Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K+ channels in mouse B cells.

Abstract

Glucose stimulation of insulin release involves closure of ATPsensitive K+ channels (K+-ATP channels), depolarization, and Ca" influx in B cells. However, by using diazoxide to open K+-ATP channels, and 30 mM K to depolarize the membrane, we could demonstrate that another mechanism exists, by which glucose can control insulin release independently from changes in K+-ATP channel activity and in membrane potential (Gembal et al. 1992. J. Clin. Invest. 89:1288-1295). A similar approach was followed here to investigate, with mouse islets, the nature of this newly identified mechanism. The membrane potential-independent increase in insulin release produced by glucose required metabolism of the sugar and was mimicked by other metabolized secretagogues. It also required elevated levels of cytoplasmic CO', but was not due to further changes in CO'. It could not be ascribed to acceleration of phosphoinositide metabolism, or to activation of protein kinases A or C. Thus, glucose did not increase inositol phosphate levels and hardly affected cAMP levels. Moreover, increasing inositol phosphates by vasopressin or cAMP by forskolin, and activating protein kinase C by phorbol esters did not mimic the action of glucose on release, and down-regulation of protein kinase C did not prevent these effects. On the other hand, it correlated with an increase in the ATP/ADP ratio in islet cells. We suggest that the membrane potential-independent control of insulin release exerted by glucose involves changes in the energy state of B cells. (J. Clin. Invest. 1993.91:871-880.)

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

“…In the diazoxide experiments, the cells, in presence of 250 μmol/l diazoxide and 30 mmol/l KCl, were stimulated with 2.5 mmol/l glucose and then with 15 mmol/l glucose. The second incubation at 15 mmol/l glucose, reflecting the amplifying effect of the sugar on insulin secretion [22], was significantly reduced in REST-expressing INS-1E cells (ESM Fig. 1a).…”

Glucose-regulated pulsatile insulin release from mouse islets via the K(ATP) channel-independent pathway

“…Glucose also has a stimulatory effect on insulin secretion independent of the K ATP channel. This pathway can be studied by keeping the K ATP (18,19). The K ATP channel-independent glucosesignaling pathway has been demonstrated also in human islets (23).…”

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). Kelly et al (1994) suggested that the enhanced phosphoinositide (PI) response was partially Ca 2+ -dependent and might involve activation of distinct isozymes of PLC expressed in the islets.…”

“…However, current information about the cellular localization of PLC isozymes has so far been mainly limited to the brain and related organs (Ross et al, 1989;Peng et al, 1997). Therefore the pancreatic islet appears to be an interesting region in which to study the distribution of PLC isozymes mainly to provide clues to solving the controversy concerning the role of PLC isozymes in insulin secretion (Gembal et al, 1993;Vadakekalam et al, 1997). Moreover, several protein kinase C (PKC) isozymes, the downstream molecules for the PLC signaling pathway, were found from mouse pancreatic islets (Knutson and Hoenig, 1997).…”