Úvod: V České republice (ČR) jsou pacienti s diagnózou diabetes mellitus (DM) sledováni a léčeni převážně u specialistů (přibližně 80 % v odborné diabetologické ambulanci), menší část praktickými lékaři (do 20 %). Doposud nebyl zhodnocen dlouhodobý vývoj změn preskripce metforminu a sulfonylurey v České republice a jeho konkordance s doporučenými postupy. Cíl: Porovnání vývoje preskripce metforminu (MET) a sulfonylurey (SU) v letech 2002–2006 s vývojem v letech 2010–2014 v reprezentativním vzorku populace pacientů s DM v ČR vedených v databázi Všeobecné zdravotní pojišťovny České republiky (VZP), u které bylo v roce 2014 pojištěno 63 % populace ČR. Metodika: V databázi VZP jsme identifikovali všechny osoby, které měly v letech 2002–2006 a 2010–2014 záznam o diagnóze DM (E10–E16 podle MKN 10) nebo předpis jakékoliv antidiabetické terapie (ATC skupina A10). Pro analýzu byl extrahován soubor osob, které měly v daném roce předepsanou nejméně jednou látku ze skupiny A10 (308 962 evidovaných v roce 2002 a 426 695 evidovaných v roce 2014). Pro každý rok byl vyhodnocen počet osob, které měly předepsán nejméně jednou MET nebo SU. Počet osob léčených MET nebo SU byl pak vyjádřen v procentech ze všech, kteří měli v daném roce předepsanou jakoukoliv terapii ze skupiny A10. Výsledky: Preskripce metforminu stoupá lineárně ze 43 % na 77 %, preskripce sulfonylurey se lineárně snižuje z 65 % na 37 %. Závěr: Naše analýza je prvním zhodnocením vývoje preskripce metforminu v ČR a zhodnocením její konkordance s doporučenými postupy pro léčbu DM. Preskripce metforminu v ČR se zvýšila mezi roky 2002–2014 ze 43 % na 77 % a preskripce SU se snížila z 65 % na 37 %. Tento vývoj a aktuální poměr preskripce MET a SU je potvrzením implementace doporučených postupů do praxe a důkazem vysoké kvality péče o pacienty s DM2T v České republice. Klíčová slova: diabetes mellitus 2. typu – metformin – sulfonylurea, Introduction: In the Czech Republic, patients with diabetes mellitus (DM) are followed and treated predominantly by specialists (approx. 80% at a specialist diabetology clinic), a minor part by general practitioners (up to 20%). Long-term development of the changes in prescribing metformin and sulfonylurea in the Czech Republic and its concordance with recommended procedures has not been evaluated until now. Goal: Comparison of the development of metformin (MET) and sulfonylurea (SU) prescriptions in the period of 2002–2006 with that of 2010–2014 in a representative sample of the patient population with DM kept in the database of the General Health Insurance Company of the Czech Republic (VZP) which provided health care coverage for 63% of Czech Republic population in 2014. Methodology: We identified all individuals in the VZP database who had a record of DM diagnosis (E10 – E16 based on ICD 10) or who had any antidiabetic therapy prescribed (ATC group A10) in the periods of 2002–2006 and 2010–2014. A cohort of patients was extracted for analysis, who had an agent from A10 group prescribed at least once in a relevant year (n = 308 962 in 2002; n = 426 695 in 2014). A number of patients was evaluated for each year, who had at least once MET or SU prescribed. The number of patients treated with MET or SU was then expressed as a percentage of all who had any therapy from A10 group prescribed in the year in question. Results: Metformin prescriptions have linearly risen from 43% to 77%, while sulfonylurea prescriptions have linearly decreased from 65% to 37%. Conclusion: The analysis presents the first evaluation of the development of metformin prescriptions conducted in the Czech Republic and evaluation of its concordance with the recommended procedures for the treatment of DM. The amount of metformin prescribed in the Czech Republic increased from 43% to 77% while the amount of SU prescribed decreased from 65% to 37% between 2002 and 2014. This development and the current ratio between the prescribed amounts of MET and SU demonstrate the implementation of the recommended procedures into practice and prove the high quality of care for patients with DM2T in specialists – diabetologists‘ surgeries. Key words: type 2 diabetes mellitus – metformin – sulfonylurea, and Denisa Janíčková-Žďarská, Petr Honěk, Ladislav Dušek, Tomáš Pavlík, Milan Kvapil
