Theophylline prevents the inhibitory effect of prostaglandin E 2 on glucose-induced insulin secretion in man

1988 ◽  
Vol 118 (2) ◽  
pp. 187-192 ◽  
Author(s):  
D. Giugliano ◽  
D. Cozzolino ◽  
T. Salvatore ◽  
R. Giunta ◽  
R. Torella
Keyword(s):  
Insulin Secretion ◽  
Inhibitory Action ◽  
Insulin Response ◽  
Inhibitory Effect ◽  
Prostaglandin E ◽  
Intracellular Camp ◽  
Adenylate Cyclase System ◽  
Loading Dose ◽  
Phosphodiesterase Activity ◽  
Acute Insulin Response

Abstract. This study was undertaken to assess the mechanism by which prostaglandins of the E series inhibit glucose-induced insulin secretion in man. Acute insulin response (mean change 3–10 min) to iv glucose (0.33 g/kg) was decreased by 40% during the infusion of prostaglandin E2 (10 μg/min) and glucose disappearance rates were reduced (P < 0.05). Insulin response to arginine (5 g iv) and tolbutamide (1 g iv) were not affected by the same rate of prostaglandin E2 infusion. The inhibitory effect of prostaglandin E2 on glucoseinduced insulin secretion was prevented by theophylline (100 mg as a loading dose followed by a 5 mg/min infusion), a drug that increases the intracellular cAMP concentrations by inhibiting phosphodiesterase activity. Our data suggest the involvement of the adenylate cyclase system in the inhibitory action of prostaglandin E2 on glucose-induced insulin secretion in man.

Beta-endorphin and islet hormone release in humans: evidence for interference with cAMP

1989 ◽  
Vol 257 (3) ◽  
pp. E361-E366 ◽  
Author(s):  
D. Giugliano ◽  
D. Cozzolino ◽  
A. Ceriello ◽  
T. Salvatore ◽  
G. Paolisso ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Inhibitory Effect ◽  
Prostaglandin E ◽  
Intracellular Camp ◽  
Intravenous Glucose ◽  
Beta Endorphin ◽  
Clear Cut ◽  
Glucose Disappearance ◽  
Endogenous Prostaglandin ◽  
Glucagon Suppression

The present studies were undertaken to characterize further the influence of synthetic human beta-endorphin (0.5 mg/h) on insulin and glucagon responses to intravenous glucose in humans. Infusion of beta-endorphin in 10 normal volunteers caused a clear-cut inhibition of the overall insulin responses to a glucose pulse (0.33 g/kg iv) with values of glucose disappearance rates in the diabetic range [0.89 +/- 0.09 (P less than 0.01) vs. saline 1.82 +/- 0.15%/min]. Glucose-induced glucagon suppression was significantly lower during beta-endorphin, a fact that could have contributed to the reduced glucose utilization rates. The infusion of theophylline (150 mg + 350 mg/h) to increase the intracellular cAMP activity by inhibiting phosphodiesterase completely reversed the inhibitory effect of beta-endorphin on glucose-induced insulin secretion. As a consequence, glucose disappearance rates rose to 1.77 +/- 0.18%/min. Theophylline did not influence significantly the glucagon-releasing effect of beta-endorphin as well as the reduced glucagon suppression. An infusion of exogenous calcium (100 mg as iv bolus + 5 mg/min) to raise serum calcium in the hypercalcemic range (15 mg/dl) and lysine acetylsalicylate (72 mg/min) to block the synthesis of endogenous prostaglandin E did not interfere with the inhibiting effect of beta-endorphin on insulin secretion. These data confirm that beta-endorphin stimulates glucagon and inhibits basal and glucose-stimulated insulin secretion and suggest that the opioid influences the intraislet adenylate cyclase activity.

