Abstract
Hyperglycaemia has multiple effects on β-cells, some clearly prosecretory, including hyperplasia and elevated insulin content, but eventually, a 'glucotoxic' effect which leads to pancreatic β-cell dysfunction, reduced β-cell mass and insulin deficiency, is an important part of diabetes pathophysiology. Myriad underlying cellular and molecular processes could lead to such dysfunction. High glucose will stimulate glycolysis and oxidative phosphorylation, which will in turn increase β-cell membrane excitability through K(ATP) channel closure. Chronic hyperexcitability will then lead to persistently elevated [Ca(2+)](i), a key trigger to insulin secretion. Thus, at least a part of the consequence of 'hyperstimulation' by glucose has been suggested to be a result of 'hyperexcitability' and chronically elevated [Ca(2+)](i). This link is lost when the [glucose], K(ATP) -channel activity link is broken, either pharmacologically or genetically. In isolated islets, such studies reveal that hyperexcitability causes a largely reversible chronic loss of insulin content, but in vivo chronic hyperexcitability per se does not lead to β-cell death or loss of insulin content. On the other hand, chronic inexcitability in vivo leads to systemic diabetes and consequential β-cell death, even while [Ca(2+)](i) remains low.