Damaging Loss of Self-Control by Stressed β-Cells
- Centre for Diabetes, Blizard Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, U.K.
- Corresponding author: Mark J. Holness, .
Only 15–20% of obese individuals with severe insulin resistance develop type 2 diabetes mellitus (T2DM). In healthy individuals, β-cell compensation ensures that enhanced glucose-stimulated insulin secretion (GSIS) balances the degree of insulin resistance. However, individuals predisposed to T2DM are unable to secrete the increased insulin required to compensate for insulin resistance in order to maintain glucose and lipid homeostasis. It is unclear why certain insulin-resistant individuals compensate with enhanced islet function and β-cell hyperplasia and remain healthy, while others develop β-cell failure characterized by insulin secretory defects coupled with relative loss of β-cell mass. In this issue of Diabetes, Halperin et al. (1) highlight the potential importance for β-cell dysfunction and T2DM of insulin resistance in the islet itself. Their observations provide novel insights into the battery of insults that can adversely impact β-cell function.
The endocrine pancreas contains ∼1 million islets of Langerhans that comprise 2–3% of total pancreatic mass. Major cell types include β-cells that secrete insulin and glucagon-secreting α-cells. The integrated secretory responses of islet cells exceed those of segregated islet cell lines, indicating that interactions between individual islet cells are required for normal secretory function (2–5). The actions of individual cells comprising the islet may also be modulated by responses to their own secretions.
Insulin exerts its effects in target cells through binding to and activating its cell surface receptors. This is followed by an intricate and complex web of signaling pathways beginning with tyrosine phosphorylation of intracellular substrates including the insulin receptor substrate (IRS) proteins (Fig. 1). The finding that both the insulin receptor (IR) and the IRS proteins are expressed in rodent β-cells (6,7) and that all downstream elements belonging to the IR signaling pathway are expressed in human pancreatic β-cells (8) led to the prospect of a potential role …