@phdthesis{Kluth2012,
  author    = {Kluth, Oliver},
  title     = {Einfluss von Glucolipotoxizit{\"a}t auf die Funktion der β-Zellen diabetessuszeptibler und -resistenter Mausst{\"a}mme},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-61961},
  school      = {Universit{\"a}t Potsdam},
  year      = {2012},
  abstract  = {Ziel der vorliegenden Arbeit war es, die Auswirkungen von Glucose- und Lipidtoxizit{\"a}t auf die Funktion der β-Zellen von Langerhans-Inseln in einem diabetesresistenten (B6.V-Lepob/ob, ob/ob) sowie diabetessuszeptiblen (New Zealand Obese, NZO) Mausmodell zu untersuchen. Es sollten molekulare Mechanismen identifiziert werden, die zum Untergang der β-Zellen in der NZO-Maus f{\"u}hren bzw. zum Schutz der β-Zellen der ob/ob-Maus beitragen. Zun{\"a}chst wurde durch ein geeignetes di{\"a}tetisches Regime in beiden Modellen durch kohlenhydratrestriktive Ern{\"a}hrung eine Adipositas(Lipidtoxizit{\"a}t) induziert und anschließend durch F{\"u}tterung einer kohlenhydrathaltigen Di{\"a}t ein Zustand von Glucolipotoxizit{\"a}t erzeugt. Dieses Vorgehen erlaubte es, in der NZO-Maus in einem kurzen Zeitfenster eine Hyperglyk{\"a}mie sowie einen β-Zelluntergang durch Apoptose auszul{\"o}sen. Im Vergleich dazu blieben ob/ob-M{\"a}use l{\"a}ngerfristig normoglyk{\"a}misch und wiesen keinen β-Zelluntergang auf. Die Ursache f{\"u}r den β-Zellverlust war die Inaktivierung des Insulin/IGF-1-Rezeptor-Signalwegs, wie durch Abnahme von phospho-AKT, phospho-FoxO1 sowie des β-zellspezifischen Transkriptionsfaktors PDX1 gezeigt wurde. Mit Ausnahme des Effekts einer Dephosphorylierung von FoxO1, konnten ob/ob-M{\"a}use diesen Signalweg aufrechterhalten und dadurch einen Verlust von β-Zellen abwenden. Die glucolipotoxischen Effekte wurden in vitro an isolierten Inseln beider St{\"a}mme und der β-Zelllinie MIN6 best{\"a}tigt und zeigten, dass ausschließlich die Kombination hoher Glucose und Palmitatkonzentrationen (Glucolipotoxizit{\"a}t) negative Auswirkungen auf die NZO-Inseln und MIN6-Zellen hatte, w{\"a}hrend ob/ob-Inseln davor gesch{\"u}tzt blieben. Die Untersuchung isolierter Inseln ergab, dass beide St{\"a}mme unter glucolipotoxischen Bedingungen keine Steigerung der Insulinexpression aufweisen und sich bez{\"u}glich ihrer Glucose-stimulierten Insulinsekretion nicht unterscheiden. Mit Hilfe von Microarray- sowie immunhistologischen Untersuchungen wurde gezeigt, dass ausschließlich ob/ob-M{\"a}use nach Kohlenhydratf{\"u}tterung eine kompensatorische transiente Induktion der β-Zellproliferation aufwiesen, die in einer nahezu Verdreifachung der Inselmasse nach 32 Tagen m{\"u}ndete. Die hier erzielten Ergebnisse lassen die Schlussfolgerung zu, dass der β-Zelluntergang der NZO-Maus auf eine Beeintr{\"a}chtigung des Insulin/IGF-1-Rezeptor-Signalwegs sowie auf die Unf{\"a}higkeit zur β- Zellproliferation zur{\"u}ckgef{\"u}hrt werden kann. Umgekehrt erm{\"o}glichen der Erhalt des Insulin/IGF-1-Rezeptor-Signalwegs und die Induktion der β-Zellproliferation in der ob/ob-Maus den Schutz vor einer Hyperglyk{\"a}mie und einem Diabetes.},
  language  = {de}
}
@phdthesis{Kehm2019,
  author    = {Kehm, Richard},
  title     = {The impact of metabolic stress and aging on functionality and integrity of pancreatic islets and beta-cells},
  doi       = {10.25932/publishup-44109},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-441099},
  school      = {Universit{\"a}t Potsdam},
  pages     = {VI, 138},
  year      = {2019},
  abstract  = {The increasing age of worldwide population is a major contributor for the rising prevalence of major pathologies and disease, such as type 2 diabetes, mediated by massive insulin resistance and a decline in functional beta-cell mass, highly associated with an elevated incidence of obesity. Thus, the impact of aging under physiological conditions and in combination with diet-induced metabolic stress on characteristics of pancreatic islets and beta-cells, with the focus on functionality and structural integrity, were investigated in the present dissertation. Primarily induced by malnutrition due to chronic and excess intake of high caloric diets, containing large amounts of carbohydrates and fats, obesity followed by systemic inflammation and peripheral insulin resistance occurs over time, initiating metabolic stress conditions. Elevated insulin demands initiate an adaptive response by beta-cell mass expansion due to increased proliferation, but prolonged stress conditions drive beta-cell failure and loss. Aging has been also shown to affect beta-cell functionality and morphology, in particular by proliferative limitations. However, most studies in rodents were performed under beta-cell challenging conditions, such as high-fat diet interventions. Thus, in the first part of the thesis (publication I), a characterization of age-related alterations on pancreatic islets and beta-cells was performed by using plasma samples and pancreatic tissue sections of standard diet-fed C57BL/6J wild-type mice in several age groups (2.5, 5, 10, 15 and 21 months). Aging was accompanied by decreased but sustained islet proliferative potential as well as an induction of cellular senescence. This was associated with a progressive islet expansion to maintain normoglycemia throughout lifespan. Moreover, beta-cell function and mass were not impaired although the formation and accumulation of AGEs occurred, located predominantly in the islet vasculature, accompanied by an induction of oxidative and nitrosative (redox) stress. The nutritional behavior throughout human lifespan; however, is not restricted to a balanced diet. This emphasizes the significance to investigate malnutrition by the intake of high-energy diets, inducing metabolic stress conditions that synergistically with aging might amplify the detrimental effects on endocrine pancreas. Using diabetes-prone NZO mice aged 7 weeks, fed a dietary regimen of carbohydrate restriction for different periods (young mice - 11 weeks, middle-aged mice - 32 weeks) followed by a carbohydrate intervention for 3 weeks, offered the opportunity to distinguish the effects of diet-induced metabolic stress in different ages on the functionality and integrity of pancreatic islets and their beta-cells (publication II, manuscript). Interestingly, while young NZO mice exhibited massive hyperglycemia in response to diet-induced metabolic stress accompanied by beta-cell dysfunction and apoptosis, middle-aged animals revealed only moderate hyperglycemia by the maintenance of functional beta-cells. The loss of functional beta-cell mass in islets of young mice was associated with reduced expression of PDX1 transcription factor, increased endocrine AGE formation and related redox stress as well as TXNIP-dependent induction of the mitochondrial death pathway. Although the amounts of secreted insulin and the proliferative potential were comparable in both age groups, islets of middle-aged mice exhibited sustained PDX1 expression, almost regular insulin secretory function, increased capacity for cell cycle progression as well as maintained redox potential. The results of the present thesis indicate a loss of functional beta-cell mass in young diabetes-prone NZO mice, occurring by redox imbalance and induction of apoptotic signaling pathways. In contrast, aging under physiological conditions in C57BL/6J mice and in combination with diet-induced metabolic stress in NZO mice does not appear to have adverse effects on the functionality and structural integrity of pancreatic islets and beta-cells, associated with adaptive responses on changing metabolic demands. However, considering the detrimental effects of aging, it has to be assumed that the compensatory potential of mice might be exhausted at a later point of time, finally leading to a loss of functional beta-cell mass and the onset and progression of type 2 diabetes. The polygenic, diabetes-prone NZO mouse is a suitable model for the investigation of human obesity-associated type 2 diabetes. However, mice at advanced age attenuated the diabetic phenotype or do not respond to the dietary stimuli. This might be explained by the middle age of mice, corresponding to the human age of about 38-40 years, in which the compensatory mechanisms of pancreatic islets and beta cells towards metabolic stress conditions are presumably more active.},
  language  = {en}
}