Cushingovy nemoci, pacienti však nemají jeho typické tělesné příznaky. K terapii rezistence na glukokortikoidy byly navrženy vysoké dávky syntetických kortikoidů bez mineralokortikoidní účinnosti, které aktivuje mutantní a divoké glukokortikoidní receptory a potlačují tak sekreci ACTH.

Chrousos syndrome is generalized glucocorticoid resistance caused by defects in the NR3C1 gene that encodes human glucocorticoid receptors. It presents clinically in greatly variable forms from nearly asymptomatic course to very expressive consequences of higher mineralocorticoid activity and higher androgens. Besides hyperandrogenisation, more striking in women, hypertension is frequently found as a consequence of mineralocortcoid action. Laboratory hormonal analysis shows high cortisol concentration in the circulation, high excretion of free cortisol in urine a frequently higher ACTH. Those data are close to the findings common in Cushing’s disease, none of the patients, however, had overt Cushing’s syndrome signs. For the treatment of generalised glucocorticoid resistance, high doses of mineralocorticoid sparing synthetic glucocorticoids were suggested. The high doses should activate the mutant or wild-type glucocorticoid receptors and suppress the secretion of ACTH.

• Klíčová slova
• Chrousosův syndrom,
• MeSH
• dexamethason terapeutické užití   MeSH
• glukokortikoidy MeSH
• hirzutismus etiologie   MeSH
• hydrokortison krev   moč   MeSH
• hypertenze etiologie   MeSH
• lidé MeSH
• mineralokortikoidy škodlivé účinky   MeSH
• nemoci endokrinního systému * diagnóza   genetika   terapie   MeSH
• receptory glukokortikoidů * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Glucagon-like peptide-1 (GLP-1) receptor agonists mimic the action of the endogenous GLP-1 incretin hormone, improving glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. However, as cardiovascular (CV) morbidity and mortality is common in patients with T2DM, several trials with the use of GLP-1 receptor agonists (RAs) have been performed focusing on endpoints related to cardiovascular disease rather than metabolic control of T2DM. Following the positive cardiovascular effects of liraglutide, dulaglutide and semaglutide observed in these trials, major changes in T2DM management guidelines have occurred. This document from a Eastern and Southern European Diabetes Expert Group discusses the results of GLP-1 RA CV outcomes trials, their impact on recent clinical guidelines for the management of T2DM, and some selected combination regimens utilising GLP-1 RAs. We also propose an algorithm for guiding GLP-1 RA-based treatment according to patients' characteristics, which can be easily applied in every day clinical practice.

• MeSH
• diabetes mellitus 2. typu * diagnóza   farmakoterapie   epidemiologie   MeSH
• glukagonu podobný peptid 1 metabolismus   MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• kardiovaskulární nemoci * farmakoterapie   epidemiologie   MeSH
• lidé MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• receptor pro glukagonu podobný peptid 1 agonisté   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients' cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.

• MeSH
• beta-buňky metabolismus   MeSH
• diabetes mellitus 1. typu genetika   metabolismus   patologie   MeSH
• diabetes mellitus 2. typu genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• homeostáza genetika   MeSH
• IGFBP-3 genetika   metabolismus   MeSH
• imunoblotting MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši inbrední NOD MeSH
• myši knockoutované MeSH
• myši transgenní MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• regulace genové exprese * MeSH
• signální transdukce genetika   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.

• MeSH
• apoptóza * genetika   MeSH
• beta-buňky metabolismus   MeSH
• biologické modely MeSH
• diabetes mellitus 2. typu etiologie   metabolismus   MeSH
• endoplazmatické retikulum metabolismus   MeSH
• fyziologický stres MeSH
• lidé MeSH
• mastné kyseliny metabolismus   MeSH
• metabolismus lipidů MeSH
• mitochondrie genetika   metabolismus   MeSH
• signální transdukce MeSH
• viabilita buněk genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH