Investigating the role of PHD3 in mouse and human β-cell glucose metabolism

Cuozzo, Federica ORCID: 0000-0001-8399-1281 (2022). Investigating the role of PHD3 in mouse and human β-cell glucose metabolism. University of Birmingham. Ph.D.

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Abstract

Prolyl-4-hydroxylase 3 (PHD3) is a dioxygenase that uses oxygen and α-ketoglutarate (α-KG) to hydroxylate prolyl residues. Although historically known to hydroxylate the hypoxia-inducible factor α-subunits (HIFα), PHD3 has been associated with several other targets, involved in numerous cellular events. Given the importance of the PHD3 co-factor, α-KG, for the amplification of glucose-stimulated insulin secretion, PHD3 represents a strong candidate for the regulation of glucose homeostasis. Previous work highlight a role for PHD3 in liver insulin sensitivity and insulin secretion from immortalized INS-1 832/13 cells. Whether and how PHD3 might influence primary β-cell function, both in vivo and in vitro, remains unknown.

In this thesis, a central role for PHD3 in β-cell glucose metabolism is described, through the characterization of a β-cell specific PHD3 knockout (βPHD3KO) mouse model. In the early phase of metabolic stress, induced by high fat feeding, βPHD3KO islets rewire their metabolism to rely on the β-oxidation of fatty acids to fuel the TCA cycle for insulin secretion. At the same time, the glycolytic supply is diverted into the direct conversion of pyruvate to lactate. However, these adaptations lead to generalized β-cell failure in mice exposed to longer durations of high fat feeding. Finally, through gas chromatography-mass spectrometry (GC-MS)- and nuclear magnetic resonance (NMR)-based metabolomics, it is shown that results from the rodent model are likely to translate to human β-cells.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):