Calcitonin modulation of insulin and glucagon secretion in man

1982 ◽  
Vol 242 (3) ◽  
pp. E206-E213 ◽  
Author(s):  
D. Giugliano ◽  
N. Passariello ◽  
S. Sgambato ◽  
R. Torella ◽  
F. D'Onofrio
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Insulin Response ◽  
Glucagon Secretion ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Acute Insulin Response ◽  
Insulin Responses ◽  
Effect Of Glucose

These studies were undertaken to evaluate the effect of different doses of calcitonin on insulin and glucagon responses to intravenous glucase loads and to assess the mechanism/s by which calcitonin inhibits insulin secretion in man. In our studies, even the infusion of the 1-U dose of calcitonin was found to inhibit by 45% the acute insulin response to a glucose (20 g) pulse. This effect was associated with a significant decrease in glucose disappearance rates. These negative effects of calcitonin on both insulin secretion and glucose tolerance were dose-related. The inhibition of the acute insulin response to glucose was 65% and up to 90% with the infusion of the 4- and 8-U doses, respectively. The suppressive effect of glucose on glucagon secretion was significantly reduced by calcitonin. The inhibitory effect of calcitonin on insulin responses to glucose (5 g) and glucose tolerance was reversed by both theophylline and calcium. By contrast, infusion of lysine acetylsalicylate to block the synthesis of endogenous prostaglandins did not diminish the inhibitory effect of calcitonin on insulin secretion. These results demonstrate that a) calcitonin inhibits glucose-induced insulin responses and deteriorates glucose tolerance in normal humans in a dose-dependent manner; b) calcitonin reduces the suppressive effect of glucose on glucagon secretion in a dose-related fashion; and c) both theophylline and calcium reverse the inhibitory effect of calcitonin on insulin secretion. It is hypothesized that calcitonin effects on insulin and glucagon release are mediated via a change in calcium redistribution in the islet cells.

A role for endogenous prostaglandin E in biphasic pattern of insulin release in humans

1983 ◽  
Vol 245 (6) ◽  
pp. E591-E597 ◽  
Author(s):  
D. Giugliano ◽  
P. Di Pinto ◽  
R. Torella ◽  
N. Frascolla ◽  
F. Saccomanno ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Insulin Response ◽  
Physiological Role ◽  
Prostaglandin E ◽  
Glucose Stimulation ◽  
Biphasic Pattern ◽  
Endogenous Prostaglandin ◽  
Lysine Acetylsalicylate ◽  
Biphasic Insulin Release

These studies were undertaken to evaluate in humans the possible physiological role of prostaglandins of the E series (PGE) in modulating insulin release and to assess whether endogenous PGE synthesis may account for the biphasic pattern of insulin secretion. We used a square-wave glucose stimulation previously determined to give maximal biphasic insulin release. Infusion of lysine acetylsalicylate to block the synthesis of endogenous PGE increased by twofold total insulin response to glucose and also converted insulin release to a multiphasic pattern. The infusion of exogenous PGE1 (0.2 microgram X kg-1 X min-1) or PGE2 (10 micrograms/min) in addition to lysine acetylsalicylate restored the typical biphasic pattern of insulin release and also decreased total insulin release to values similar to those of control studies. Infusion of either PGE1 or PGE2 in the absence of lysine acetylsalicylate reset insulin secretion to a lower level without altering the kinetics of release. On the basis of these results, it is hypothesized that endogenous PGE released in response to glucose stimulation exert an inhibiting effect on insulin release that becomes biphasic in appearance.

scholarly journals Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells)

1999 ◽  
Vol 277 (4) ◽  
pp. R959-R966 ◽  
Author(s):  
Bo Ahrén ◽  
Peter J. Havel
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Insulin Response ◽  
Signal Transduction Pathway ◽  
Intracellular Camp ◽  
Intracellular Content ◽  
Pituitary Adenylate Cyclase ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide 1 ◽  
Activate Protein Kinase

The effect of leptin on insulin secretion is controversial due to conflicting results in the literature. In the present study, we incubated insulin-producing rat insulinoma INS-1 cells for 60 min and examined the effects of recombinant murine leptin (20 nmol/l). We found that leptin (0.1–100 nmol/l) did not affect the insulin response to glucose (1–20 mmol/l). However, when cells were incubated with agents that increase the intracellular content of cAMP, i.e., glucagon-like peptide-1 (100 nmol/l), pituitary adenylate cyclase activating polypeptide (100 nmol/l), forskolin (2.5 μmol/l), dibutyryl-cAMP (1 mmol/l), or 3-isobutyl-1-methylxanthine (100 μmol/l), leptin significantly reduced insulin secretion (by 34–58%, P < 0.05–0.001). In contrast, when insulin secretion was stimulated by the cholinergic agonist carbachol (100 μmol/l) or the phorbol ester 12- O-tetradecanoylphorbol 13-acetate (1 μmol/l), both of which activate protein kinase C, leptin was without effect. We conclude that leptin inhibits insulin secretion from INS-1 cells under conditions in which intracellular cAMP is increased. This suggests that the cAMP-protein kinase A signal transduction pathway is a target for leptin to inhibit insulin secretion in insulin-producing cells.

