Navrhovaný projekt by měl přispět k získání dosud chybějících poznatků o patofyziologických mechanismech inzulinové rezistence a diabetu 2. typu a naznačit možnosti racionální prevence a léčby. Cílem je 1) ověřit aditivní účinky šesti měsíčního podáváníomega-3 mastných kyselin (n3MK) v dávce 5 g denně samostatně/v kombinaci s pioglitazonem v dávce 15 mg denně na IR, glukózovou toleranci a lipidový metabolismus nemocných s diabetem 2.typu a 2) charaterizovat mechanismy účinku kombinované léčby v tukovétkáni a svalu. Jde o placebem kontrolovanou, paralelní, 6 měsíců trvající studii, do níž bude zařazeno 60 pacientů s diabetem 2. typu léčených metforminem, kteří budou randomizováni do 4 větví (n3MK, n3MK + pioglitazon, placebo +pioglitazon, placebo). Vzhledem k plánovanému testování mechanismů, které by se na efektu mohly podílet, bude zařazen pilotní pokus, v němž bude sledován vliv n3MK a pioglitazonu na aktivitu AMPK ve svalu a tuku myší.; Double-blind, randomised, placebo-controlled study aiming 1) to verify additive beneficial effects of the 6-month usage of the omega-3 fatty acids (n3FA), dosage of 5g per day alone/ in combination with 15 mg per day of pioglitazone, on IR, glucose tolerance and lipid metabolism of type 2 diabetics (T2D) treated by metformin; and 2) to explore the underlying mechanisms in adipose and muscle tissue. 60 patients with T2D will be included and randomized into 4 groups: 1) n3FA; 2) placebo; 3) pioglitazone and n3FA; and 4) pioglitazone and placebo. In order to evaluate the involvement of AMP-activated protein kinase (AMPK) in muscle and adipose tissue in the effects of the combination treatment in humans, a pilot study in mice will be also performed.

• MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• inzulinová rezistence MeSH
• kombinovaná farmakoterapie MeSH
• omega-3 mastné kyseliny terapeutické užití   MeSH
• thiazolidindiony terapeutické užití   MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• diabetologie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Strategies to prevent and treat obesity aim to decrease energy intake and/or increase energy expenditure. Regarding the increase of energy expenditure, two key intracellular targets may be considered (1) mitochondrial oxidative phosphorylation, the major site of ATP production, and (2) AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Experiments performed mainly in transgenic mice revealed a possibility to ameliorate obesity and associated disorders by mitochondrial uncoupling in metabolically relevant tissues, especially in white adipose tissue (WAT), skeletal muscle (SM), and liver. Thus, ectopic expression of brown fat-specific mitochondrial uncoupling protein 1 (UCP1) elicited major metabolic effects both at the cellular/tissue level and at the whole-body level. In addition to expected increases in energy expenditure, surprisingly complex phenotypic effects were detected. The consequences of mitochondrial uncoupling in WAT and SM are not identical, showing robust and stable obesity resistance accompanied by improvement of lipid metabolism in the case of ectopic UCP1 in WAT, while preservation of insulin sensitivity in the context of high-fat feeding represents the major outcome of muscle UCP1 expression. These complex responses could be largely explained by tissue-specific activation of AMPK, triggered by a depression of cellular energy charge. Experimental data support the idea that (1) while being always activated in response to mitochondrial uncoupling and compromised intracellular energy status in general, AMPK could augment energy expenditure and mediate local as well as whole-body effects; and (2) activation of AMPK alone does not lead to induction of energy expenditure and weight reduction.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides. METHODOLOGY/PRINCIPAL FINDINGS: In a 'prevention study', C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ∼35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine. CONCLUSIONS/SIGNIFICANCE: Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT.

• MeSH
• analýza rozptylu MeSH
• bílá tuková tkáň metabolismus   MeSH
• biologická dostupnost MeSH
• dieta s vysokým obsahem tuků MeSH
• endokanabinoidy MeSH
• fosfolipidy metabolismus   MeSH
• imunohistochemie MeSH
• játra účinky léků   metabolismus   MeSH
• kosterní svaly metabolismus   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• kyselina eikosapentaenová metabolismus   MeSH
• kyseliny dokosahexaenové metabolismus   MeSH
• metabolomika MeSH
• mikroskopie MeSH
• modulátory kanabinoidních receptorů metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita dietoterapie   prevence a kontrola   MeSH
• omega-3 mastné kyseliny aplikace a dávkování   metabolismus   farmakologie   MeSH
• tělesná hmotnost MeSH
• triglyceridy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy.