Metformin is the first line therapy of type 2 diabetics, but continued reduction of their life expectancy warrants further investigation into alternative treatment strategies. This study reports on the combinational use of metformin with aspalathin, a C-glucosyl dihydrochalcone with known glucose lowering and antioxidant properties, as an effective hypoglycemic therapy in a type 2 diabetic (db/db) mouse model. When tested as a monotherapy, a low dose of aspalathin (13 mg/kg) showed no effect, while a high dose (130 mg/kg) has already displayed a better potential than metformin in protecting against diabetes associated symptoms in db/db mice. Thus, it remains of interest to determine whether this dihydrochalcone can improve the efficacy of metformin. The results showed that this combination therapy was more effective than the use of metformin as a monotherapy in ameliorating diabetes associated symptoms, including abnormal raised fasting plasma glucose levels, impaired glucose tolerance, as well as excessively increased body weights and fat content. The treated mice also had reduced food and water consumption when compared to untreated controls, with a pronounced effect evident in the last week of treatment. Therefore, this study supports further investigations into the ameliorative effect of combination therapy of metformin and aspalathin against diabetes associated symptoms., P. V. Dludla, K. B. Gabuza, C. J. F. Muller, E. Joubert, J. Louw, R. Johnson., and Obsahuje bibliografii
In this study, we focused on an analysis of biguanides effects on mitochondrial enzyme activities, mitochondrial membrane potential and membrane permeabili ty transition pore function. We used phenformin, which is more efficient than metformin, and evaluated its effect on rat liver mitochondria and isolated hepatocytes. In contrast to prev iously published data, we found that phenformin, after a 5 min pr e-incubation, dose-dependently inhibits not only mitochondrial complex I but also complex II and IV activity in isolated mitochondria. The enzymes complexes inhibition is paralleled by the decreased respiratory control index and mitochondrial membrane potent ial. Direct measurements of mitochondrial swelling revealed that phenformin increases the resistance of the permeability transition pore to Ca 2+ ions. Our data might be in agreement with the hypothesis of Schäfer (1976) that binding of biguanides to membrane phospholipids alters membrane properties in a non-specific manner and, subsequently, different enzyme activities are modified via lipid phase. However, our measurements of anisotropy of fluorescence of hydrophobic membrane probe diphenylhexatriene have not shown a measurable effect of membrane fluidity with the 1 mM concentration of phenformin that strongly inhibited complex I activity. Our data therefore suggest that biguanides could be considered as agents with high efficacy but low specifity., Z. Drahota ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Diabetes mellitus a karcinom pankreatu vytvářejí oboustranný vztah, přičemž jedno primární onemocnění může ovlivnit rozvoj druhého. V přehledu jsou uvedeny patogenetické mechanizmy, které se podílejí na jejich vzájemném působení. Časná diagnostika je cestou ke zlepšení prognózy pacientů s maligním nádorem. Léčba diabetu antidiabetiky poskytuje rozdílná rizika rozvoje karcinomu pankreatu, ale mnoho poznatků stále ještě chybí., Diabetes mellitus and pancreatic cancer establish both-side relationship, one disease may have influence a development of the other. Pathogenic mechanisms sharing their relationship are overviewed. Early diagnosis may contribute to better prognosis of the patients with malign tumor. The treatment by antidiabetic drugs offer to diabetic patients different risks of pancreatic cancer but lots of data are still lacking., and Jan Škrha, Pavel Škrha, Přemysl Frič
Farmakogenetika je vedný odbor, ktorý skúma efekt jednotlivých liekov v závislosti od genotypu. V súčasnosti sú liečebné odporúčania pre liečbu niektorých monogenénových diabetov založené na genetickej diagnostike. Aj v oblasti farmakogenetiky perorálnych antidiabetík boli už publikované prvé štúdie, ktoré zistili asociácie jednotlivých génových variantov s liečebnou odozvou. Odozva na deriváty sulfonylurey bola signifikantne asociovaná s variantmi KCNJ11/ABCC8, TCF7L2 a CYP2C9. Odozva na liečbu metformínom bola asociovaná s variantmi génov ATM a SLC47A1. Odozva na liečbu glitazónmi bola asociovaná s variantom génu PPARG. Terapeutická odozva na liečbu gliptínmi bola asociovaná s variantmi génov TCF7L2 a CTRB1/2. Je možné očakávať, že v blízkej budúcnosti budú farmakogenetické poznatky využívané aj pri personalizácii liečby diabetu 2. typu., Pharmacogenetics is the study of how genes (individual genotypes) affect a person‘s response to drugs. At present, recommendations made about the treatment of some monogenic forms of diabetes are based on genetic diagnostics. The first studies in the field of pharmacogenetics of oral antidiabetics have now been published which have identified associations of individual genetic variants with response to treatment. The response to sulfonylurea derivatives was significantly associated with the variants KCNJ11/ABCC8, TCF7L2 and CYP2C9. The response to metformin treatment was associated with the genetic variants ATM and SLC47A1. The response to treatment with glitazones was associated with the genetic variant PPARG. The therapeutic response to the treatment with gliptins was associated with the genetic variants TCF7L2 and CTRB1/2. It may be expected that in the near future pharmacogenetic knowledge will also be used within personalized treatment of type 2 diabetes., and Ivan Tkáč
