Die vorliegende Arbeit untersucht die positiven Auswirkungen des Angiotensin-II-Rezeptor-Antagonisten Telmisartan auf die endotheliale Funktion und Thrombozytenaktivierung bei Ratten mit Streptozotocin-induziertem Diabetes mellitus. In Gefäßreaktivitätsstudien, Luminometer- und Fluoreszenzmessungen und mit Hilfe der Durchflusszytometrie wurden die Wirkungen des Medikamentes überprüft. Es konnte gezeigt werden, dass sich durch Telmisartan die NO-Bioverfügbarkeit verbessert, welche maßgeblich für die endotheliale Funktion verantwortlich ist und durch Ca2+-abhängige Aktivierung der eNOS und dehnungsinduzierte, Ca2+-unabhängigen NO-Bildung beeinflusst wird. Positiv wird des Weiteren die Sensitivität der glatten Gefäßmuskelzellen gegenüber NO beeinflusst, was zur Vasodilatation führt. Die atherosklerosefördernde Superoxidbildung wird zusätzlich reduziert. Es erfolgten außerdem Messungen von thrombozytengebundenem Fibrinogen, dementsprechend der GP IIb/IIIa-Aktivität, und der VASP-Phosphorylierung, demzufolge dem NO/cGMP-Signalweg, in Thrombozyten durch FITC-markierte Antikörper mit Hilfe der Durchflusszytometrie. Es wurde gezeigt, dass die Thrombozytenaktivierung, die für den initialen Schritt der Atherosklerose verantwortlich gemacht wird, durch Telmisartan verringert wird. Alle Messungen wurden vergleichend in einer Kontroll-, Placebo- und Telmisartangruppe durchgeführt. Die beobachtete Blutdrucksenkung ist, nach früheren Betrachtungen, nicht alleine verantwortlich für die verbesserte endotheliale Funktion, welche bei dem Einsatz von AT-II-Antagonisten beobachtet wird. Telmisartan wirkt, laut einer Studie, als einziger AT-II-Antagonist als partieller PPAR-Rezeptor, so dass Insulinresistenz und metabolische Parameter verbessert werden. Über diese Wirkungen beeinflusst Telmisartan auch die endotheliale Funktion und die Thrombozytenaktivierung. Zur Reduktion von vaskulären Komplikationen bei Diabetes mellitus erscheint Telmisartan aufgrund der vorliegenden Ergebnisse als sinnvolle medikamentöse Therapie. / Diabetes is associated with endothelial dysfunction and platelet activation, which are positively modulated by chronic treatment with telmisartan.

Zugl.: Giessen, Univ., Diss., 2009

Zugl.: Giessen, Universiẗat, Diss., 2009.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 141-162). Also available in print.

Techn. Universiẗat, Diss., 2005--München.

Regensburg, Univ., Diss., 2002.

Boston University. University Professors Program Senior theses. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-02

Currently, it is reported that ~65% and 34% of the U.S. population is overweight and obese, respectively. Obesity is a major risk factor for cardiovascular disease. Overweight and obese individuals are also at an increased risk of developing hypertension. Whole-body insulin sensitivity is reduced in obesity, resulting in insulin resistance and increased risk of type 2 diabetes. One possible mechanism contributing to insulin resistance in obesity hypertension is renin-angiotensin system (RAS) overactivation. The RAS exhibits vasocontricting and sodium-retaining properties, yet in vivo and in vitro animal experiments suggest impairment of whole-body insulin sensitivity with increased angiotensin II (Ang II) exposure. Furthermore, evidence from clinical studies indicates Ang II receptor blockers (ARBs) may reduce the incidence of new-onset diabetes compared to other antihypertensive agents in at-risk hypertensive patients. However, it is unclear if whole-body insulin sensitivity is improved with Ang II receptor blockade in humans. Thus, we tested the hypothesis that 8-week Ang II receptor blockade with olmesartan would improve whole-body insulin sensitivity in overweight and obese individuals with elevated blood pressure (BP). Olmesartan was selected for the present study because it is devoid of partial PPARγ agonist activity. To test our hypothesis, intravenous glucose tolerance tests were performed to measure insulin sensitivity before and after control and ARB treatment in a randomized crossover manner. Because skeletal muscle tissue accounts for ~75-90% of insulin-stimulated glucose uptake, a secondary exploratory aim was to examine skeletal muscle inflammatory and collagen response in relation to insulin sensitivity during ARB treatment. No baseline differences were observed between treatments (P>0.05). Both systolic (-11.7 mmHg; P=0.008) and diastolic (-12.1 mmHg; P=0.000) BP were reduced with ARB treatment. Insulin sensitivity was not different between treatments (P>0.05). No correlates of insulin sensitivity were identified. In addition, skeletal muscle inflammatory and collagen gene expression did not change from pre- to post-ARB treatment (P>0.05). Our findings suggest that short-term RAS blockade in overweight and obese adults with elevated BP does not improve whole-body insulin sensitivity, despite a significant BP reduction. Further studies are needed to clarify the role of individual RAS blockers on insulin sensitivity during RAS inhibition in obesity hypertension. / Ph. D.

Fetal pancreatic tissues can be a promising source for pancreatic progenitor cells (PPCs). In this regard, we have successfully isolated and characterized a population of fetal PPCs from first trimester human fetal pancreas using a previously established basic protocol. Upon exposure to a cocktail of conventional growth factors, these PPCs are amenable to differentiate into insulin-secreting islet-like cell clusters (ICCs); however, these ICCs have yet to exert additional efforts to direct to glucose-responsive cells. To address this issue, we have proposed two novel morphogenic factors in the present study, namely PDZ-domain-containing 2 (PDZD2) and angiotensin II (Ang II), a physiologically active peptide of the renin-angiotensin system (RAS), that potentially promote the differentiation and maturation of PPCs/ICCs. / In light of these findings, we conclude that we have discovered two novel mechanisms, the PDZD2 and Ang II/AT2 receptor signaling pathways, in the regulation of the development of PPCs/ICCs, thus implying their novel roles during islet development in vivo. The present study provides a "proof-of-principle" that a local RAS is critically involved in governing islet cell development. This work may contribute to devising protocols for maturation of pancreatic progenitors for clinical islet transplantation. / Local RASs have been reported to regulate the differentiation of tissue progenitor cells. It has yet to be confirmed whether such systems exist and govern the PPC development. To address this issue, we herein provided evidence that expression of RAS components was highly regulated throughout PPC differentiation. Locally generated Ang II was found to maintain PPC growth and differentiation via mediation of the Ang II type 1 and type 2 (AT1 and AT 2) receptors. We found that the AT2, but not AT1, receptor was a key mediator of Ang II-induced upregulation of beta-cell transcription factors. Transplantation of AT2 receptor-depleted ICCs into immune-privileged diabetic mice failed to ameliorate hyperglycemia, implying that AT2 receptors are indispensable during ICC maturation in vivo. / PDZD2 and its secreted form (sPDZD2) have been found to express in our fetal PPCs. We first evaluated the potential role of sPDZD2 in stimulating PPC differentiation and established an optimal concentration for such stimulation. We found that 10-9 M sPDZD2 promoted PPC differentiation, as evidenced by the up-regulation of the pancreatic endocrine markers and C-peptide content in the ICCs. It enhanced their expression of the L-type voltage-gated calcium ion channel (Cav1.2) and conferred an ability to secrete insulin in response to membrane depolarization. Yet these ICCs remained glucose-unresponsive because of the minimal expression of GLUT-2. We thus attempted to study another potential morphogenic candidate, Ang II. / To further test whether a functional RAS is present and if so, whether it regulates islet development in vivo, we employed a mouse embryo model at different embryonic days and reported a stronger AT2 receptor expression during the 2nd developmental transition of pancreas development. AT2 receptor blockade from e8.0 resulted in abnormalities in fetal pancreatic development. Neonates from these mother mice displayed destructed pancreas/islet architecture, a hampered ability in glucose-stimulated insulin-secretion possibly attributed to a decreased ratio of beta-cell to alpha-cell, and an impaired glucose tolerance at 4-wk old. / Leung, Kwan Keung. / Adviser: Po Sing Leung. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 254-284). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.