Glucose-sensing mechanisms in pancreatic beta-cells

Abstract

The appropriate secretion of insulin from pancreatic beta-cells is critically important to the maintenance of energy homeostasis. The beta-cells must sense and respond suitably to postprandial increases of blood glucose, and perturbation of glucose-sensing in these cells can lead to hypoglycaemia or hyperglycaemias and ultimately diabetes. Here, we review beta-cell glucose-sensing with a particular focus on the regulation of cellular excitability and exocytosis. We examine in turn: (i) the generation of metabolic signalling molecules; (ii) the regulation of beta-cell membrane potential; and (iii) insulin granule dynamics and exocytosis. We further discuss the role of well known and putative candidate metabolic signals as regulators of insulin secretion.

Figure 1

Proximal and distal events in pancreatic β-cell glucose-sensing. Proximal events, including glucose entry, glycolysis and entry into mitochondrial metabolism, lead to the generation of mitochondrial signals. These signals regulate insulin secretion by controlling distal effectors including membrane excitability, Ca²⁺ signalling, insulin granule recruitment and exocytosis. This scheme differs somewhat from the popular concept of ‘triggering’ and ‘amplifying’ pathways, which overlap within the distal mechanism.

Figure 2

Mitochondrial signal generation. NADH generated from pyruvate entry into the TCA cycle and NADH transported into the mitochondria by the malate–aspartate (Mal–Asp) and glycerol–phosphate (Gly–P) shuttles drive respiratory chain generation of a H⁺ gradient and hyperpolarization of the mitochondrial matrix. H⁺ gradient dissipation drives ATP production by ATP synthase. Matrix hyperpolarization promotes the entry of Ca²⁺ which further stimulates TCA cycle activity and export of ATP. The export of malate and citrate (also isocitrate, not shown) and subsequent conversion to pyruvate generates an increase in cytoplasmic NADPH. Also, exported citrate can be converted to acetyl-CoA and then malonyl-CoA which blocks the LC-CoA transporter carnitine palmitoyltransferase 1 (CPT1). This leads to an increase in cytoplasmic LC-CoA and potential downstream lipid-derived messengers such as diacylglycerol (DAG). Important signals for distal signalling are boxed in grey.

Figure 3

Stimulus–secretion coupling in the pancreatic β-cell. Glucose entry and mitochondrial metabolism increases the intracellular ATP-to-ADP ratio which leads to closure of K_ATP channels and membrane depolarization. This activates VDCCs, allowing influx of Ca²⁺ which triggers exocytosis of insulin granules. Kv channels also activate upon depolarization to mediate action potential repolarization, limiting Ca²⁺ entry and insulin secretion. Established and putative metabolic signalling molecules may regulate insulin secretion at a number of sites. These include the activity of ion channels, release of intracellular Ca²⁺ stores, mobilization and priming of secretory vesicles, and exocytosis. Here, we have shown the established (green), likely (yellow) and putative (red) regulatory interactions.