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Synthesis and biochemical characterization of hybrid analogues of human insulin and IGF-2
Povalová, Anna ; Stiborová, Marie (advisor) ; Koberová, Monika (referee)
The ever-increasing occurrence of diabetes mellitus brings about the need for development of new therapeutic agents to provide adequate treatment for patients. An important element in this research area is elucidation how insulin works, mainly in connection with insulin-like growth factors (IGF-1 and IGF-2), which show significant structural homology to each other. In addition, their respective receptors - insulin receptor (IR) and receptor for IGF-1 and IGF-2 (IGF-1R) - exhibit very high similarity. As a result, IGF-1 and IGF-2 can bind to IR and insulin can bind to IGF-1R. Of a particular importance is the high affinity binding of IGF-2 to the isoform A of IR. Unlike insulin, which predominantly mediates glucose entry into cells, IGFs induce growth or mitogenic effects. The finding which structural determinants in insulin and IGFs are responsible for the differences in the activation of their cognate receptors could provide an explanation for different functional responses upon binding of these hormones to different target cells. Understanding of this mechanism could also help in the development of functionally selective analogues of these hormones. The aim of this study was the synthesis and characterization of analogues of human insulin extended at the C terminus of the B chain with the amino...
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Identification of biomarkers involved in the pathophysiology of gestational diabetes mellitus.
Šimják, Patrik ; Pařízek, Antonín (advisor) ; Karásek, David (referee) ; Novotný, Zdeněk (referee)
Identification of biomarkers involved in the pathophysiology of gestational diabetes mellitus ABSTRACT Gestational diabetes mellitus is a disorder of glucose metabolism that occurs in pregnancy and resolves after delivery. Increasing production of pregnancy-related hormones leads to insulin resistance which is not adequately compensated by increased insulin secretion. Since obesity is an important risk factor for gestational diabetes and is also associated with adipose tissue dysfunction and increased peripheral insulin resistance, the question arises as to what extent is the adipose tissue involved in the development of gestational diabetes. The first part of the thesis focuses on the identification of changes in plasma concentration and mRNA expression of adipokines fetuin A, fetuin B and FGF21. In our study we did not show that the presence of gestational diabetes significantly influenced the plasma concentration of fetuin A, fetuin B and FGF21 during pregnancy. An important finding was that women who had pregnancy complicated with gestational diabetes had a significantly higher concentration of FGF21 several months after delivery in comparison to healthy pregnant women. We have been able to demonstrate the production of fetuin A in the placenta and fetuin B in perineal and subcutaneous tissue. However,...
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Synthesis and biochemical characterization of hybrid analogues of human insulin and IGF-2
Povalová, Anna ; Stiborová, Marie (advisor) ; Koberová, Monika (referee)
The ever-increasing occurrence of diabetes mellitus brings about the need for development of new therapeutic agents to provide adequate treatment for patients. An important element in this research area is elucidation how insulin works, mainly in connection with insulin-like growth factors (IGF-1 and IGF-2), which show significant structural homology to each other. In addition, their respective receptors - insulin receptor (IR) and receptor for IGF-1 and IGF-2 (IGF-1R) - exhibit very high similarity. As a result, IGF-1 and IGF-2 can bind to IR and insulin can bind to IGF-1R. Of a particular importance is the high affinity binding of IGF-2 to the isoform A of IR. Unlike insulin, which predominantly mediates glucose entry into cells, IGFs induce growth or mitogenic effects. The finding which structural determinants in insulin and IGFs are responsible for the differences in the activation of their cognate receptors could provide an explanation for different functional responses upon binding of these hormones to different target cells. Understanding of this mechanism could also help in the development of functionally selective analogues of these hormones. The aim of this study was the synthesis and characterization of analogues of human insulin extended at the C terminus of the B chain with the amino...
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