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YAMAGATA Lab.
Department of Medical Biochemistry
Faculty of Life Sciences, Kumamoto University
Japan Agency for Medical Research and Development (AMED)
“Project for Elucidation and Control of Aging Mechanisms”
Center for Solid and Organ Aging Research (2017-2022)
Attached to the Graduate School of Life Sciences, Kumamoto University
Collaborate with Research Center for Metabolic Regulation for Healthy Longevity (2018-)
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Research content
Oxygen environment and oxygen metabolism in pancreatic β-cells
Why are β cells starved for oxygen?
How does β-cell function change under hypoxia?
Pancreatic β-cells are mitochondria-rich tissues and consume a large amount of oxygen because a large amount of ATP is required during insulin secretion. For this reason, it was found that pancreatic β-cells are more susceptible to hypoxia than other cells, even with a slight decrease in oxygen supply (JBC2011). Furthermore, mice with obesity and diabetes have increased insulin demand, and it was thought that hypoxia would occur due to the collapse of the oxygen supply-demand balance.It is still unclear what kind of molecular mechanism causes hypoxia.(Research subject ①).
Hypoxia also reduces pancreatic β-cell function (insulin secretion and β-cell proliferation),We have found various gene expression declines (PLoSONE2014, JBC2017),It is still unknown what factors are involved in this process.(Research subject 2)
The homeostasis of oxygen metabolism in β-cells worsens due to this vicious cycle in which more oxygen is required to lower blood sugar despite the lack of oxygen. We suspected that deterioration of the oxygen environment of pancreatic β cells caused by obesity (insulin resistance: a state in which insulin does not work) might be one of the important mechanisms for the onset or exacerbation of diabetes. Our research focuses on the mechanism of deficiency and the cellular response mechanism (figure below).
Pancreatic β-cell dysfunction by hypoxic stress
What causes β-cell hypoxia?
How low oxygen compromises β-cell function ?
Cellular oxygen levels are determined by oxygen supply and oxygen consumption.β-cells, a mitochondria rich tissue consume a lot of oxygen to produce ATP for insulin secretion, which renders them severely hypoxic even when surrounding oxygen level slightly becomes lower (JBC2011). Besides hypoxia response gene expression (glycolytic genes etc.) was upregulated in a HIF-1α dependent manner and functionalβ-cell gene expression (such asMafaandSlc2a2) was downregulated in a HIF-1αindependent manner under hypoxic conditions (PLoSONE2014, JBC2017).
Acute or chronic hypoxia lowers insulin secretion from pancreaticβ-cells while insulin secretion defect becomes a trigger of hyperglycemia, leading to further increase of insulin demand.β-cell function and systemic glucose homeostasis.β-cell hypoxia" could be a trigger of onset or progression of diabetes, and try to uncover thisβ-cell deterioration mechanism by hypoxia.
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