| Summary: | <p>Chronic hyperglycaemia severely impairs the coupling between pancreatic β-cell glucose metabolism and insulin secretion that forms an essential part of blood glucose homeostasis. This thesis focuses on two effects of hyperglycaemia-induced alterations in β-cell metabolism: a decline in insulin biosynthesis and accumulation of glycogen.</p>
<p>Chronic hyperglycaemia results in large reductions in insulin mRNA levels and insulin content. In this thesis, I show that the severity of the decline in insulin biosynthesis depends on the level and duration of hyperglycaemia, both in intact islets and in β-cell lines. I then explore the metabolic signals that cause this loss, using the rat β-cell line INS-1 832/13. Downregulation of insulin gene expression was prevented by glucokinase inhibition and induced by GAPDH inhibition, indicating that accumulation of glycolytic intermediates downstream of glucokinase and upstream of GAPDH was responsible. Further experiments using a non-metabolisable glucose analogue suggested that glucose-6-phosphate is the most critical of these metabolites.</p>
<p>Chronic hyperglycaemia also results in the formation of large glycogen deposits. Since β-cells do not normally store glycogen, the causes and consequences of β-cell glycogen accumulation are incompletely understood and contested. In this thesis, I explore how changes in glucose metabolism and the AMPK/mTOR signalling axis relate to increased glycogen storage during hyperglycaemia. Glycogen accumulation was prevented by inhibition of the gluconeogenic enzyme fructose-1,6-bisphosphatase and by inhibition of mTORC1 signalling through S6K1 but was increased by AMPK activation. Glycogen accumulation appears to be driven both by direct effects of glucose-6-phosphate and indirect effects of the accumulation of glycolytic intermediates, including activation of mTORC1. Further work is needed to determine whether glycogen affects β-cell function, such as by interfering with metabolism-secretion coupling or impairing autophagy.</p>
<p>These studies help to clarify the mechanisms by which diabetes/chronic hyperglycaemia inhibits the principal function of pancreatic β-cells, the production of insulin.</p>
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