The broad long term objective of this research is to obtain new clues about metabolic signals for insulin secretion. The immediate purpose of this project is to gain an understanding of mitochondrial hydrogen shuttles and their role in metabolizable secretagogue-induced insulin secretion in the pancreatic beta cell. Much of our effort will focus on the mitochondrial glycerol phosphate dehydrogenase (mGPD), the key enzyme in the glycerol phosphate shuttle, to test the hypothesis that mGPD plays an important role in cellular metabolism dehydrogenase (mGPD), the key enzyme in the glycerol phosphate shuttle, to test the hypothesis that mGPD plays an important role in cellular metabolism, including insulin secretion. mGPD is abundant in the normal beta cell, but is reduced in diabetics humans and in rodent models. While a mouse strain (BALB/cHeA) exists that possesses a naturally-occurring null nutation of the cytosolic glycerol phosphate dehydrogenase (the cytosolic half of the shuttle), no mutations or potent inhibitors have been described to eliminate mGPD activity.
The first aim i s to use a recently produced mGPD knockout mouse and the cytosolic null animal to study the role of the glycerol phosphate shuttle and its component enzymes in the whole animals and in isolated islets and mitochondria.
The second aim i s to continue studies of the mGPD promoter to determine factors responsible for high mGPD expression in the beta cell and its decrease in diabetes.
The third aim of this project is to test the hypothesis that there are NADP(H) shuttles in the pancreatic beta cells besides the pyruvate malate shuttle. Much recent evidence suggests that the pyruvate malate shuttle is present in islets. This shuttle utilizes pyruvate carboxylase in the mitochondrial matrix as the enzyme that maintains unidirectionality of the shuttle, and malic enzyme in the cytosol as the NADP(H) oxidoreductase. It is proposed that other shuttles may exist in the beta cell that require the carboxylase, but in combination with other cytosolic with the cytosolic dehydrogenases. Since the levels of both mGPD and pyruvate carboxylase, but in combination with other cytosolic dehydrogenases. Since the levels of both mGPD and pyruvate carboxylase in the beta cell are among the highest in the body, but are decreased in the beta cell in non-insulin dependent diabetes (NIDDM), studies of their regulation will increase the understanding of fuel-stimulated insulin secretion and its defects in NIDDM.
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