Prolactin, progesterone, and dexamethasone coordinately and adversely regulate glucokinase and cAMP/PDE cascades in MIN6 β-cells

2004 ◽  
Vol 286 (2) ◽  
pp. E304-E310 ◽  
Author(s):  
Jianhua Shao ◽  
Liping Qiao ◽  
Jacob E. Friedman
Keyword(s):  
Insulin Secretion ◽  
Islet Cells ◽  
Late Pregnancy ◽  
Inhibitory Effect ◽  
Late Gestation ◽  
Intracellular Camp ◽  
Β Cell ◽  
Protein Levels ◽  
Glucose Stimulated Insulin Secretion ◽  
Camp Levels

Islet cells undergo major changes in structure and function to meet the demand for increased insulin secretion during pregnancy, but the nature of the hormonal interactions and signaling events is incompletely understood. Here, we used the glucose-responsive MIN6 β-cell line treated with prolactin (PRL), progesterone (PRG), and dexamethasone (DEX, a synthetic glucocorticoid), all elevated during late pregnancy, to study their effects on mechanisms of insulin secretion. DEX alone or combined with PRL and PRG inhibited insulin secretion in response to 16 mM glucose-stimulating concentrations. However, in the basal state (3 mM glucose), the insulin levels in response to DEX treatment were unchanged, and the three hormones together maintained higher insulin release. There were no changes of protein levels of GLUT2 or glucokinase (GK), but PRL or PRG treatment increased GK activity, whereas DEX had an inhibitory effect on GK activity. α-Ketoisocaproate (α-KIC)-stimulated insulin secretion was also reduced by DEX alone or combined with PRL and PRG, suggesting that DEX may inhibit distal steps in the insulin-exocytotic process. PRL treatment increased the concentration of intracellular cAMP in response to 16 mM glucose, suggesting a role for cAMP in potentiation of insulin secretion, whereas DEX alone or combined with PRL and PRG reduced cAMP levels by increasing phosphodiesterase (PDE) activity. These data provide evidence that PRL and to a lesser extent PRG, which increase in early pregnancy, enhance basal and glucose-stimulated insulin secretion in part by increasing GK activity and amplifying cAMP levels. Glucocorticoid, which increases throughout gestation, counteracts only glucose-stimulated insulin secretion under high glucose concentrations by dominantly inhibiting GK activity and increasing PDE activity to reduce cAMP levels. These adaptations in the β-cell may play an important role in maintaining the basal hyperinsulinemia of pregnancy while limiting the capacity of PRL and PRG to promote glucose-stimulated insulin secretion during late gestation.

Calcitonin gene-related peptide and islet amyloid polypeptide stimulate insulin secretion in RINm5F cells through a common receptor coupled to a generation of cAMP

1994 ◽  
Vol 14 (1) ◽  
pp. 1-13 ◽  
Author(s):  
A. Barakat ◽  
G. Skoglund ◽  
C. Boissard ◽  
G. Rosselin ◽  
J.-C. Marie
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Direct Action ◽  
Inhibitory Effect ◽  
Intracellular Camp ◽  
Rinm5f Cells ◽  
Islet Amyloid ◽  
Camp Pathway ◽  
Common Receptor ◽  
Calcitonin Gene

The question as to whether the homologous peptides CGRP and IAPP can regulate insulin secretion in RINm5F cells was addressed. Chicken CGRP displayed a reproducible inhibitory effect on insulin secretion within 0.1 and 1 nM concentrations and a stimulatory effect at higher concentrations. The maximal stimulatory effects on insulin secretion were obtained with 1.0 μM of chicken CGRP (cCGRP), human α-CGRP (h α-CGRP) and human IAPP (hIAPP) which caused 246 ± 22, 302 ± 63 and 224 ± 14 percent increases of control levels, respectively (p < 0.001). Similarly, maximal accumulations of cAMP were obtained with 1.0 μM of cCGRP, h α-CGRP and hIAPP with the respective percent increases of control levels of 587 ± 24, 436 ± 41 and 410 ± 25 (p < 0.005). Thus the stimulatory effects on insulin secretion in RINm5F cells by cCGRP, h α-CGRP and hIAPP appear to be mediated by the cAMP pathway. Chicken CGRP, the most potent peptide tested, displayed a correlated dose response stimulation of intracellular cAMP and insulin release within the concentration range of 10–1000nM. The EC50 values of cCGRP for cAMP accumulation and insulin release were similar (20nM and 10 nM respectively). The stimulatory effect of IAPP on cAMP was not additive with that of cCGRP suggesting that IAPP action was mediated by CGRP receptors. This hypothesis was further sustained by a preferential inhibition of125I[His]h α-CGRP binding to RINm5F cells by cCGRP as compared to IAPP. We conclude that CGRP and IAPP, through a direct action on a chicken CGRP preferring receptor present in β cells, stimulated insulin by a cAMP mediated pathway.

Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2

2003 ◽  
Vol 285 (2) ◽  
pp. E287-E294 ◽  
Author(s):  
Haiying Cheng ◽  
Susanne G. Straub ◽  
Geoffrey W. G. Sharp
Keyword(s):  
Insulin Secretion ◽  
G Proteins ◽  
Inhibitory Effect ◽  
Specific Protein ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Acyltransferase Activity ◽  
Distal Site ◽  
Protein Acylation

The major physiological inhibitors of insulin secretion, norepinephrine, somatostatin, galanin, and prostaglandin E2, act via specific receptors that activate pertussis toxin (PTX)-sensitive G proteins. Four inhibitory mechanisms are known: 1) activation of ATP-sensitive K channels and repolarization of the β-cell; 2) inhibition of L-type Ca2+ channels; 3) decreased activity of adenylyl cyclase; and 4) inhibition of exocytosis at a “distal” site in stimulus-secretion coupling. We have examined the underlying mechanisms of inhibition at this distal site. In rat pancreatic islets, 2-bromopalmitate, cerulenin, and polyunsaturated fatty acids, all of which suppress protein acyltransferase activity, blocked the distal inhibitory effects of norepinephrine in a concentration-dependent manner. In contrast, control compounds such as palmitate, 16-hydroxypalmitate, and etomoxir, which do not block protein acylation, had no effect. Furthermore, 2-bromopalmitate also blocked the distal inhibitory actions of somatostatin, galanin, and prostaglandin E2. Importantly, neither 2-bromopalmitate nor cerulenin affected the action of norepinephrine to decrease cAMP production. We also examined the effects of norepinephrine, 2-bromopalmitate, and cerulenin on palmitate metabolism. Palmitate oxidation and its incorporation into lipids seemed not to contribute to the effects of 2-bromopalmitate and cerulenin on norepinephrine action. These data suggest that protein acylation mediates the distal inhibitory effect on insulin secretion. We propose that the inhibitors of insulin secretion, acting via PTX-sensitive G proteins, activate a specific protein acyltransferase, causing the acylation of a protein or proteins critical to exocytosis. This particular acylation and subsequent disruption of the essential and precise interactions involved in core complex formation would block exocytosis.

Calcium-binding proteins and insulin release

1987 ◽  
Vol 116 (2) ◽  
pp. 241-246 ◽  
Author(s):  
Yodphat Krausz ◽  
Ludmilla Eylon ◽  
Erol Cerasi
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Calcium Binding ◽  
Binding Proteins ◽  
Insulin Response ◽  
Inhibitory Effect ◽  
Calcium Binding Proteins ◽  
Second Phase ◽  
Glucose Effect ◽  
First Phase Insulin Release

Abstract. Calcium and cAMP are interdependent regulators of glucose-induced insulin release. In the present study we investigated the importance of cAMP and calcium-binding proteins for biphasic insulin secretion by assessing the effects of two phenothiazines known to block such proteins, trifluoroperazine (TFP) and promethazine (PMZ). In isolated rat islets, during 60-min incubations with 16.7 mmol/l glucose both agents inhibited the insulin response with ID50 values of 15 μmol/l for TFP and 5 μmol/l for PMZ. Both agents decreased the maximal insulin response without gross changes in the islet sensitivity to glucose. TFP (15 μmol/l), whereas inducing 50% inhibition of second-phase insulin release, totally suppressed the cAMP response to glucose and the accompanying first-phase insulin secretion (5-min incubations); these effects of TFP could be partially reversed by isobutyl methylxanthine (IBMX). In contrast, 5 μmol/l PMZ, which produced 60% inhibition of second-phase insulin release, had no effect on first-phase insulin and cAMP responses to glucose. Furthermore, IBMX did not modify the inhibitory effect of PMZ on second-phase insulin secretion. The following is concluded: 1. TFP acts preferentially on first-phase insulin release and inhibits cAMP formation; this suggests that calmodulin plays a major role in mediating the initial glucose effect on secretion via stimulation of cAMP. 2. The islet probably contains calcium-sensitive proteins other than calmodulin, since the low concentrations of PMZ shown to inhibit second-phase insulin release lack effects on calmodulin. Synexin could be such a protein. 3. PMZ had no effect on cAMP generation and first-phase insulin release; it is speculated that synexin-like proteins may mediate the glucose effect on second-phase release by increasing the responsiveness of the islet to calcium/cAMP.