• MeSH
• dietní tuky aplikace a dávkování   MeSH
• homeostáza MeSH
• hypoglykemika aplikace a dávkování   MeSH
• krevní glukóza analýza   MeSH
• lipidy krev   MeSH
• metabolomika MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita prevence a kontrola   MeSH
• omega-3 mastné kyseliny aplikace a dávkování   MeSH
• thiazolidindiony aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• diabetes mellitus 2. typu * farmakoterapie   terapie   MeSH
• diabetes mellitus * terapie   MeSH
• farmakoterapie metody   MeSH
• hyperglykemie * farmakoterapie   terapie   MeSH
• hypoglykemika * terapeutické užití   MeSH
• inzulin aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• metformin * terapeutické užití   MeSH
• obezita * komplikace   prevence a kontrola   MeSH
• sulfonylmočovinové sloučeniny terapeutické užití   MeSH
• thiazolidindiony terapeutické užití   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• mořské ryby, kardiovaskulární onemocnění,
• MeSH
• diabetes mellitus prevence a kontrola   terapie   MeSH
• dyslipidemie prevence a kontrola   terapie   MeSH
• hypolipidemika terapeutické užití   MeSH
• kardiovaskulární nemoci prevence a kontrola   terapie   MeSH
• kyselina eikosapentaenová metabolismus   terapeutické užití   MeSH
• kyseliny dokosahexaenové metabolismus   terapeutické užití   MeSH
• kyseliny mastné omega-6 metabolismus   terapeutické užití   MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• omega-3 mastné kyseliny metabolismus   terapeutické užití   MeSH
• potravní doplňky MeSH
• ryby MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• životní styl MeSH
• Check Tag
• lidé MeSH

• MeSH
• časové faktory MeSH
• glukosa metabolismus   MeSH
• glykemický clamp metody   využití   MeSH
• inzulin aplikace a dávkování   krev   sekrece   MeSH
• inzulinová rezistence MeSH
• inzulinové infuzní systémy MeSH
• reprodukovatelnost výsledků MeSH
• triglyceridy krev   MeSH

OBJECTIVE: Telmisartan improves glucose and lipid metabolism in rodents. This study evaluated the effect of telmisartan on insulin sensitivity, substrate utilization, selected plasma adipokines and their expressions in subcutaneous adipose tissue (SAT) in metabolic syndrome. DESIGN AND METHODS: Twelve patients with impaired fasting glucose completed the double-blind, randomized, crossover trial. Patients received telmisartan (160 mg/day) or placebo for 3 weeks and vice versa with a 2-week washout period. At the end of each period, a hyperinsulinemic euglycemic clamp (HEC) combined with indirect calorimetry was performed. During HEC (0, 30, and 120 min), plasma levels of adipokines were measured and a needle biopsy (0 and 30 min) of SAT was performed. RESULTS: Fasting plasma glucose was lower after telmisartan compared with placebo (P<0.05). There were no differences in insulin sensitivity and substrate utilization. We found no differences in basal plasma adiponectin, resistin and tumour necrosis factor α (TNFα), but an increase was found in basal leptin, after telmisartan treatment. Insulin-stimulated plasma adiponectin (P<0.05), leptin and resistin (P<0.001) were increased, whereas TNFα was decreased (P<0.05) after telmisartan treatment. Expression of resistin, but not adiponectin, TNFα and leptin was increased after telmisartan treatment. CONCLUSIONS: Despite the decrease in fasting plasma glucose, telmisartan does not improve insulin sensitivity and substrate utilization. Telmisartan increases plasma leptin as well as insulin-stimulated plasma adiponectin, leptin and resistin, and decreases plasma TNFα during HEC. Changes in plasma adipokines cannot be explained by their expressions in SAT. The changes in plasma adipokines might be involved in the metabolic effects of telmisartan in metabolic syndrome.

• MeSH
• adipokiny krev   MeSH
• benzimidazoly terapeutické užití   MeSH
• benzoáty terapeutické užití   MeSH
• dospělí MeSH
• glykemický clamp MeSH
• hypoglykemika terapeutické užití   MeSH
• inhibitory ACE terapeutické užití   MeSH
• inzulin terapeutické užití   MeSH
• inzulinová rezistence fyziologie   MeSH
• krevní glukóza účinky léků   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolický syndrom krev   farmakoterapie   MeSH
• porucha glukózové tolerance krev   farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH