The diabetic β-cell: hyperstimulated vs. hyperexcited

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.

Figure 1

Dependence of islet excitation and intracellular [Ca²⁺] on stimulatory [glucose]. In the normal wild type (WT) pancreatic β-cell, elevated [glucose] leads to insulin secretion via coupling to electrical excitation. By removing the K_ATP channel sensitivity to metabolic state, this link can be broken and the effects of hyperstimulation of metabolism and hyperexcitation can be separated. Islets lacking K_ATP channels (e.g. SUR1^−/− and Kir6.2^−/−) will be chronically excited, even when metabolism is not stimulated (pink). Conversely, islets with ATP-insensitive K_ATP subunits (e.g. Kir6.2[ΔN30]) will be inexcitable, even when metabolism is stimulated (blue).