Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells.

Abstract

Glucose stimulation of insulin release involves closure of ATPsensitive K+ channels, depolarization, and Ca2+ influx in B cells. Mouse islets were used to investigate whether glucose can still regulate insulin release when it cannot control ATP-sensitive K+ channels. Opening ofthese channels by diazoxide (100-250 Mmol/liter) blocked the effects of glucose on B cell membrane potential (intracellular microelectrodes), free cytosolic Ca2+ (fura-2 method), and insulin release, but it did not prevent those of high K (30 mmol/liter). K-induced insulin release in the presence of diazoxide was, however, dose dependently increased by glucose, which was already effective at concentrations (2-6 mmol/liter) that are subthreshold under normal conditions (low K and no diazoxide). This effect was not accompanied by detectable changes in B cell membrane potential.Measurements of 'Ca fluxes and cytosolic Ca2" indicated that glucose slightly increased Ca2+ influx during the first minutes of depolarization by K, but not in the steady state when its effect on insulin release was the largest. In conclusion, there exists a mechanism by which glucose can control insulin release independently from changes in K+-ATP channel activity, in membrane potential, and in cytosolic Ca2+. This mechanism may serve to amplify the secretory response to the triggering signal (closure of K+-ATP channels -depolarization -Ca2" influx) induced by glucose. (J. Clin. Invest. 1992. 89:1288-1295

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

“…It was first shown by Jean-Claude Henquin [50,51] and Toru Aizawa [52] and their collaborators that glucose could stimulate insulin secretion in a K ATP -channel independent manner. In a now widely used experimental paradigm, diazoxide was added to inhibit the closure of K ATP -channels by glucose (Fig.…”

“…Despite the presence of diazoxide, the addition of stimulatory glucose concentrations promotes insulin secretion, resembling the slowly increasing second phase of secretion (Fig. 8) [50,51].…”

Mathematical modeling and statistical analysis of calcium-regulated insulin granule exocytosis in β-cells from mice and humans

“…The amplifying pathway is also referred to as the KATP-independent pathway, and it is not activated until the triggering pathway has depolarized the membrane and increased intracellular Ca 2+ . The amplifying pathway can be investigated under depolarized conditions bypassing the KATP-channel such as when stimulating insulin secretion using high K + in presence of diazoxide (Gembal et al, 1992) or performing patch-clamp capacitance measurements Ammälä et al, 1993b) The most known amplifying factors are ATP and cAMP (Gillis and Misler, 1993;Renström et al, 1997). Other potentiating factors include MalonylCoA (Prentki et al, 1992), glutamate (Maechler and Wollheim, 1999) and NADPH (Ivarsson et al, 2005).…”

Immunohistochemical localization of eight phospholipase C isozymes in pancreatic islets of the mouse

“…Glucose can augment insulin secretion independently of K + channel closure, provided that the cytoplasmic free Ca 2+ concentration is elevated (Gembal et al, 1992). A role for phospholipase C (PLC) in this phenomenon has been both claimed (Turk et al, 1993;Zawalich and Zawalich, 1997) and refuted (Gembal et al, 1993;Vadakekalam et al, 1997).…”