Browsing by Author "Makrecka-Kūka, Marina"

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
    Discovery of a Novel Cardioprotective Drug Methyl-GBB: Pharmacological Potential for Lowering Acyl-Carnitines. Doctoral Thesis
    (Rīga Stradiņš University, 2015) Makrecka-Kūka, Marina; Dambrova, Maija
    Ischemic heart disease is a major cause of disability and death in millions of people annually. The important pathological consequences of ischemic heart disease arise from impaired cellular energy metabolism. Therefore, a pharmacological intervention that targets cardiac energy metabolism pathways is suggested for the development of novel treatment strategies to improve the clinical outcomes of patients with ischemic heart disease. L-carnitine, a cofactor of acyltransferases, participates in the regulation of mitochondrial energy metabolism. The aim of the thesis was to elucidate the roles of L-carnitine and its metabolites in the regulation of cardiac energy metabolism and to discover novel drug targets to achieve cardioprotection. This thesis describes the importance of glucose and fatty acid energy metabolism pattern in the outcome of cardiac ischemia-reperfusion injury, the role of long-chain acylcarnitines in the regulation of energy metabolism, and the decreasing of the L-carnitine concentration as a strategy to regulate acyl-carnitine availability. The results demonstrate that the long-chain acyl-carnitine concentration determines the energy metabolism pattern in the heart. In addition, the accumulation of long-chain acyl-carnitines impairs glucose metabolism and increases the severity of cardiac ischemia-reperfusion injury. A decrease in acyl-carnitine availability can be achieved by lowering the L-carnitine concentration. The inhibition of both L-carnitine transport via OCTN2 and its biosynthesis via γ-butyrobetaine dioxygenase represent potential stategies for decreasing L-carnitine. The results show that the selective inhibition of L-carnitine transport via OCTN2 compared with the selective inhibition of γ-butyrobetaine dioxygenase is a far more effective approach for decreasing the L-carnitine concentration and inducing cardioprotective effects. A novel cardioprotective agent, Methyl- GBB, a novel inhibitor of γ-butyrobetaine dioxygenase and OCTN2, effectively reduces the concentrations of acyl-carnitines in the heart and mitochondria and limits FA oxidation, thereby stimulating glucose oxidation in heart tissues. Methyl-GBB decreases infarct size and improves survival after myocardial infarction in vivo in rats. This thesis demonstrates that cardioprotection can be achieved by the inhibition of L-carnitine transport via OCTN2, thereby decreasing L-carnitine and acyl-carnitine availability and stimulating glucose metabolism.
  • No Thumbnail Available
    Item
    Discovery of a Novel Cardioprotective Drug Methyl-GBB: Pharmacological Potential for Lowering Acyl-Carnitines. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2015) Makrecka-Kūka, Marina; Dambrova, Maija
    Ischemic heart disease is a major cause of disability and death in millions of people annually. The important pathological consequences of ischemic heart disease arise from impaired cellular energy metabolism. Therefore, a pharmacological intervention that targets cardiac energy metabolism pathways is suggested for the development of novel treatment strategies to improve the clinical outcomes of patients with ischemic heart disease. L-carnitine, a cofactor of acyltransferases, participates in the regulation of mitochondrial energy metabolism. The aim of the thesis was to elucidate the roles of L-carnitine and its metabolites in the regulation of cardiac energy metabolism and to discover novel drug targets to achieve cardioprotection. This thesis describes the importance of glucose and fatty acid energy metabolism pattern in the outcome of cardiac ischemia-reperfusion injury, the role of long-chain acylcarnitines in the regulation of energy metabolism, and the decreasing of the L-carnitine concentration as a strategy to regulate acyl-carnitine availability. The results demonstrate that the long-chain acyl-carnitine concentration determines the energy metabolism pattern in the heart. In addition, the accumulation of long-chain acyl-carnitines impairs glucose metabolism and increases the severity of cardiac ischemia-reperfusion injury. A decrease in acyl-carnitine availability can be achieved by lowering the L-carnitine concentration. The inhibition of both L-carnitine transport via OCTN2 and its biosynthesis via γ-butyrobetaine dioxygenase represent potential stategies for decreasing L-carnitine. The results show that the selective inhibition of L-carnitine transport via OCTN2 compared with the selective inhibition of γ-butyrobetaine dioxygenase is a far more effective approach for decreasing the L-carnitine concentration and inducing cardioprotective effects. A novel cardioprotective agent, Methyl- GBB, a novel inhibitor of γ-butyrobetaine dioxygenase and OCTN2, effectively reduces the concentrations of acyl-carnitines in the heart and mitochondria and limits FA oxidation, thereby stimulating glucose oxidation in heart tissues. Methyl-GBB decreases infarct size and improves survival after myocardial infarction in vivo in rats. This thesis demonstrates that cardioprotection can be achieved by the inhibition of L-carnitine transport via OCTN2, thereby decreasing L-carnitine and acyl-carnitine availability and stimulating glucose metabolism.
