Browsing by Author "Voļska, Kristīne"

Now showing 1 - 4 of 4
  • No Thumbnail Available
    Item
    Decreases in Circulating Concentrations of Long-Chain Acylcarnitines and Free Fatty Acids During the Glucose Tolerance Test Represent Tissue-Specific Insulin Sensitivity
    (2019) Makarova, Elīna; Makrecka-Kūka, Marina; Vilks, Karlis; Voļska, Kristīne; Sevostjanovs, Eduards; Grinberga, Solveiga; Zarkova-Malkova, Olga; Dambrova, Maija; Liepinsh, Edgars; Faculty of Pharmacy
    Background: Insulin plays a pivotal role in the regulation of both carbohydrate and lipid intermediate turnover and metabolism. In the transition from a fasted to fed state, insulin action inhibits lipolysis in adipocytes, and acylcarnitine synthesis in the muscles and heart. The aim of this study was to measure free fatty acid (FFA) and acylcarnitine levels during the glucose tolerance test as indicators of tissue-specific insulin resistance. Results: Insulin release in response to glucose administration decreased both FFA and long-chain acylcarnitine levels in plasma in healthy control animals by 30% (120 min). The glucose tolerance test and [3H]-deoxy-D-glucose uptake in tissues revealed that high fat diet-induced lipid overload in C57bl/6N mice evoked only adipose tissue insulin resistance, and plasma levels of FFAs did not decrease after glucose administration. In comparison, db/db mice developed type 2 diabetes with severely impaired insulin sensitivity and up to 70% lower glucose uptake in both adipose tissues and muscles (skeletal muscle and heart), and both plasma concentrations of FFAs and long-chain acylcarnitines did not decrease in response to glucose administration. Conclusions: These results link impaired adipose tissue insulin sensitivity with continuous FFA release in the transition from a fasted to postprandial state, while a blunted decrease in long-chain acylcarnitine levels is associated with muscle and heart insulin resistance.
  • No Thumbnail Available
    Item
    Metil-GBB aizsargājošo efektu un darbības mehānismu izpēte diabēta un tā komplikāciju eksperimentālajos modeļos. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2019) Voļska, Kristīne; Dambrova, Maija
    Diabēta prevalence pasaulē turpina pieaugt, vienlaikus pacientiem palielinot aterosklerozes un išēmiskās sirds slimības kā kardiovaskulāro komplikāciju risku. Nepilnīga taukskābju oksidācija un sekojoša taukskābju metabolītu, garķēžu acilkarnitīnu, uzkrāšanās ir saistīta ar insulīna rezistences un kardiovaskulāro slimību attīstību. Lai uzlabotu cukura diabēta un tā kardiovaskulāro komplikāciju pacientu klīnisko iznākumu, ir nepieciešamas jaunas ārstēšanas stratēģijas, kuru darbības mehānisms ietver taukskābju metabolisma izmaiņas. Promocijas darba mērķis bija pētīt jaunas acilkarnitīnu līmeni pazeminošas vielas metil-GBB ietekmi uz enerģijas metabolisma procesiem un noskaidrot tās iespējamos farmakoloģiskos darbības mehānismus cukura diabēta, aterosklerozes un sirds išēmijasreperfūzijas eksperimentālajos modeļos. Šajā darbā ir aprakstīti garķēžu acilkarnitīnu pārmērīgas uzkrāšanās molekulārie mehānismi un tās izraisīto bojājumu nozīme insulīna rezistences un išēmijas-reperfūzijas izraisītu bojājumu attīstībā. Ir aprakstīti metil-GBB terapijas izraisītā garķēžu acilkarnitīnu līmeņa samazinājuma aizsargājošie efekti eksperimentālajos diabēta un aterosklerozes modeļos. Rezultāti liecina, ka garķēžu acilkarnitīnu uzkrāšanās postprandiālā stāvokļa laikā ierobežo metabolisma elastīgumu un veicina hiperglikēmijas un hiperinsulinēmijas veidošanos. Metil-GBB terapijas izraisītāgarķēžu acilkarnitīnu līmeņa samazināšanās uzlabo insulīna jutību un ievērojami samazina glikozes un insulīna līmeņus asinīs pelēm ar insulīna rezistenci un diabētu. Rezultāti liecina, ka garķēžu acilkarnitīni ir galvenie taukskābju metabolīti, kuri nosaka išēmijas-reperfūzijas izraistītos bojājumus, kavējot oksidatīvo fosforilēšanu un sekojoši izsaucot mitohondriju membrānas hiperpolarizāciju un stimulējot reaktīvo skābekļa formu veidošanās sirds mitohondrijos. Metil-GBB terapijas pretaterosklerozes mehānisms ir saistīts ar garķēžu acilkarnitīnu daudzuma samazinājumu vaskulārajos audos, kā arī makrofāgu un monocītu infiltrācijas kavēšanu aterosklerotiskajās pangās aortas sīnusā. Šī pētījuma laikā tika pierādīts, ka farmakoloģiski izraisīta garķēžu acilkarnitīnu līmeņa samazināšana ar metil-GBB veicina glikozes metabolismu, uzlabo insulīna jutību, aizsargā sirds mitohondrijus pret išēmijasreperfūzijas bojājumu un kavē aterosklerozes attīstību, un tādēļ tas ir pielietojams diabēta un tā komplikāciju ārstēšanā.