scholarly journals Increased insulin secretion and normalization of glucose tolerance by cholinergic agonism in high fat-fed mice

1999 ◽  
Vol 277 (1) ◽  
pp. E93-E102 ◽  
Author(s):  
Bo Ahrén ◽  
Per Sauerberg ◽  
Christian Thomsen
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Insulin Response ◽  
Acute Insulin Response ◽  
High Fat ◽  
Cholinergic Agonist ◽  
Insulin Resistant ◽  
Glucose Stimulated Insulin Secretion ◽  
Improve Glucose Tolerance

Increased insulinotropic activity by the cholinergic agonist carbachol exists in insulin-resistant high fat-fed C57BL/6J mice. We examined the efficiency and potency of carbachol to potentiate glucose-stimulated insulin secretion and to improve glucose tolerance in these animals. Intravenous administration of carbachol (at 15 and 50 nmol/kg) markedly potentiated glucose (1 g/kg)-stimulated insulin secretion in mice fed both a control and a high-fat diet (for 12 wk), with a higher relative potentiation in high fat-fed mice measured as increased (1–5 min) acute insulin response and area under the 50-min insulin curve. Concomitantly, glucose tolerance was improved by carbachol. In fact, carbachol normalized glucose-stimulated insulin secretion and glucose tolerance in mice subjected to a high-fat diet. Carbachol (>100 nmol/l) also potentiated glucose-stimulated insulin secretion from isolated islets with higher efficiency in high fat-fed mice. In contrast, binding of the muscarinic receptor antagonist [ N- methyl-3H]scopolamine to islet muscarinic receptors and the contractile action of carbachol on ileum muscle strips were not different between the two groups. We conclude that carbachol normalizes glucose tolerance in insulin resistance.

PACAP contributes to insulin secretion after gastric glucose gavage in mice

2000 ◽  
Vol 279 (2) ◽  
pp. R424-R432 ◽  
Author(s):  
Karin Filipsson ◽  
Jens Juul Holst ◽  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Gastric Inhibitory Polypeptide ◽  
Inhibitory Effect ◽  
Intravenous Glucose ◽  
Parasympathetic Nerves ◽  
Prandial Insulin ◽  
Pituitary Adenylate Cyclase ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Pituitary adenylate cyclase-activating polypeptide (PACAP) is localized to pancreatic ganglia governing the parasympathetic nerves, which contribute to prandial insulin secretion. We hypothesized that this contribution involves PACAP and show here that the PACAP receptor antagonist PACAP-(6—27) (1.5 nmol/kg iv) reduces the 15-min insulin response to gastric glucose (150 mg/mouse) by 18% in anesthetized mice ( P = 0.041). The reduced insulinemia was not due to inhibited release of the incretin factor glucagon-like peptide 1 (GLP-1) because PACAP-(6—27) enhanced the GLP-1 response to gastric glucose. Furthermore, the GLP-1 antagonist exendin-3-(9—39) (30 nmol/kg) exerted additive inhibitory effect on the insulin response when combined with PACAP-(6—27). The PACAP antagonism was specific because intravenous PACAP-(6—27) inhibited the insulin response to intravenous PACAP-27 plus glucose without affecting the insulin response to intravenous glucose alone (1 g/kg) or glucose together with other insulin secretagogues of potential incretin relevance of intestinal (GLP-1, gastric inhibitory polypeptide, cholecystokinin) and neural (vasoactive intestinal peptide, gastrin-releasing peptide, cholinergic agonism) origin. We conclude that PACAP contributes to the insulin response to gastric glucose in mice and suggest that PACAP is involved in the regulation of prandial insulin secretion.

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