Elevated levels of insulin have been reported to induce both an arterial vasodilation mediated by nitric oxide (NO), and vasoconstriction mediated by endothelin and reactive oxygen radicals. Metformin, used to control blood glucose levels in type 2 diabetes, has also been shown to cause NO-mediated dilation of conduit arteries. It is possible that these contradictory vascular effects are due to a non-direct action on arteries. Therefore, the direct effect of high levels of insulin and metformin infusion on resistance artery diameter was evaluated. Experiments were carried out on the anesthetized pig; blood flow and pressure were measured in the iliac artery. An adjustable snare was applied to the iliac above the pressure and flow measurement site to induce step decreases (3-4 occlusions at 5 min intervals were performed for each infusion) in blood flow, and hence iliac pressure, and the conductance (Δflow / Δpressure) calculated. Saline, insulin (20 and 40 mUSP/l/min), and metformin (1 μg/ml/min) were infused separately downstream of the adjustable snare and their effect on arterial conductance assessed. Insulin at both infusion rates and metformin caused a significant reduction in peripheral vascular conductance. In conclusion, hyperinsulinemia and metformin infusion constrict resistance arterial vessels in vivo., F. Markos, C. M. Shortt, D. Edge, T. Ruane-O'Hora, M. I. M. Noble., and Obsahuje bibliografii
Metformin is widely used in the treatment of Type 2 diabetes, however, mechanisms of its antihyperglycemic effect were not yet fully elucidated. Complex I of mitochondrial respiration chain is considered as one of the possible targets of metformin action. In this paper, we present data indicating that the inhibitory effect of metformin can be tested also in liver homogenate. Contrary to previous findings on hepatocytes or mitochondria under our experimental conditions, lower metformin concentrations and shorter time of preincubation give significant inhibitory effects. These conditions enable to study the mechanism of the inhibitory effect of metformin in small samples of biological material (50-100 mg wet weight) and compare more experimental groups of animals because isolation of mitochonria is unnecessary., E. Páleníčková ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Chronická hyperglykemie u pacientů s diabetem 2. typu vede k vývoji mikrovaskulárních a makrovaskulárních komplikací a signifikantně ovlivňuje morbiditu a mortalitu. Řada velkých klinických studií dokazuje, že normalizace hladiny glykemií může zabránit nebo zpomalit progresi pozdních komplikací diabetu. Asi 25 % pacientů léčených perorálními antidiabetiky potřebuje inzulinoterapii ke kompenzaci progrese selhání β‑buněk a zabezpečení kontroly glykemie. Podle doporučení ADA/EASD je možné při neuspokojivé kompenzaci diabetu perorálními antidiabetiky zahájit inzulinoterapii přidáním bazálního inzulinu ke stávající léčbě. Dlouhodobě působící inzulinová analoga (glargin, degludec, detemir) ve studiích prokazují signifikantně nižší riziko hypoglykemických příhod, především nočních. K ovlivnění postprandiální hyperglykemie při terapii bazálním inzulinem je možné využít kombinace s krátkodobě působícími agonisty GLP‑1 receptorů. Léčba má nižší riziko hypoglykemických příhod než terapie inzulinem bazál/bolus a také nižší riziko zvyšování hmotnosti. Zasahuje přímo do patofyziologie diabetu 2. typu., Chronic hyperglycaemia in patients with type 2 diabetes mellitus leads to the development of microvascular and macrovascular complications while significantly affecting morbidity and mortality. A whole line of major clinical studies have proven that normalization of glycaemia levels can prevent or slow down the progression of later complications associated with diabetes. Around 25% of patients treated with oral antidiabetic drugs require insulin therapy to compensate for the progress of b‑cell failure and to ensure glycaemic control. According to the ADA/EASD guidelines, it is possible, if the diabetes is not satisfactorily controlled with oral antidiabetic drugs, to introduce insulin therapy by adding basal insulin to the existing treatment. In studies, the long‑term acting insulin analogues (glargine, degludec, detemir) have established the evidence of significantly reduced risk of hypoglycaemia, especially at night. In order to influence postprandial hyperglycaemia during basal insulin therapy it is possible to use the combination with short‑term acting GLP‑1 receptor agonists. The therapy presents a reduced risk of hypoglycaemia than basal/bolus insulin therapy as well as a lower risk of weight increase. It directly impacts the pathophysiology of type 2 diabetes mellitus., and Adamíková A.
