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.

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.

L-leucine methyl ester stimulates insulin secretion and islet glutamate dehydrogenase

1983 ◽  
Vol 245 (4) ◽  
pp. E338-E346 ◽  
Author(s):  
P. Knudsen ◽  
H. Kofod ◽  
A. Lernmark ◽  
C. J. Hedeskov
Keyword(s):  
Insulin Secretion ◽  
Methyl Ester ◽  
Glutamate Dehydrogenase ◽  
Insulin Release ◽  
Methyl Esters ◽  
Tumor Cell Line ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Amino Acid Derivative ◽  
Mouse Pancreatic Islets

Column perifusion of collagenase-isolated mouse pancreatic islets was used to study the dynamics of insulin release in experiments lasting for several hours. The methyl esters of L-leucine and L-arginine were synthesized. Whereas L-arginine methyl ester (L-arginine OMe) had no effect, L-leucine OMe stimulated the release of insulin. The effect of L-leucine OMe was maximal at 5 mmol/liter. Whereas the Km for glucose-stimulated insulin release was unaffected by 1 mmol/liter L-leucine OMe, the maximal release of D-glucose was increased by the amino acid derivative that appeared more effective than L-leucine. L-Leucine OMe was also a potent stimulus of insulin release from the perfused mouse pancreas. In the presence of 10 mmol/liter L-glutamine, 1 mmol/liter L-leucine OMe induced a 50- to 75-fold increase in insulin release. A similar stimulatory effect was also observed in column-perifused RIN 5F cells, a cloned rat islet tumor cell line. A twofold increase in islet glutamate dehydrogenase activity was induced by 5 mmol/liter L-leucine OMe, a larger effect than that of L-leucine (P less than 0.02), whereas L-arginine OMe had a small inhibitory effect. We conclude that L-leucine OMe is a potent stimulus of insulin secretion and that its effect on the beta-cells may be exerted by activating islet glutamate dehydrogenase.

scholarly journals Activation of protein kinase C partially alleviates noradrenaline inhibition of insulin secretion

1993 ◽  
Vol 289 (2) ◽  
pp. 497-501 ◽  
Author(s):  
S J Persaud ◽  
P M Jones ◽  
S L Howell
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Insulin Release ◽  
Inhibitory Effect ◽  
Kinase C ◽  
Dependent Protein ◽  
Glucose Stimulated Insulin Secretion ◽  
Rat Islets Of Langerhans

The sympathetic neurotransmitter noradrenaline (NA) fully inhibited both phases of glucose-stimulated insulin secretion from rat islets of Langerhans. The secretory response to the protein kinase C (PKC) activator, 4 beta-phorbol myristate acetate (4 beta PMA), in the absence of exogenous glucose was also abolished by NA. However, at 20 mM glucose 4 beta PMA partially alleviated the inhibitory effect of NA both on insulin release and on cyclic AMP generation. Inhibition of insulin release by NA, albeit much decreased, was still observed in the presence of maximal stimulatory concentrations of both 4 beta PMA and dibutyryl cyclic AMP. The relieving effect of 4 beta PMA on the inhibition of insulin secretion by NA was not overcome by the competitive antagonist of cyclic AMP-dependent protein kinase, Rp-adenosine 3′,5′-cyclic phosphorothioate. Down-regulation of islet PKC activity by overnight exposure to 4 beta PMA did not affect the inhibitory capacity of NA. These results suggest that NA inhibits insulin release independently of interaction with PKC, but that activation of this enzyme decreases the inhibitory effect of NA at stimulatory concentrations of glucose. This protective effect of 4 beta PMA could not be attributed to a decrease in NA inhibition of cyclic AMP generation.

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.

Differential effects of microtubule-altering agents on beta-cells during development

1983 ◽  
Vol 245 (4) ◽  
pp. E391-E400
Author(s):  
R. S. Hill ◽  
W. B. Rhoten
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Insulin Release ◽  
High Glucose ◽  
Deuterium Oxide ◽  
Inhibitory Effect ◽  
Secretory Response ◽  
Second Phase ◽  
Insulin Secretory Response

The effect of microtubule-altering agents on the insulin secretory response to glucose during the perinatal period was investigated with an in vitro perifusion system. Rat pancreatic mince from day 17 of gestation (D17G) to day 6 postnatally (D6PN) were perifused for 60 min in basal glucose followed by 45 min with high glucose (3.5 mg/ml) or with high glucose plus 10 mM arginine (D17G). The two phases of insulin secretion in response to high glucose developed in an age-dependent and asynchronous manner. The first phase matured between D17G and D18G, and maturation of the second phase occurred subsequently. Vinblastine (VB) (20 or 100 microM) had a differential effect on the insulin secretory response. VB did not inhibit stimulated insulin release at D17G. This absence of an inhibitory effect of VB at D17G could not be explained by the absence of polymerized tubulin because microtubules were present in the control beta-cells and, in addition, VB treatment resulted in the formation of paracrystalline deposits. Subsequently in development, and with isolated islets of the adult, VB inhibited stimulated insulin release. Heavy water (deuterium oxide, D2O) inhibited stimulated insulin secretion at D17G but blocked completely insulin release from the near-term beta-cell. The inhibition of insulin secretion by D2O was rapidly reversed when water replaced D2O in the perifusion media. The results indicate that the maturation of the second phase of insulin secretion coincides with the ability of the microtubule-altering agents to modify the insulin secretory response. One possible explanation for these findings is that at D17G the microtubules are not coupled physicochemically to other molecules or structures necessary for their role in insulin secretion to be expressed fully.