  • No Thumbnail Available
    Item
    Jauna kardioprotektīva savienojuma metil-GBB atklāšana: farmakoloģiska pieeja acil-karnitīnu samazināšanai. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2015) Makrecka-Kūka, Marina; Dambrova, Maija
    Sirds išēmiskā slimība ik gadu ir galvenais invaliditātes un nāves cēlonis miljoniem cilvēku. Sirds išēmiskās slimības patoģenēze saistīta ar traucētu šūnu enerģijas metabolismu. Tāpēc farmakoloģiska sirds enerģijas metabolisma signālceļu regulācija tiek piedāvāta kā jauna ārstēšanas stratēģija, lai uzlabotu klīnisko iznākumu pacientiem ar sirds išēmisko slimību. L-karnitīns ir aciltransferāžu kofaktors, kas piedalās enerģijas metabolisma regulācijā mitohondrijos. Promocijas darba mērķis bija noskaidrot L-karnitīna un tā atvasinājumu lomu sirds enerģijas metabolisma regulācijā un atklāt jaunus kardioprotektīvu zāļu mērķus L-karnitīna sistēmā. Promocijas darbā aprakstīta glikozes un taukskābju enerģijas metabolisma izmaiņu ietekme uz sirds išēmijas-reperfūzijas bojājumu, garķēžu acil-karnitīnu loma enerģijas metabolisma regulācijā, kā arī L-karnitīna daudzuma samazināšana, lai regulētu acil-karnitīnu pieejamību. Iegūtie rezultāti parāda, ka garķēžu acil-karnitīnu koncentrācija nosaka enerģijas metabolisma norises sirdī. Turklāt, garķēžu acil-karnitīnu uzkrāšanās pasliktina glikozes metabolismu un palielina sirds išēmijas-reperfūzijas bojājumu. Garķēžu acil-karnitīnu daudzumu varētu samazināt, samazinot L-karnitīna koncentrāciju. Kā veidi L-karnitīna samazināšanai varētu izmantot OCTN2 nodrošinātā L-karnitīna transporta un enzīma γ-butirobetaīna dioksigenāzes veicināto L-karnitīna biosintēzes kavēšanu. Darbā parādīts, ka, salīdzinot ar selektīvu L-karnitīna biosintēzes kavēšana, inhibējot γ-butirobetaīna dioksigenāzi, selektīva OCTN2 nodrošinātā karnitīna transporta inhibēšana ir daudz efektīvāks veids, lai samazinātu L-karnitīna daudzumu un sasniegtu kardioprotektīvo efektu. Atrasts jauns kardioprotektīvs savienojums Metil-GBB, kas darbojas kā γ-butirobetaīna dioksigenāzes un OCTN2 inhibitors. Metil-GBB efektīvi samazina acil-karnitīnu daudzumu sirdī un mitohondrijos, kavē taukskābju oksidāciju un vienlaicīgi stimulē glikozes oksidāciju sirds audos. Metil-GBB samazina infarkta lielumu un uzlabo izdzīvošanu pēc miokarda infarkta in vivo žurku eksperimentālajā modelī. Promocijas darbā parādīts, ka kardioptotektīvo efektu var sasniegt, kavējot OCTN2 nodrošināto L-karnitīna transportu, tādējādi samazinot L-karnitīna un garķēžu acil-karnitīnu daudzumu un stimulējot glikozes metabolismu.