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Preparation and characterization of selective analogues of insulin and IGF-II for various isoforms of the insulin receptor
Křížková, Květoslava ; Stiborová, Marie (advisor) ; Obšilová, Veronika (referee)
Modern lifestyle with its lack of exercise and healthy diet often leads to obesity which is accompanied by a decreasing biological effect of insulin and the onset of hyperinsulinemia, and consequently type 2 diabetes. Persistently high levels of insulin stimulate signalling pathways with growth effects; cells thus become more sensitive to mitogenic effects of all growth factors which may even lead to the loss of control over cell proliferation and the rise of various malignancies. Due to a high degree of structure homology of insulin, IGF-I/II as well as particular IR (existing in "mitogenic" IR-A isoform and "metabolic" IR-B isoform) and IGF-1R, there are a number of cross- interaction among hormones and receptors; nevertheless, the biological response may be different during the binding to a receptor. The determination of the crucial structural regions in insulin and IGF which are responsible for binding to the receptors could lead to the evolution of selective insulin analogues with strengthen metabolic effects, or could lead to the evolution of selective antagonism of IGF which would, in turn, suppress the mitogenic effect. The highest overlap is between insulin and IGF-II since both hormones are able to bind to the isoform A of an insulin receptor (IR-A) with a high affinity, and to activate...
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Preparation and characterization of GlnB22-insulin, a naturally occurring mutant in diabetic patients
Křížková, Květoslava ; Žáková, Lenka (advisor) ; Haluzík, Martin (referee)
Diabetes mellitus is a widespread disease which can be diagnosed in all age groups from newborns to seniors. Diabetes has multiple causes. The final disorder of blood glucose regulation is caused by a complex of factors and agents, in many cases by genetic defects connected with an unhealthy lifestyle. Moreover, a recently discovered form of diabetes, referred to as the monogenic diabetes, results from a gene mutation whereby only a single gene defect causes the onset of disease. The gene encoding the insulin primary structure belongs to several fundamental genes. Each change in a peptide chain is unique and leads to variation in this disease. Diagnosing patients with this mutation results in more detailed specification of their treatment and often also in the improvement of their living conditions. Mutations of the insulin gene have various symptoms. Some of the changes lead to the neonatal diabetes and patients are fully addicted to insulin since their birth. Other variations will never break out at their carriers. Seriousness of the disease course depends on characteristics of an original amino acid, its function in the insulin biosynthesis, its interaction with the insulin receptor, and on characteristics of a newly inserted amino acid and its influence on natural processes. The pathogenic...
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