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dc.contributor.advisorShirihai, Orian S.en_US
dc.contributor.advisorCorkey, Barbara E.en_US
dc.contributor.authorAlsabeeh, Nouren_US
dc.date.accessioned2018-06-12T12:31:39Z
dc.date.available2018-06-12T12:31:39Z
dc.date.issued2018
dc.identifier.urihttps://hdl.handle.net/2144/29271
dc.description.abstractPancreatic beta cells sense fluctuations in circulating nutrients and adjust the rate of insulin secretion to maintain glucose homeostasis. Mitochondria integrate changes in nutrient flux to the generation of signals that modulate insulin secretion via oxidative phosphorylation. Type 2 Diabetes (T2D) is characterized by beta cell mitochondrial dysfunction and impairment of insulin secretion. Early stage progression of this disease in obese and pre-diabetic subjects is characterized by basal hypersecretion of insulin and increased insulin resistance in peripheral tissues including muscle, liver and adipose tissue. Whether basal hypersecretion of insulin or insulin resistance is the primary defect in T2D progression is still debated. The molecular mechanism underlying basal insulin hypersecretion and how it may lead to beta cell failure are not understood. Herein, we optimize a model of glucolipotoxicity that results in increased basal and reduced stimulated insulin secretion response. Furthermore, we show that pancreatic islets exposed to excess nutrients in vitro or isolated from high fat diet fed animals, have a decreased bioenergetic efficiency, which is characterized by increased mitochondrial proton leak. Leak represents the fraction of oxygen consumed that is not coupled to ATP production. We show that leak is sufficient to induce insulin secretion at basal glucose levels and that nutrient-induced insulin secretion at basal glucose is leak-dependent. Finally, we identify the mitochondrial permeability transition pore (PTP) as the source of the leak. Our findings suggest the PTP may be a potential therapeutic target to prevent/delay the onset of hyperinsulinemia in pre-diabetic subjects.en_US
dc.language.isoen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subjectPhysiologyen_US
dc.subjectCyclophilin Den_US
dc.subjectDiabetesen_US
dc.subjectInsulin secretionen_US
dc.subjectIsleten_US
dc.subjectMitochondriaen_US
dc.subjectProton leaken_US
dc.titleRole of mitochondrial dysfunction in the development of nutrient-induced hyperinsulinemiaen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2018-06-12T01:00:43Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplinePhysiologyen_US
etd.degree.grantorBoston Universityen_US


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Attribution-NonCommercial-ShareAlike 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International