Insulin is a peptide responsible for regulating the metabolic homeostasis of the organism; it elicits its effects through binding to the transmembrane insulin receptor (IR). Insulin mimetics with agonistic or antagonistic effects toward the receptor are an exciting field of research and could find applications in treating diabetes or malignant diseases. We prepared five variants of a previously reported 20-amino acid insulin-mimicking peptide. These peptides differ from each other by the structure of the covalent bridge connecting positions 11 and 18. In addition to the peptide with a disulfide bridge, a derivative with a dicarba bridge and three derivatives with a 1,2,3-triazole differing from each other by the presence of sulfur or oxygen in their staples were prepared. The strongest binding to IR was exhibited by the peptide with a disulfide bridge. All other derivatives only weakly bound to IR, and a relationship between increasing bridge length and lower binding affinity can be inferred. Despite their nanomolar affinities, none of the prepared peptide mimetics was able to activate the insulin receptor even at high concentrations, but all mimetics were able to inhibit insulin-induced receptor activation. However, the receptor remained approximately 30% active even at the highest concentration of the agents; thus, the agents behave as partial antagonists. An interesting observation is that these mimetic peptides do not antagonize insulin action in proportion to their binding affinities. The compounds characterized in this study show that it is possible to modulate the functional properties of insulin receptor peptide ligands using disulfide mimetics.

• MeSH
• disulfidy chemie   MeSH
• inzulin * metabolismus   MeSH
• peptidy chemie   MeSH
• receptor inzulinu * MeSH
• Publikační typ
• časopisecké články MeSH

Insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively) are protein hormones involved not only in normal growth and development but also in life span regulation and cancer. They exert their functions mainly through the IGF-1R or by binding to isoform A of the insulin receptor (IR-A). The development of IGF-1 and IGF-2 antagonists is of great clinical interest. Mutations of A4 and A8 sites of human insulin lead to disproportionate effects on hormone IR binding and activation. Here, we systematically modified IGF-1 sites 45, 46, and 49 and IGF-2 sites 45 and 48, which correspond, or are close, to insulin sites A4 and A8. The IGF-1R and IR-A binding and autophosphorylation potencies of these analogues were characterized. They retained the main IGF-1R-related properties, but the hormones with His49 in IGF-1 and His48 in IGF-2 showed significantly higher affinities for IR-A and for IR-B, being the strongest IGF-1- and IGF-2-like binders of these receptors ever reported. All analogues activated IR-A and IGF-1R without major discrepancies in their binding affinities. This study revealed that IR-A and IGF-1R contain specific sites, likely parts of their so-called sites 2', which can interact differently with specifically modified IGF analogues. Moreover, a clear importance of IGF-2 site 44 for effective hormone folding was also observed. These findings may facilitate novel and rational engineering of new hormone analogues for IR-A and IGF-1R studies and for potential medical applications.

• MeSH
• fosforylace MeSH
• insulinu podobný růstový faktor I chemie   genetika   MeSH
• insulinu podobný růstový faktor II chemie   genetika   MeSH
• inzulin chemie   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární evoluce MeSH
• mutace MeSH
• protein - isoformy MeSH
• receptor inzulinu chemie   metabolismus   MeSH
• receptory somatomedinů chemie   genetika   MeSH
• signální transdukce MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Adenosine is known to influence different kinds of cells, including β-cells of the pancreas. However, the role of this nucleoside in the regulation of insulin secretion is not fully elucidated. In the present study, the effects of adenosine A1 receptor antagonism on insulin secretion from isolated rat pancreatic islets were tested using DPCPX, a selective adenosine A1 receptor antagonist. It was demonstrated that pancreatic islets stimulated with 6.7 and 16.7 mM glucose and exposed to DPCPX released significantly more insulin compared with islets incubated with glucose alone. The insulin-secretory response to glucose and low forskolin appeared to be substantially potentiated by DPCPX, but DPCPX was ineffective in the presence of glucose and high forskolin. Moreover, DPCPX failed to change insulin secretion stimulated by the combination of glucose and dibutyryl-cAMP, a non-hydrolysable cAMP analogue. Studies on pancreatic islets also revealed that the potentiating effect of DPCPX on glucose-induced insulin secretion was attenuated by H-89, a selective inhibitor of protein kinase A. It was also demonstrated that formazan formation, reflecting metabolic activity of cells, was enhanced in islets exposed to DPCPX. Moreover, DPCPX was found to increase islet cAMP content, whereas ATP was not significantly changed. These results indicate that adenosine A1 receptor blockade in rat pancreatic islets potentiates insulin secretion induced by both physiological and supraphysiological glucose concentrations. This effect is proposed to be due to increased metabolic activity of cells and increased cAMP content.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• AMP cyklický metabolismus   MeSH
• antagonisté adenosinového receptoru A1 farmakologie   MeSH
• inzulin sekrece   MeSH
• krysa rodu rattus MeSH
• Langerhansovy ostrůvky metabolismus   účinky léků   MeSH
• potkani Wistar MeSH
• receptor adenosinový A1 metabolismus   MeSH
• xanthiny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• adrenergní receptory fyziologie   patofyziologie   MeSH
• alfa blokátory MeSH
• inzulin krev   sekrece   MeSH
• krysa rodu rattus MeSH
• receptory buněčného povrchu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• albuminurie farmakoterapie   MeSH
• aplikace orální MeSH
• cinnamáty aplikace a dávkování   farmakologie   chemie   MeSH
• diabetes mellitus 2. typu farmakoterapie   genetika   imunologie   patologie   MeSH
• diabetické nefropatie genetika   imunologie   patologie   prevence a kontrola   MeSH
• financování organizované MeSH
• hodnoty glomerulární filtrace účinky záření   MeSH
• lidé MeSH
• makrofágy imunologie   patologie   účinky léků   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• piperaziny aplikace a dávkování   farmakologie   chemie   MeSH
• podocyty patologie   účinky léků   MeSH
• receptory CCR2 antagonisté a inhibitory   genetika   MeSH
• renální insuficience prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH

• MeSH
• ateroskleróza etiologie   prevence a kontrola   MeSH
• hořčík metabolismus   MeSH
• inzulinová rezistence MeSH
• lidé MeSH
• sodíkové kanály fyziologie   MeSH
• vápníkové kanály fyziologie   MeSH
• Check Tag
• lidé MeSH

OBJECTIVES: Ondansetron is an antagonist of 5-HT3 receptors mostly used as an antiemetic yet known to modulate metabolism and appetite. We tested the metabolic effects of ondansetron in newly derived congenic rat strain, carrying limited chromosome 8 regions of (PD) Brown Norway (BN) and polydactylous (PD) strain origins (including variant serotonin receptor Htr3b gene) within the genomic background of highly inbred model of metabolic syndrome, the spontaneously hypertensive rat (SHR). METHODS: Adult, standard diet-fed male rats of SHR and the congenic SHR.(PD/BN)8 strains received ondansetron (2mg/kg body weight/day) or vehicle (n=6/strain/treatment) via oral gavage for 14 days while we followed their metabolic and morphometric profiles including glucose tolerance and triacylgycerol and cholesterol concentrations in 20 lipoprotein fractions. RESULTS: We fine-mapped the chromosome 8 differential segment in the new SHR.(PD/BN)8 congenic strain: it comprises BN-derived region together with an adjacent 422kb stretch of PD origin. The SHR.(PD/BN)8 rats were heavier than SHR, the fasting glucose was significantly higher in ondansetron-treated congenic than in SHR (post-hoc Tukey's HSD p=0.02). Compared to SHR, ondansetron induced significantly more robust increases of cholesterol and triacylglycerol concentrations in total, chylomicron, VLDL and HDL particles in the SHR.(PD/BN)8 congenic strain. CONCLUSION: We established new congenic model with distinct pharmacogenetic profile related to metabolic effects of ondansetron, facilitating thus the search for responsible genetic variants within the limited genomic region demarcated by the differential segment.

• MeSH
• hypertenze farmakoterapie   genetika   metabolismus   MeSH
• krysa rodu rattus MeSH
• lipidy krev   MeSH
• metabolický syndrom farmakoterapie   genetika   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• ondansetron farmakologie   MeSH
• polydaktylie genetika   MeSH
• porucha glukózové tolerance farmakoterapie   genetika   metabolismus   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR * MeSH
• receptory serotoninové 5-HT3 genetika   metabolismus   MeSH
• savčí chromozomy MeSH
• serotoninové receptory 5-HT3 - antagonisté farmakologie   MeSH
• zvířata kongenní MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• antagonisté receptorů pro angiotenzin MeSH
• inzulinová rezistence MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• klinické zkoušky jako téma MeSH
• medicína založená na důkazech MeSH
• receptory angiotensinu MeSH
• renin-angiotensin systém účinky léků   MeSH
• tetrazoly terapeutické užití   MeSH
• valin analogy a deriváty   terapeutické užití   MeSH
• Publikační typ
• kongresy MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• kardiologie

• MeSH
• agregace trombocytů fyziologie   účinky léků   MeSH
• diabetes mellitus 2. typu farmakoterapie   patofyziologie   MeSH
• inhibitory agregace trombocytů aplikace a dávkování   farmakologie   MeSH
• klopidogrel * aplikace a dávkování   farmakologie   MeSH
• léková rezistence MeSH
• lidé MeSH
• prasugrel hydrochlorid farmakologie   terapeutické užití   MeSH
• purinergní receptory P2Y - antagonisté farmakologie   terapeutické užití   MeSH
• vyšetření funkce trombocytů metody   přístrojové vybavení   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• blokátory receptoru 1 pro angiotenzin II aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• diabetes mellitus 2. typu etiologie   komplikace   metabolismus   MeSH
• finanční podpora výzkumu jako téma MeSH
• financování organizované MeSH
• hypertenze etiologie   komplikace   metabolismus   MeSH
• inzulinová rezistence fyziologie   genetika   imunologie   MeSH
• lidé MeSH
• medicína založená na důkazech statistika a číselné údaje   trendy   MeSH
• metabolický syndrom etiologie   komplikace   metabolismus   MeSH
• obezita etiologie   komplikace   metabolismus   MeSH
• renin-angiotensin systém fyziologie   genetika   imunologie   MeSH
• tukové buňky fyziologie   metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH