Synergistic interaction of glucose and neurohumoral agonists to stimulate islet phosphoinositide hydrolysis

1995 ◽  
Vol 269 (3) ◽  
pp. E575-E582 ◽  
Author(s):  
G. G. Kelley ◽  
K. C. Zawalich ◽  
W. S. Zawalich
Keyword(s):  
Insulin Secretion ◽  
Phospholipase C ◽  
Insulin Release ◽  
Synergistic Interaction ◽  
Highly Sensitive ◽  
Isolated Rat Islets ◽  
Pi Hydrolysis ◽  
First Time ◽  
Isolated Rat ◽  
Stimulation Of

The interaction between neurohumoral agonists and glucose to stimulate phosphoinositide (PI)-specific phospholipase C (PLC) and insulin release was examined. In freshly isolated rat islets, maximal glucose (40 mM), cholecystokinin (CCK; 300 nM), or carbachol (CCh; 1 mM) stimulated PI hydrolysis 6.5-, 9.8-, and 5.7-fold, respectively, above basal. The combination of glucose and CCK or of glucose and CCh, but not of CCK and CCh, synergistically increased PI hydrolysis 23.2- and 21.6-fold, respectively, indicating that these secretagogues activate PLC by distinct pathways and that there is an interaction between them. This synergy was maximal at physiological concentrations of stimulatory glucose (8-10 mM) and was paralleled by a marked synergistic stimulation of insulin secretion. The enhanced PI response was partially Ca2+ dependent and may involve the activation of distinct isozymes of PLC, which we identify in islets. These studies demonstrate for the first time a unique and highly sensitive synergistic interaction between glucose and neurohumoral agonists to stimulate PI hydrolysis, and they suggest that enhanced PI hydrolysis is important in the potentiation of glucose- and neurohumoral-stimulated insulin secretion.

Stimulation of insulin secretion from isolated rat islets by SaRI 59-801

Diabetes ◽  
1985 ◽  
Vol 34 (6) ◽  
pp. 548-552 ◽  
Author(s):  
R. L. Hanson ◽  
C. M. Isaacson ◽  
L. D. Boyajy
Keyword(s):  
Insulin Secretion ◽  
Rat Islets ◽  
Isolated Rat Islets ◽  
Isolated Rat ◽  
Stimulation Of

Role for GTP in glucose-induced phospholipase C activation in pancreatic islets

1996 ◽  
Vol 271 (1) ◽  
pp. E85-E95 ◽  
Author(s):  
J. Vadakekalam ◽  
M. E. Rabaglia ◽  
Q. H. Chen ◽  
S. A. Metz
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Phospholipase C ◽  
Insulin Release ◽  
Mycophenolic Acid ◽  
Phosphoinositide Hydrolysis ◽  
Intact Cells ◽  
Rat Islets ◽  
First Time ◽  
Permissive Role

We have previously demonstrated a permissive role for GTP in insulin secretion; in the current studies, we examined the effect of GTP on phospholipase C (PLC) activation to explore one possible mechanism for that observation. In rat islets preexposed to the GTP synthesis inhibitors mycophenolic acid (MPA) or mizoribine (MZ), PLC activation induced by 16.7 mM glucose (or by 20 mM alpha-ketoisocaproic acid) was inhibited 63% without altering the labeling of phosphoinositide substrates. Provision of guanine, which normalizes islet GTP content and insulin release, prevented the inhibition of PLC by MPA. Glucose-induced phosphoinositide hydrolysis was blocked by removal of extracellular Ca2+ or by diazoxide. PLC induced directly by Ca2+ influx (i.e., 40 mM K+) was reduced 42% in MPA-pretreated islets but without inhibition of the concomitant insulin release. These data indicate that glucose-induced PLC activation largely reflects Ca2+ entry and demonstrate (for the first time in intact cells) that adequate GTP is necessary for glucose (and Ca(2+)-)-induced PLC activation but not for maximal Ca(2+)-induced exocytosis.

scholarly journals Studies on the role of inositol trisphosphate in the regulation of insulin secretion from isolated rat islets of Langerhans

1985 ◽  
Vol 228 (3) ◽  
pp. 713-718 ◽  
Author(s):  
N G Morgan ◽  
G M Rumford ◽  
W Montague
Keyword(s):  
Insulin Secretion ◽  
Islets Of Langerhans ◽  
Islet Cells ◽  
Inositol Trisphosphate ◽  
Rat Islets ◽  
Isolated Rat Islets ◽  
Rat Islets Of Langerhans ◽  
Isolated Rat ◽  
Stimulation Of

Glucose (20 mM) and carbachol (1 mM) produced a rapid increase in [3H]inositol trisphosphate (InsP3) formation in isolated rat islets of Langerhans prelabelled with myo-[3H]inositol. The magnitude of the increase in InsP3 formation was similar when either agent was used alone and was additive when they were used together. In islets prelabelled with 45Ca2+ and treated with carbachol (1 mM), the rise in InsP3 correlated with a rapid, transient, release of 45Ca2+ from the cells, consistent with mobilization of 45Ca2+ from an intracellular pool. Under these conditions, however, insulin secretion was not increased. In contrast, islets prelabelled with 45Ca2+ and exposed to 20mM-glucose exhibited a delayed and decreased 45Ca2+ efflux, but released 7-8-fold more insulin than did those exposed to carbachol. Depletion of extracellular Ca2+ failed to modify the increase in InsP3 elicited by either glucose or carbachol, whereas it selectively inhibited the efflux of 45Ca2+ induced by glucose in preloaded islets. Under these conditions, however, glucose was still able to induce a small stimulation of the first phase of insulin secretion. These results demonstrate that polyphosphoinositide metabolism, Ca2+ mobilization and insulin release can all be dissociated in islet cells, and suggest that glucose and carbachol regulate these parameters by different mechanisms.

Dexamethasone suppresses phospholipase C activation and insulin secretion from isolated rat islets

Metabolism ◽  
2006 ◽  
Vol 55 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Walter S. Zawalich ◽  
Gregory J. Tesz ◽  
Hanae Yamazaki ◽  
Kathleen C. Zawalich ◽  
William Philbrick
Keyword(s):  
Insulin Secretion ◽  
Phospholipase C ◽  
Rat Islets ◽  
Isolated Rat Islets ◽  
Isolated Rat

scholarly journals Metabolism and insulin-releasing capabilities of glucosamine and N-acetylglucosamine in isolated rat islets

1979 ◽  
Vol 180 (1) ◽  
pp. 145-152 ◽  
Author(s):  
W S Zawalich ◽  
E S Dye ◽  
F M Matschinsky
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Maximal Effect ◽  
Metabolic Rates ◽  
Stimulate Insulin Secretion ◽  
Rat Islets ◽  
Isolated Rat Islets ◽  
Secretion Rates ◽  
Isolated Rat

The ability of glucosamine and N-acetylglucosamine to stimulate insulin secretion from perifused rat islets and the suitability of these hexoses to be metabolized in a static incubation was studied under various conditions. N-Acetylglucosamine alone stimulated insulin release with a threshold of 10 mM, with half-maximal effect at approx. 16 mM, and maximally at 20 mM. With higher concentrations stimulation was slightly diminished. Release caused by 20 mM-N-acetylglucosamine was unaffected by 30 mM-mannoheptulose, but was blocked by 2-deoxyglucose or iodoacetate (1 mM). At moderate concentrations, (2.75–20 mM), the metabolism of N-acetyl[1-3H]glucosamine was similar to that of [1-3H]glucose and secretion rates paralleled the corresponding rates of metabolism with these hexoses. Glucosamine (27.5 mM) alone weakly stimulated insulin secretion, which was unaltered by 30 mM-mannoheptulose but blocked by 2-deoxyglucose or iodoacetate. A lower rate of [1-3H]glucosamine metabolism appeared to account for its weaker stimulatory efficacy. Insulin release caused by 27.5 mM-glucosamine or 27.5 mM-N-acetylglucosamine in the presence of basal (2.75 mM) glucose was accurately predicted based on the summed metabolic rates of these compounds. The data strengthen the theory proposing that metabolites or cofactors generated during metabolism are essential for triggering insulin secretion.

Roles of GTP and phospholipase C in the potentiation of Ca2+-induced insulin secretion by glucose in rat pancreatic islets

1997 ◽  
Vol 153 (1) ◽  
pp. 61-71 ◽  
Author(s):  
J Vadakekalam ◽  
M E Rabaglia ◽  
S A Metz
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Phospholipase C ◽  
Mycophenolic Acid ◽  
High Glucose ◽  
Secretory Response ◽  
Rat Pancreatic Islets ◽  
Isolated Rat Islets ◽  
Effect Of Glucose ◽  
Isolated Rat

Abstract Glucose can augment insulin secretion independently of K+ channel closure, provided cytoplasmic free Ca2+ concentration is elevated. A role for phospholipase C (PLC) in this phenomenon has been both claimed and refuted. Recently, we have shown a role for GTP in the secretory effect of glucose as well as in glucose-induced PLC activation, using islets pre-treated with GTP synthesis inhibitors such as mycophenolic acid (MPA). Therefore, in the current studies, we examined first, whether glucose augments Ca2+-induced PLC activation and second, whether GTP is required for this effect, when K+(ATP) channels are kept open using diazoxide. Isolated rat islets pre-labeled with [3H]myo-inositol were studied with or without first priming with glucose. There was a 98% greater augmentation of insulin secretion by 16·7 mm glucose (in the presence of diazoxide and 40 mm K+) in primed islets; however, the ability of high glucose to augment PLC activity bore no relationship to the secretory response. MPA markedly inhibited PLC in both conditions; however, insulin secretion was only inhibited (by 46%) in primed islets. None of these differences were attributable to alterations in labeling of phosphoinositides or levels of GTP or ATP. These data indicate that an adequate level of GTP is critical for glucose's potentiation of Ca2+-induced insulin secretion in primed islets but that PLC activation can clearly be dissociated from insulin secretion and therefore cannot be the major cause of glucose's augmentation of Ca2+-induced insulin secretion. Journal of Endocrinology (1997) 153, 61–71

Effects of flavonoids on insulin secretion and 45Ca2+ handling in rat islets of Langerhans

1985 ◽  
Vol 107 (1) ◽  
pp. 1-8 ◽  
Author(s):  
C.S.T. Hii ◽  
S.L. Howell
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Hormone Release ◽  
Short Term ◽  
Rat Islets ◽  
Naturally Occurring ◽  
Isolated Rat Islets ◽  
Rat Islets Of Langerhans ◽  
Isolated Rat

ABSTRACT The effects of some flavonoids, a group of naturally occurring pigments one of which has been claimed to possess antidiabetic activities, on insulin release and 45Ca2+ handling have been studied in isolated rat islets of Langerhans. Insulin release was enhanced by approximately 44–70% when islets were exposed to either (−)epicatechin (0·8 mmol/l) or quercetin (0·01–0·1 mmol/l); others such as naringenin (0·1 mmol/l) and chrysin (0·08 mmol/l) inhibited hormone release by approximately 40–60%. These effects were observed only in the presence of 20 mmol glucose/l. Quercetin (0·01 mmol/l) and (−)epicatechin (0·8 mmol/l) both inhibited 45Ca2+ efflux in the presence and absence of extracellular Ca2+. In the presence of 20 mmol glucose/l both the short-term (5 min) and steady-state (30 min) uptake of 45Ca2+ were significantly increased by either quercetin or (−)epicatechin. These results suggest that the stimulatory compounds such as quercetin and (−)epicatechin may, at least in part, exert their effects on insulin release via changes in Ca2+ metabolism. J. Endocr. (1985) 107, 1–8

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