The Role of Mitochondrial Dynamics in Pancreatic Beta Cell Function and the Development of Type 2 Diabetes.
Stiles, Linsey.
2011
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Abstract: The prevalence of obesity and type 2 diabetes is increasing rapidly in all age groups. Therefore, a better understanding of the pathogenesis of these diseases is critical for the development of novel treatments and interventions. Mitochondria play an important role in the regulation of metabolism throughout the body. Specifically, they have a particularly critical role in pancreatic -cel... read morels. Mitochondria work to integrate nutrient signals, such as glucose, and generate secretagogues for both the triggering and amplifying pathways of insulin secretion. We sought to further describe how -cell mitochondria respond to physiological and toxic nutrient environments and, in turn, how they affect -cell function in response to these nutrients. We first characterized mitochondrial dynamics in -cells. Mitochondria go through continuous cycles of fusion and fission, yet a description of -cell mitochondrial dynamics and how fusion and fission contribute to -cell function had not previously been investigated. Despite their short size, -cell mitochondria undergo continuous cycles of fusion and fission. A toxic, high-nutrient environment, termed glucolipotoxicity, leads to mitochondrial fragmentation in vitro, which is the result of inhibition of mitochondrial fusion. Maintaining mitochondrial morphology by inhibiting mitochondrial fission restored mitochondrial fusion capacity and prevented the cell death caused by glucolipotoxicity. To examine the role of -cell mitochondrial fusion in vivo, we measured the expression of the mitochondrial fusion protein, Mfn2, in islets from animals fed a high-fat diet. We observed a decrease in Mfn2 expression in the islets of these animals as well as in other animal models of diabetes. To determine the role of reduced fusion in diet-induced obesity and diabetes, we excised Mfn2 from insulin-producing cells. In the absence of Mfn2, -cell mitochondria became fragmented, while other islet cell types retained normal mitochondrial morphology. Mfn2KO mice became obese and exhibited metabolic dysfunction, including impaired glucose tolerance that occurred before the development of obesity. These mice also displayed an increase in basal insulin secretion and uncoordinated glucose-stimulated insulin secretion. Basal hypersecretion of insulin is a hallmark of metabolic dysfunction; however, the mechanism behind increased insulin secretion is still unclear. Consequently, we investigated mechanisms that could contribute to hypersecretion in Mfn2KO islets. We found that these islets have increased basal and uncoupled oxygen consumption indicative of a harder working, less efficient electron transport chain. Similarly, both acute fuel challenges and chronic elevation of nutrients induced proton leak in -cells. We found that the induction of leak in response to nutrients is regulated, in part, by reactive oxygen species (ROS) and the adenine nucleotide translocase (ANT). We hypothesize that ROS generation in response to stimulatory fuel levels regulates proton leak in the islet, in part, through the ANT. This leads to increased flux through the TCA cycle and the generation of TCA-cycle derived secretagogues. These metabolic species contribute to the amplifying pathway of insulin secretion. When chronic, high levels of nutrients are present, oscillations in this system no longer occur and the continuous generation of TCA-cycle derived secretagogues would lead to increased basal insulin secretion. Taken together, all of these results suggest that nutrient-induced disruption of mitochondrial fusion may underlie the metabolic dysfunctions that contribute to the development of diabetes.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisors: Orian Shirihai, and Martin Beinborn.
Committee: Richard Shader, John Castellot, and Jude Deeney.
Keyword: Pharmacology.read less - ID:
- m900p643q
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