High-mobility group box 1 (HMGB1) is newly discovered protein, which play a crucial role in the pathogenesis of systemic inflammation. Recent studies showed that HMGB1 is one of the important pathophysiological mechanisms in the occurrence and development of atherosclerosis. The purpose of the present study was to investigate the relationship between serum HMGB1 levels and endothelial function in patients with polycystic ovary syndrome (PCOS). Eighty newly diagnosed patients with PCOS and eighty normal women of similar age were selected. Metformin treatment (1,500 mg/day) was initiated in all patients for a period of consecutive 3 months. Serum HMGB1 levels were measured by ELISA. High resolution ultrasound was used to measure the brachial artery diameter at rest, after reactive hyperemia (flow-mediated arterial dilation, FMD) and after sublingual glyceryltrinitrate. Serum HMGB1 levels in PCOS were 24.87±14.93 ng/ml, which were significantly higher than that in controls (8.82±3.55 ng/ml, p<0.01). After 3 months treatment, serum HMGB1 levels decreased significantly (p<0.05). By dividing the distribution of HMGB1 levels into quartiles, serum HMGB1 levels were increased gradually with the increase of testosterone levels (p<0.05), whereas the FMD levels decreased (p<0.05). Multiple stepwise linear regression analysis showed that FMD (estimated coefficient β=-0.69, p=0.005), testosterone (β=0.31, p=0.045), TBARS (β=0.69, p=0.012) and hs-CRP levels (β=0.68, p=0.001) were significantly associated with HMGB1. The absolute changes in HMGB1 showed a positive correlation with the changes in testosterone (p<0.05) and negative correlation with the changes in FMD (p<0.05) in patients with PCOS during the course of metformin therapy. Serum HMGB1 levels are correlated with endothelial dysfunction in patients with PCOS. Our study suggests that HMGB1 may contribute to the early stage of atherosclerosis in patients with PCOS.
The skin matrix metalloproteinase 3, tissue inhibitors of matrix metalloproteinase 2 and collagen III content changes in type 1 diabetes and insulin resistance treated with insulin a nd metformin were studied. Healthy adult male Wistar rats were obtained from experimental animal house, Department of Experimental Pharmacology, Medical University in Bialystok. The rats were divided randomly into five groups of 8 rats each. Control rats were injected intraperitoneally by NaCl. Type IDDM was induced by a single injection of Streptozocin. Insulin resistance was induced by a high -fat diet. The chosen groups of rats were also treated with insulin or metformin. ELISA K its (USCN Life Science, China) were used to measure content of matrix metallo - proteinase 3 (ELISA Kit for Matrix Metalloproteinase 3 - MMP3), tissue inhibitor of matrix metalloproteinase 2 (ELISA Kit for Tissue Inhibitors of Metalloproteinase 2 - TIMP2) and content of collagen type 3 (ELISA Kit for Collagen Type III - COL3). The results were reported as a median. The statistical significance was defined as p<0.05. Type 1 diabetes and insulin resistance have significantly reduced the quality of the skin, shown by the increase in cont ent of matrix metalloproteinase 3 and the decrease in content of tissue inhibitors of matrix metalloproteinase 2. Type 1 diabetes and insulin resistance have reduced the quality of the skin expressed by type III collagen content decrease but for future studies it is recommend to determine rat interstitial collagenase, MMP -13, as well. Insulin and metformin treatment improved the quality of the diabetic skin, demonstrated by the type III collagen content increase., M. Knaś, K. Wołosik, A. Zalewska, A. Mikucka-Niczyporuk, I. Kasacka, M. Niczyporuk., and Obsahuje bibliografii