Insulin, insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively), and their receptors (IR and IGF-1R) are the key elements of a complex hormonal system that is essential for the development and functioning of humans. The C and D domains of IGFs (absent in insulin) likely play important roles in the differential binding of IGF-1 and -2 to IGF-1R and to the isoforms of IR (IR-A and IR-B) and specific activation of these receptors. Here, we attempted to probe the impact of IGF-1 and IGF-2 D domains (DI and DII, respectively) and the IGF-2 C domain (CII) on the receptor specificity of these hormones. For this, we made two types of insulin hybrid analogues: (i) with the C-terminus of the insulin A chain extended by the amino acids from the DI and DII domains and (ii) with the C-terminus of the insulin B chain extended by some amino acids derived from the CII domain. The receptor binding affinities of these analogues and their receptor autophosphorylation potentials were characterized. Our results indicate that the DI domain has a more negative impact than the DII domain does on binding to IR, and that the DI domain Pro-Leu-Lys residues are important factors for a different IR-A versus IR-B binding affinity of IGF-1. We also showed that the additions of amino acids that partially "mimic" the CII domain, to the C-terminus of the insulin B chain, change the binding and autophosphorylation specificity of insulin in favor of the "metabolic" IR-B isoform. This opens new venues for rational enhancement of insulin IR-B specificity by modifications beyond the C-terminus of its B chain.

• MeSH
• embryo savčí cytologie   metabolismus   MeSH
• fibroblasty cytologie   metabolismus   MeSH
• fosforylace MeSH
• hypoglykemika metabolismus   MeSH
• insulinu podobný růstový faktor I metabolismus   MeSH
• insulinu podobný růstový faktor II metabolismus   MeSH
• inzulin metabolismus   MeSH
• konformace proteinů MeSH
• kultivované buňky MeSH
• lidé MeSH
• lymfocyty cytologie   metabolismus   MeSH
• molekulární sondy metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• receptor IGF typ 1 metabolismus   MeSH
• receptor inzulinu metabolismus   MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hypoglykemika MeSH
• insulinu podobný růstový faktor I MeSH
• insulinu podobný růstový faktor II MeSH
• inzulin MeSH
• molekulární sondy MeSH
• receptor IGF typ 1 MeSH
• receptor inzulinu MeSH

In our previous studies we described functional expression of organic cation transporter 3 (OCT3) and multidrug and toxin extrusion 1 (MATE1) protein in the rat placenta. Since metformin is a substrate of both OCT3 and MATE1, in this study we used the model of dually perfused rat placenta to investigate the role of these transporters in metformin passage across the placenta. We observed concentration-dependent transplacental clearance of metformin in both maternal-to-fetal and fetal-to-maternal directions; in addition metformin crossed the placenta from the fetal to maternal compartment even against its concentration gradient. This transport was completely inhibited by MPP(+), a common OCT3 and MATE1 inhibitor. Furthermore, we observed that the oppositely directed H(+)-gradient can drive the secretion of metformin from placenta to maternal circulation, confirming apical efflux of metformin from trophoblast by MATE1. In conclusion, we suggest an important role of OCT3 and MATE1 in the transplacental transfer of metformin.

• MeSH
• antiportéry metabolismus   MeSH
• hypoglykemika metabolismus   MeSH
• krysa rodu Rattus MeSH
• maternofetální výměna látek MeSH
• metformin metabolismus   MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• přenašeče organických aniontů nezávislé na sodíku metabolismus   MeSH
• proteiny přenášející organické kationty metabolismus   MeSH
• techniky in vitro MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiportéry MeSH
• hypoglykemika MeSH
• metformin MeSH
• organic anion transport protein 3 MeSH Prohlížeč
• přenašeče organických aniontů nezávislé na sodíku MeSH
• proteiny přenášející organické kationty MeSH
• Slc47a1 protein, rat MeSH Prohlížeč

AIM: The present study was designed to investigate the activity of two glibenclamide derivatives on glucose concentration. An additional aim was to identify the biodistribution of glibenclamide derivatives in different organs in a diabetic animal model. METHODS: The effects of two glibenclamide derivatives on glucose concentration were evaluated in a diabetic animal model. In addition, glibenclamide derivatives were bound to Tc-99m using radioimmunoassay methods. To evaluate the pharmacokinetics of the glibenclamide derivatives over time (15, 30, 45 and 60 min) the Tc-99m-glibenclamide conjugates were used. RESULTS: The results showed that glibenclamide-pregnenolone had greater hypoglycemic activity than glibenclamide or glibenclamide-OH. The data also showed that the biodistribution of Tc-99m-glibenclamide-OH in all organs was less than that of the Tc-99m-glibenclamide-pregnenolone derivative. CONCLUSIONS: The glibenclamide-pregnenolone derivative had greater hypoglycemic effects and its biodistribution was wider than glibenclamide-OH. The data suggest that the steroid nucleus may be important to the hypoglycemic activity of the glibenclamide-pregnenolone derivative and this could be related to the degree of lipophilicity induced by the steroid nucleus in the chemical structure of glibenclamide-pregnenolone.

