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Mitochondrial Dynamics: Regulation of Insulin Secretion and Novel Quantification Methods
Başlık:
Mitochondrial Dynamics: Regulation of Insulin Secretion and Novel Quantification Methods
Yazar:
Miller, Nathanael Alan, author.
ISBN:
9780438066915
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (167 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Orian Shirihai; Jude Deeney Committee members: Tamar Aprahamian; Susan Fried; Marc Liesa.
Özet:
The recent surge in Type 2 Diabetes (T2D) has renewed interest in the study of cellular metabolism -- which mitochondria tightly control. Previous work has shown mitochondrial dysfunction plays a critical role in the development of metabolic diseases, such as T2D. The pancreatic beta-cell synthesizes and secretes insulin in vivo in response to diverse fuel signals such as glucose, fatty acids, and amino acids; failure or loss of beta-cell mass is a hallmark of T2D. Pancreatic beta-cell mitochondria are dynamic organelles living a life of fusion, fission, and movement collectively called mitochondrial dynamics. Mitochondrial fusion is impaired in obesity and models of obesity, while basal secretion of insulin is elevated. Previous studies demonstrate that hyperinsulinemia alone is sufficient to induce insulin resistance, yet the relationship between mitochondrial morphology and basal insulin secretion has not yet been studied. Here, we investigated the link between loss of mitochondrial fusion and insulin secretion at basal glucose concentrations by reducing the expression of mitofusin 2 (Mfn2), which controls mitochondrial morphology and metabolism. We found that forced mitochondrial fragmentation caused increased insulin secretion at basal glucose concentrations. In addition, fragmentation of mitochondria enhanced the secretory response of islets to palmitate at nonstimulatory glucose concentrations and increased fatty acid uptake and oxidation in a cell model of pancreatic beta-cells. We developed unique solutions to challenges posed by the measurement of mitochondrial dynamics via confocal microscopy by using novel image analysis techniques, including a novel method of mitochondrial segmentation. This technique also revealed novel biology of brown adipose tissue mitochondria dependent on their localization within the cell. Our findings demonstrate that changes to mitochondrial dynamics in the beta-cell can lead to increased insulin secretion at basal glucose concentrations. These data support the possibility that hyperinsulinemia and the downstream outcome of insulin resistance can be initiated by altered mitochondrial function in the beta-cell independently of other tissues. By uncovering a new process that governs basal insulin secretion, we provide novel targets for regulation, such as mitochondrial morphology or fatty acid induced insulin secretion that may present new approaches to treatment of diabetes.
Notlar:
School code: 0017
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(679039.1) | 679039-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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