Philippe de Timary

Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets

Changes in the ATP:ADP ratio in pancreatic B cells may participate in the regulation of insulin secretion by glucose. Here, we have investigated the possible role of guanine nucleotides. Mouse islets were incubated in a control medium (when K+-ATP channels are the major site of regulation) or in a high K+ medium (when glucose modulates the effectiveness of cytosolic Ca2+ on exocytosis). Glucose induced a concentration-dependent (0-20 mM) increase in GTP and a decrease in GDP in both types of medium, thus causing a progressive rise of the GTP:GDP ratio. ATP and ADP levels were 4-5-fold higher but varied in a similar way as those of guanine nucleotides. Insulin secretion was inversely correlated with ADP and GDP levels and positively correlated with the ATP:ADP and GTP:GDP ratios between 6 and 20 mM glucose in control medium and between 0 and 20 mM glucose in high K+ medium. The increases in the GTP:GDP and ATP:ADP ratios induced by a rise of glucose were faster than the decreases induced by a fall in glucose, but the changes of both ratios were again parallel. In conclusion, glucose causes large, concentration-dependent changes in guanine as well as in adenine nucleotides in islet cells. This raises the possibility that both participate in the regulation of nutrient-induced insulin secretion.

Signal transduction: regulation of insulin secretion by changes in Ca2+ concentration and action in pancreatic B-cells

Defects in the regulation of insulin secretion from pancreatic β-cells largely contribute to the perturbations of glucose homeostasis in noninsulin-dependent diabetes (Type 2 diabetes). Under physiological conditions, the rate of insulin release is controlled by variations in the concentration of circulating nutrients and by various hormonal and neural signals. Hormones and neurotransmitters modulate β-cell function by binding to membrane receptors and activating transduction pathways essentially similar to those existing in other cell types. In contrast, glucose, the major physiological stimulus, does not bind to a receptor but must be metabolized to induce insulin secretion. The acceleration of β-cell metabolism results in the production of a number of potential second messengers that might trigger or modulate exocytosis of storage granules containing insulin. Another peculiarity of β-cells is not so much that they are electrically excitable, but that their membrane potential is controlled by metabolism. The electrical activity induced by glucose involves marked changes in the flux of many ions across the plasma membrane. One of these ions, Ca2+, plays a pre-eminent role in the regulation of insulin secretion. The first indication that Ca2+ ions are essential players in stimulus-secretion coupling in β-cells dates back to the observation that the stimulation of insulin secretion by glucose and other agents was abrogated by omission of extracellular Ca2+.