Východiska: Metformin je lékem první volby u diabetiků, lékem stále šířeji využívaným i v nediabetické populaci, a to zejména díky kombinaci efektivity a excelentního bezpečnostního profilu. Nad rámec známých metabolických efektů prokázaly retrospektivní epidemiologické studie, že užívání metforminu u diabetiků snižuje riziko vzniku nádorů a/nebo zlepšuje prognózu ve srovnání s těmi, kteří užívají jiná antidiabetika. Toto je velmi silný argument pro to, uvažovat o změně účelu indikace metforminu jako případného adjuvancia v onkologických indikacích, nicméně je bezpodmínečně nutné ověřit tuto domněnku v duchu medicíny založené na důkazech. Metformin patří mezi biguanidy a v kontextu diabetu typu 2 zvyšuje citlivost tkání k inzulinu. Účinkuje především na úrovni jater, kde inhibuje oxidativní fosforylaci, což vede k supresi glukoneogeneze a způsobuje pokles koncentrace glukózy v krvi. Působí také na svalové a tukové buňky, ve kterých zlepšuje utilizaci glukózy. Mechanizmy zodpovědné za protinádorový účinek metforminu jsou detailně studovány a zdá se, že nejdůležitější je jeho schopnost vyvolat intracelulární energetický stres a následně metabolické změny, které mají cytostatický nebo cytotoxický efekt. Rozsáhlá klinická zkušenost s metforminem v léčbě diabetu v kombinaci s jeho prokázaným efektem na různé typy nádorových buněk vedla k zahájení mnoha klinických studií, které testovaly jeho potenciál při léčbě nádorů. Cíl: Cílem této práce je shrnout současné znalosti o protinádorových účincích metforminu a výsledky recentních klinických studií s metforminem při léčbě různých typů nádorů.
Background: Metformin is the most commonly used antidiabetic drug with a plethora of proven metabolic and cardiovascular beneficial effects and exceptional safety profile. On top of the established metabolic effects, retrospective epidemiologic evidence shows that metformin use is associated with decreased cancer risk and/or improved disease prognosis in diabetic cancer patients on metformin compared to those treated with different antidiabetic drugs. This is a sound argument for eventual repurposing metformin as an adjuvant drug in oncology; however, evidence-based data are currently needed to establish this. Metformin is a biguanide that in the context of type 2 diabetes primarily targets the liver. Metformin inhibits oxidative phosphorylation which leads to the suppression of gluconeogenesis and causes decrease of blood glucose concentration. Mechanisms responsible for metformin anti-neoplastic effect have been investigated extensively, and key events seem to centralize around its ability to induce intracellular energetic stress with subsequent changes of metabolism resulting in cytostatic or cytotoxic action. Large clinical experience with metformin in the treatment of diabetes together with its plausible effects on different cancer cell types initiated a number of clinical trials that tested the hypothesis that metformin might have a beneficial effect in the treatment of cancer. Purpose: The aim of this review is to compile recent advances in our understanding of metformin antineoplastic effects and to give a summary of the results of recent clinical trials of metformin for treatment of different cancer types.
Methylglyoxal production is increased in diabetes. Methylglyoxal is efficiently detoxified by enzyme glyoxalase 1 (GLO1). The aim was to study the effect of diabetic and CKD milieu on (a) GLO1 gene expression in peripheral blood mononuclear cells; (b) GLO1 protein levels in whole blood; and (c) GLO1 activity in RBCs in vivo in diabetic vs. non-diabetic subjects with normal or slightly reduced vs. considerably reduced renal function (CKD1-2 vs. CKD3-4). A total of 83 subjects were included in the study. Gene expression was measured using real-time PCR, and protein levels were quantified using Western blotting. Erythrocyte GLO1 activity was measured spectrophotometrically. GLO1 gene expression was significantly higher in subjects with CKD1-2 compared to CKD3-4. GLO1 protein level was lower in diabetics than in non-diabetics. GLO1 activity in RBCs differed between the four groups being significantly higher in diabetics with CKD1-2 vs. healthy subjects and vs. nondiabeticsfig with CKD3-4. GLO1 activity was significantly higher in diabetics compared to nondiabetics. In conclusion, both diabetes and CKD affects the glyoxalase system. It appears that CKD in advanced stages has prevailing and suppressive effects compared to hyperglycaemia. CKD decreases GLO1 gene expression and protein levels (together with diabetes) without concomitant changes of GLO1 activity.
- MeSH
- chronická renální insuficience krev patologie MeSH
- diabetes mellitus krev patologie MeSH
- diabetické nefropatie krev patologie MeSH
- laktoylglutathionlyasa krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- pyruvaldehyd krev MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Growing prevalence of diabetes (type 2 as well as type 1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide. Understanding the molecular pathogenesis of chronic micro-, macro- and avascular complications mediated by hyperglycemia is of crucial importance since novel therapeutic targets can be identified and tested. Thiamine (vitamin B1) is an essential cofactor of several enzymes involved in carbohydrate metabolism and published data suggest that thiamine metabolism in diabetes is deficient. This review aims to point out the physiological role of thiamine in metabolism of glucose and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine deficiency (either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are increased in diabetes and to summarise data indicating thiamine mishandling in diabetics (by review of the studies mapping the prevalence and the degree of thiamine deficiency in diabetics). Finally, we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it could be concluded that although experimental studies mostly resulted in beneficial effects, clinical studies of appropriate size and duration focusing on the effect of thiamine supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