  • No Thumbnail Available
    Item
    Protective Effects and Mechanisms of Action of methyl-GBB in the Preclinical Models of Diabetes and Its Complications. Doctoral Thesis
    (Rīga Stradiņš University, 2019) Voļska, Kristīne; Dambrova, Maija
    The global prevalence of diabetes continues to rise concomitantly increasing the number of diabetes patients at risk of developing cardiovascular complications, such as atherosclerosis and ischaemic heart disease. Incomplete fatty acid oxidation and subsequent accumulation of fatty acid intermediates, long-chain acylcarnitines, are linked to the development of insulin resistance and cardiovascular diseases. Therefore, novel treatment strategies targeting fatty acid metabolism are needed to improve the clinical outcomes of patients with diabetes and its cardiovascular complications. The aim of the thesis was to investigate the pharmacological mechanisms of action of an acylcarnitine concentration lowering drug methyl-GBB in experimental animal models of diabetes, cardiac ischaemia/reperfusion injury and atherosclerosis. This thesis describes the molecular mechanisms of excessive accumulation of long-chain acylcarnitines and their detrimental effects during the development of insulin resistance and in the ischaemia/reperfusion-induced damage. The protective effects of lowering long-chain acylcarnitine levels by methyl-GBB treatment in experimental models of diabetes and atherosclerosis are described. The results indicate that accumulation of long-chain acylcarnitines limits metabolic flexibility and accelerates hyperglycaemia and hyperinsulinemia during the fed state. Methyl-GBB treatment-induced decrease in long-chain acylcarnitine content improves insulin sensitivity and significantly reduces blood glucose and insulin levels in mice with insulin resistance and diabetes. The results demonstrate that long-chain acylcarnitines are the main fatty acid intermediates that induce ischaemia/reperfusion-related damage by inhibiting oxidative phosphorylation and subsequent mitochondrial membrane hyperpolarization and stimulated production of reactive oxygen species in cardiac mitochondria. The anti-atherosclerotic effect of methyl-GBB treatment is mediated by decreased amounts of long-chain acylcarnitines and decreased infiltration of macrophages and monocytes into the aortic lesions of the aortic root. During this study, it was confirmed that pharmacologically induced decrease in the content of long-chain acylcarnitines by methyl-GBB facilitates glucose metabolism, improves insulin sensitivity, protects cardiac mitochondria against ischaemia/reperfusion injury and attenuates the development of atherosclerosis, and therefore represents an effective strategy for the treatment of diabetes and its complications.
  • No Thumbnail Available
    Item
    Protective Effects and Mechanisms of Action of methyl-GBB in the Preclinical Models of Diabetes and Its Complications. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2019) Voļska, Kristīne; Dambrova, Maija
    The global prevalence of diabetes continues to rise concomitantly increasing the number of diabetes patients at risk of developing cardiovascular complications, such as atherosclerosis and ischaemic heart disease. Incomplete fatty acid oxidation and subsequent accumulation of fatty acid intermediates, long-chain acylcarnitines, are linked to the development of insulin resistance and cardiovascular diseases. Therefore, novel treatment strategies targeting fatty acid metabolism are needed to improve the clinical outcomes of patients with diabetes and its cardiovascular complications. The aim of the thesis was to investigate the pharmacological mechanisms of action of an acylcarnitine concentration lowering drug methyl-GBB in experimental animal models of diabetes, cardiac ischaemia/reperfusion injury and atherosclerosis. This thesis describes the molecular mechanisms of excessive accumulation of long-chain acylcarnitines and their detrimental effects during the development of insulin resistance and in the ischaemia/reperfusion-induced damage. The protective effects of lowering long-chain acylcarnitine levels by methyl-GBB treatment in experimental models of diabetes and atherosclerosis are described. The results indicate that accumulation of long-chain acylcarnitines limits metabolic flexibility and accelerates hyperglycaemia and hyperinsulinemia during the fed state. Methyl-GBB treatment-induced decrease in long-chain acylcarnitine content improves insulin sensitivity and significantly reduces blood glucose and insulin levels in mice with insulin resistance and diabetes. The results demonstrate that long-chain acylcarnitines are the main fatty acid intermediates that induce ischaemia/reperfusion-related damage by inhibiting oxidative phosphorylation and subsequent mitochondrial membrane hyperpolarization and stimulated production of reactive oxygen species in cardiac mitochondria. The anti-atherosclerotic effect of methyl-GBB treatment is mediated by decreased amounts of long-chain acylcarnitines and decreased infiltration of macrophages and monocytes into the aortic lesions of the aortic root. During this study, it was confirmed that pharmacologically induced decrease in the content of long-chain acylcarnitines by methyl-GBB facilitates glucose metabolism, improves insulin sensitivity, protects cardiac mitochondria against ischaemia/reperfusion injury and attenuates the development of atherosclerosis, and therefore represents an effective strategy for the treatment of diabetes and its complications.