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 ... read moreβ-cells. 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
β-cell mitochondria respond to physiological and toxic nutrient environments and,
in turn, how they affect β-cell function in response to these nutrients. We first
characterized mitochondrial dynamics in β-cells. Mitochondria go through
continuous cycles of fusion and fission, yet a description of β-cell mitochondrial
dynamics and how fusion and fission contribute to β-cell function had not
previously been investigated. Despite their short size, β-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 β-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, β-cell
mitochondria became fragmented, while other islet cell types retained normal
mitochondrial morphology. βMfn2KO 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 βMfn2KO 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 β-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
- Component ID:
- tufts:20575
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- DCA Citation Guide EndNote
