intraperitoneal glucose tolerance test
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BACKGROUND/OBJECTIVES: Prolactin-releasing peptide (PrRP) has a potential to decrease food intake and ameliorate obesity, but is ineffective after peripheral administration. We have previously shown that our novel lipidized analogs PrRP enhances its stability in the circulation and enables its central effect after peripheral application. The purpose of this study was to explore if sub-chronic administration of novel PrRP analog palmitoylated in position 11 (palm11-PrRP31) to Koletsky-spontaneously hypertensive obese rats (SHROB) could lower body weight and glucose intolerance as well as other metabolic parameters. SUBJECTS/METHODS: The SHROB rats (n = 16) were used for this study and age-matched hypertensive lean SHR littermates (n = 16) served as controls. Palm11-PrRP31 was administered intraperitoneally to SHR and SHROB (n = 8) at a dose of 5 mg/kg once-daily for 3 weeks. During the dosing period food intake and body weight were monitored. At the end of the experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected. Thereafter, arterial blood pressure was measured. RESULTS: At the end of the experiment, vehicle-treated SHROB rats showed typical metabolic syndrome parameters, including obesity, glucose intolerance, dyslipidemia, and hypertension. Peripheral treatment with palm11-PrRP31 progressively decreased the body weight of SHR rats but not SHROB rats, though glucose tolerance was markedly improved in both strains. Moreover, in SHROB palm11-PrRP31 ameliorated the HOMA index, insulin/glucagon ratio, and increased insulin receptor substrate 1 and 2 expression in fat and insulin signaling in the hypothalamus, while it had no effect on blood pressure. CONCLUSIONS: We demonstrated that our new lipidized PrRP analog is capable of improving glucose tolerance in obese SHROB rats after peripheral application, suggesting that its effect on glucose metabolism is independent of leptin signaling and body weight lowering. These data suggest that this analog has the potential to be a compound with both anti-obesity and glucose-lowering properties.
- MeSH
- glukagon krev MeSH
- glukózový toleranční test MeSH
- hormon uvolňující prolaktin aplikace a dávkování analogy a deriváty farmakologie terapeutické užití MeSH
- hypertenze krev farmakoterapie MeSH
- inzulin krev metabolismus MeSH
- inzulinová rezistence MeSH
- krevní glukóza metabolismus MeSH
- krevní tlak účinky léků MeSH
- lipidy krev MeSH
- metabolický syndrom * krev farmakoterapie metabolismus MeSH
- mozek účinky léků metabolismus MeSH
- obezita * krev farmakoterapie MeSH
- porucha glukózové tolerance * krev farmakoterapie MeSH
- potkani inbrední SHR MeSH
- proteiny insulinového receptorového substrátu metabolismus MeSH
- tělesná hmotnost účinky léků MeSH
- tuková tkáň účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Článok prezentuje výsledky štúdie hypoglykemických vlastností medzi 1,2,4-triazolovými derivátmi syntetizovanými na Katedre fyzikálnej a koloidnej chémie Štátnej lekárskej univerzity v Zaporizhzhia. V súčasnosti má veľké množstvo ľudí sedavý spôsob života, aj väčšina ich stravy obsahuje často používané produkty, ktoré zvyšujú hladinu glukózy v krvi, čo môže vyvolať rozvoj závažných ochorení. Preto do dnešného dňa zostáva vytvorenie liekov, ktoré vykazujú hypoglykemickú aktivitu a majú nízku úroveň toxicity, naliehavou úlohou pre lekárne. V prvej fáze nášho výskumu bola vykonaná predpoveď akútnej toxicity. Hypoglykemická aktivita syntetizovaných zlúčenín bola hodnotená vykonaním intraperitoneálneho glukózového tolerančného testu (IPGTT) so zmenou koncentrácie glukózy v krvi zvieraťa po jeho jednorazovom intraperitoneálnom podaní vo forme 40 % roztoku v dávke 2 g/kg telesnej hmotnosti potkana. Zlúčeniny (38) rôznych tried boli študované na hypoglykemickú aktivitu. 2-{5-[(3,4-dimetoxyfenyl)-3H-1,2,4-triazol-3-yl]sulfanyl}acetát zinočnatý (3.18) vykazoval najvyššiu účinnosť z hľadiska schopnosti znižovať krv hladiny glukózy, a to o 27,3 % (približne 1,3-krát).
