On the role of IRS2 in the regulation of functional β-cell mass

Abstract

The proper regulation of blood glucose homeostasis in mammals requires an adequate relation between the capacity to produce insulin and metabolic demand. Insulin receptor substrate proteins (IRS) are signalling intermediates that are required to keep this balance because they are needed for insulin action in target tissues but also for insulin production in pancreatic β-cells. The total functional β-cell mass in an individual sets the limit of how much insulin can be produced at a given time. It can change adaptively to meet demand and studies in vivo indicate that the regulation of β-cell mass involves IRS2, while IRS1 is only required for proper insulin production in β-cells. Overexpression studies in isolated islets have shown that IRS2, but not IRS1 or Shc, is sufficient to induce proliferation of β-cells and to protect against d-glucose-induced apoptosis. In light of the finding that many growth factors can regulate Irs2 in islets, this signalling intermediate could balance capacity for insulin production with demand. This review summarizes observations in mouse models and in primary β-cells and proposes a new hypothetical model of how IRS2 might control β-cell mass.