• MeSH
• alloxan MeSH
• experimentální diabetes mellitus krev   MeSH
• fixní kombinace léků MeSH
• glibenklamid analogy a deriváty   farmakokinetika   terapeutické užití   MeSH
• hypoglykemika metabolismus   farmakokinetika   MeSH
• krevní glukóza metabolismus   MeSH
• krysa rodu Rattus MeSH
• metformin terapeutické užití   MeSH
• potkani Wistar MeSH
• pregnenolon farmakokinetika   terapeutické užití   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alloxan MeSH
• fixní kombinace léků MeSH
• glibenklamid MeSH
• hypoglykemika MeSH
• krevní glukóza MeSH
• metformin MeSH
• pregnenolon MeSH

Adipose tissue is a hormonally active tissue, producing adipocytokines which may influence activity of other tissues. Adiponectin, abundantly present in the plasma increases insulin sensitivity by stimulating fatty acid oxidation, decreases plasma triglycerides and improves glucose metabolism. Adiponectin levels are inversely related to the degree of adiposity. Anorexia nervosa and type 1 diabetes are associated with increased plasma adiponectin levels and higher insulin sensitivity. Decreased plasma adiponectin levels were reported in insulin-resistant states, such as obesity and type 2 diabetes and in patients with coronary artery disease. Activity of adiponectin is associated with leptin, resistin and with steroid and thyroid hormones, glucocorticoids, NO and others. Adiponectin suppresses expression of extracellular matrix adhesive proteins in endothelial cells and atherosclerosis potentiating cytokines. Anti-atherogenic and anti-inflammatory properties of adiponectin and the ability to stimulate insulin sensitivity have made adiponectin an important object for physiological and pathophysiological studies with the aim of potential therapeutic applications.

• MeSH
• adiponektin biosyntéza   chemie   fyziologie   MeSH
• antiflogistika nesteroidní metabolismus   MeSH
• ateroskleróza metabolismus   prevence a kontrola   MeSH
• hypoglykemika metabolismus   MeSH
• inzulinová rezistence fyziologie   MeSH
• lidé MeSH
• tukové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adiponektin MeSH
• antiflogistika nesteroidní MeSH
• hypoglykemika MeSH

Experimental hypothermia caused extensive changes in the number of both classes of insulin receptors in different rat tissues. In the liver, the number of high affinity insulin receptors (HAIRs) decreased by 50% (from 25.3 to 12.6 fmol/mg membrane protein), whereas number of low affinity insulin receptors (LAIRs) was almost unchanged in comparison to normothermic animals (5.63 and 4.39 pmol/mg, respectively). In the adipose tissue, number of both classes was reduced--HAIRs by 81% (from 24.0 to 4.50 fmol/mg) and LAIRs by 92% (from 16.0 to 1.29 pmol/mg). In the skeletal muscle, capacity of HAIRs was not changed (16.2 and 19.3 fmol/mg in normo- and hypothermic animals, respectively), whereas number of LAIRs increased by 150% (from 6.65 to 16.6 pmol/mg). Hypothermic rats also showed lower amount (by 85%) of LAIRs in the heart muscle (9.37 and 1.43 pmol/mg in control and experimental animals, respectively). Simultaneously, no significant changes were found in HAIRs (16.3 and 11.9 fmol/mg, respectively) and LAIRs (4.43 and 3.88 pmol/mg, respectively) in the brain. These differences in insulin receptors responses to hypothermia may reflect different physiological role of insulin in the regulation of target cell metabolism and/or the differences in tissue distribution of the insulin receptor isoforms.

• MeSH
• buněčná membrána metabolismus   MeSH
• hypoglykemika metabolismus   farmakologie   MeSH
• hypotermie metabolismus   MeSH
• inzulin metabolismus   farmakologie   MeSH
• játra metabolismus   MeSH
• kosterní svaly metabolismus   MeSH
• krysa rodu Rattus MeSH
• mozek metabolismus   MeSH
• myokard metabolismus   MeSH
• orgánová specificita MeSH
• potkani Wistar MeSH
• radioizotopy jodu MeSH
• receptor inzulinu metabolismus   MeSH
• tuková tkáň metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hypoglykemika MeSH
• inzulin MeSH
• radioizotopy jodu MeSH
• receptor inzulinu MeSH

• MeSH
• aplikace orální MeSH
• chromatografie na tenké vrstvě MeSH
• hypoglykemika krev   metabolismus   moč   MeSH
• intestinální absorpce MeSH
• krysa rodu Rattus MeSH
• morfoliny metabolismus   MeSH
• psi MeSH
• spektrofotometrie MeSH
• ultrafialové záření MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hypoglykemika MeSH
• morfoliny MeSH