This article presents the study results of the hypoglycemic properties among 1,2,4-triazole derivatives synthesized at the Department of Physical and Colloidal Chemistry of the Zaporizhzhia State Medical University. Today, many people have a sedentary way of life, also most of their diet contains products that they frequently use, which increase the level of glucose in the blood, which can provoke the development of serious diseases. Therefore, to date, the creation of drugs that exhibit hypoglycemic activity and have a low level of toxicity remains an urgent task for medicine and pharmacy. In the first stage of our research, acute toxicity prediction was performed. The hypoglycemic activity of the synthesized compounds was assessed by performing an intraperitoneal glucose tolerance test (IPGTT) with a change in the blood glucose concentration of the animal after its single intraperitoneal administration in the form of a 40% solution at a dose of 2 g/kg of rat body weight. Thirty-eight compounds of the different classes were studied for hypoglycemic activity. Zinc (II) 2-{5-[(3,4-methoxyphenyl)-3H-1,2,4-triazole-3-yl]thio} acetate (3.18) showed the highest efficiency in terms of the ability to lower blood glucose levels, namely, by 27.3% (approximately 1.3 times).
Decreased metabolic flexibility, i.e. a compromised ability to adjust fuel oxidation to fuel availability supports development of adverse consequences of obesity. The aims of this study were (i) to learn whether obesity-resistant A/J and obesity-prone C57BL/6J mice differ in their metabolic flexibility right after weaning; and (ii) to characterize possible differences in control of glucose homeostasis in these animals using glucose tolerance tests (GTT). A/J and C57BL/6J mice of both genders were maintained at 20 °C and weaned to standard low-fat diet at 30 days of age. During the first day after weaning, using several separate animal cohorts, (i) GTT was performed using 1 or 3 mg glucose/g body weight (BW), while glucose was administered either orally (OGTT) or intraperitoneally (IPGTT) at 20 °C; and (ii) indirect calorimetry (INCA) was performed, either in a combination with oral gavage of 1 or 7.5 mg glucose/g BW, or during a fasting/re-feeding transition. INCA was conducted either at 20 °C or 34 °C. Results of both OGTT and IPGTT using 1 mg glucose/g BW at 20 °C, and INCA using 7.5 mg glucose/g BW at 34 °C, indicated higher glucose tolerance and higher metabolic flexibility to glucose, respectively, and lower fasting glycemia in A/J mice as compared with C57BL/6J mice. Thus, control of whole body glucose metabolism between A/J and C57BL/6J mice represents a phenotypic feature differentiating between the strains right after weaning.
- MeSH
- druhová specificita MeSH
- glukosa * metabolismus farmakologie MeSH
- glukózový toleranční test MeSH
- myši MeSH
- obezita genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood-brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both Prrp-knockout and Prrp receptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague-Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.
- MeSH
- anorektika farmakologie MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- experimentální diabetes mellitus metabolismus MeSH
- glukózový toleranční test MeSH
- hormon uvolňující prolaktin analogy a deriváty farmakologie MeSH
- játra účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- leptinové receptory nedostatek MeSH
- lipoylace MeSH
- messenger RNA genetika metabolismus MeSH
- metabolismus lipidů účinky léků genetika MeSH
- myši MeSH
- obezita farmakoterapie metabolismus patologie MeSH
- potkani Sprague-Dawley MeSH
- potkani Zucker MeSH
- přijímání potravy účinky léků MeSH
- racionální návrh léčiv MeSH
- tělesná hmotnost účinky léků MeSH
- tuková tkáň účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea.
- MeSH
- adipozita účinky léků MeSH
- experimentální diabetes mellitus krev komplikace genetika patologie MeSH
- fenotyp MeSH
- glukosa metabolismus MeSH
- hypoxie komplikace metabolismus MeSH
- inzulin metabolismus MeSH
- lipolýza * účinky léků MeSH
- mastné kyseliny krev MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- obstrukční spánková apnoe krev komplikace genetika patologie MeSH
- pyraziny farmakologie MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků MeSH
- tukové buňky účinky léků patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
