Untersuchungen zur differentiellen Plasmaproteinexpression bei Diabetikern unter Glitazontherapie

In dieser Studie wurden die Auswirkungen einer Pioglitazontherapie bei Typ 2 Diabetikern auf das Proteom des menschlichen Plasmas untersucht. Mit der 2D-Gelelektrophorese konnten vielfältige Veränderungen im Proteom identifiziert werden. Die Proteine Orosomucoid (Alpha1-Acid Glykoprotein), Haptoglob...

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Bibliographic Details
Main Author: Heipel, Susanne
Contributors: Lankat-Buttgereit, B. (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2009
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This study intended to evaluate the effects of pioglitazone treatment of type 2 diabetic patients on the proteome of human plasma. Manifold changes could be identified with the 2D gelelectrophoresis. Orosomucoid (alpha1-acid glycoprotein), haptoglobin, transthyretin, haemopexin, immunoglobulin J chain, profilin and apolipoprotein A1 (HDL) altered their concentrations. All variations indicated a reduction of inflammation in the organism and an improvement of the diabetic metabolism. The protein with most prominent changes represented profiling-1. Apart from profiling the effects of pioglitazone treatment on the proteins of inflammation and the diabetic metabolism were known before, but this highlights the value of the 2D-Gelelektrophoresis. Western Blots showed, that treatment with pioglitazone increased the plasma profilin level in seven of ten diabetics. Healthy people had high levels of plasma profilin. A group of investigated coronary heart disease patients had remarkably low profilin levels in the plasma. Therefore, an immunhistochemical study with vessels of four diabetic patients and a non-diabetic person were performed using a profilin antibody. A heavy accumulation of profilin occurred in the arteriosclerotic plaques. The endothelium of diabetics seemed to contain more profilin than the non-diabetic. These discoveries suggest that profilin may be a marker for the vessel status and endothelial dysfunction. Hereupon, human umbilical vein endothelial cells (HUVECs) were investigated in their excitability induced by pioglitazon, metformin, gliclazide, interleukin 6, ketocholesterol, hydroxycholesterol and in combinations with pioglitazone. Pioglitazone proved to be the only substance, which reduced the intracellular and secreted profilin. All of the other substances raised the intracellular profilin. The profilin secretion was only affected by ketocholesterol, pioglitazone or pioglitazon plus gliclazide. In combinations pioglitazon neutralised the effect of the other substances. Though in combinations with pioglitazone and gliclazide the pioglitazone effect prevailed. The regulation of the endothelial profilin content by drugs displays a new insight. Profilin seemed to be a messenger in cellular processes and endothelial dysfunction. It also could be the mediator of the piogliazone effect, since it is involved in many signal cascades, which can be addressed by pioglitazone, too. Piogliazone apparently stopped pathological developments in the endothelium and the whole organism and cancelled them partially. Therefore, in the future it could have potential applications in the treatment of the metabolic syndrome and in arteriosclerosis.