scholarly journals Islet-cell metabolism during insulin release. Effects of glucose, citrate, octanoate, tolbutamide, glucagon and theophylline

1969 ◽  
Vol 115 (2) ◽  
pp. 257-262 ◽  
Author(s):  
W Montague ◽  
K W Taylor
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Islet Cell ◽  
Cell Metabolism ◽  
Inhibitory Effect ◽  
Linear Increase ◽  
Intracellular Concentration ◽  
Extracellular Glucose ◽  
Oxidation Of Glucose

1. Concentrations of glucose 6-phosphate and 6-phosphogluconate were studied in islets of Langerhans isolated from rat pancreas and incubated in the presence of various agents that induce insulin release. 2. In response to rising concentrations of extracellular glucose (2–10mm) there is a linear increase in the intracellular concentration of glucose 6-phosphate, though this is not the case for 6-phosphogluconate, the intracellular concentration of which only increases when the external glucose concentration exceeds 5mm. 3. Tolbutamide, octanoate and citrate, all of which promote insulin secretion from isolated islets, increase the intracellular concentrations of glucose 6-phosphate and 6-phosphogluconate. The results obtained in the presence of octanoate and citrate are compatible with an inhibitory effect of citrate on islet-cell phosphofructokinase. 4. Theophylline and glucagon when incubated with islets in vitro promote insulin release and cause a rise in 6-phosphogluconate concentration and not in that of glucose 6-phosphate. 5. It is suggested that the further metabolism of glucose 6-phosphate through a pathway other than glycolysis is essential for insulin release. One such pathway involves its oxidation to 6-phosphogluconate, which seems to be a necessary accompaniment of insulin secretion due to glucose. The possibility that agents other than glucose promote insulin release by enhancing the oxidation of glucose 6-phosphate through this pathway is discussed.

Effects of islet hormones on insulin secretion from cloned B cell lines, HIT-T15 and RINm5F

1989 ◽  
Vol 121 (3) ◽  
pp. 479-485 ◽  
Author(s):  
D. G. Lambert ◽  
T. W. Atkins
Keyword(s):  
Insulin Secretion ◽  
B Cells ◽  
Insulin Release ◽  
Pancreatic Polypeptide ◽  
Islet Cell ◽  
Fine Tuning ◽  
Rinm5f Cells ◽  
Islet Hormones ◽  
Pancreatic B Cells ◽  
Islet Cell Hormones

ABSTRACT The effects of the islet cell hormones glucagon, somatostatin-28 and pancreatic polypeptide on insulin secretion from cultured cloned pancreatic B cells (HIT-T15 and RINm5F) have been investigated. Glucagon stimulates the secretion of insulin from HIT-T15 cells in the absence and presence of glucose and from RINm5F cells in the absence and presence of glyceraldehyde. HIT-T15 cells were more sensitive to the stimulatory effect of glucagon than RINm5F cells. Somatostatin-28 and pancreatic polypeptide, both alone and in combination, reduced glucose- and glucagon-stimulated insulin release from HIT-T15 cells and glyceraldehyde- and glucagon-stimulated insulin release from RINm5F cells. HIT-T15 cells were more sensitive to the inhibitory actions of somatostatin-28 and pancreatic polypeptide than RINm5F cells. This study supports the hypothesis that insulin release from normal B cells may be modified by the paracrine activity of islet hormones, glucagon, somatostatin and pancreatic polypeptide and probably occurs before any fine tuning imposed by subsequently released insulin. Journal of Endocrinology (1989) 121, 479–485

Insulin secretion in glucosamine-induced hyperglycemia in rats

1965 ◽  
Vol 209 (4) ◽  
pp. 797-802 ◽  
Author(s):  
Julio M. Martin ◽  
Gunta Bambers
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Release ◽  
Glucose Concentration ◽  
Insulin Injection ◽  
Inhibitory Effect ◽  
Base Line ◽  
Pancreatic Insulin ◽  
Hyperglycemic Effect

The hyperglycemia response produced by the injection of glucosamine in rats has been studied by comparing the effects of equal doses of glucosamine and glucose on blood glucose, circulating insulin, and pancreatic insulin content. The effect of glucosamine and glucose on insulin release from the islets has been studied in vitro by incubating slices of pancreas from normal rats and from rats injected with glucosamine. After glucosamine injection, the blood glucose rose and the circulating insulin decreased. In the glucose-injected group the hyperglycemia was lower and the circulating insulin higher. Insulin output from incubated pancreatic slices of normal rats rose when the glucose concentration in the medium was increased or when tolbutamide was added. A decrease below the base line occurred on the addition of glucosamine or when pancreas slices from glucosamine-injected rats were incubated. Insulin injection decreased the hyperglycemic effect of glucosamine whereas tolbutamide was ineffective. These results suggest that glucosamine exerts an inhibitory effect on insulin release from the pancreas.

Augmentation of glucose induced insulin secretion by pertussis vaccine, phentolamine and benextramine: involvement of mechanisms additional to prevention of the inhibitory actions of catecholamines in rats

1988 ◽  
Vol 118 (1) ◽  
pp. 89-95 ◽  
Author(s):  
Maureen Smith ◽  
Brian L. Furman
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Pertussis Vaccine ◽  
Ex Vivo ◽  
Blocking Agent ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Release In Vitro ◽  
The Relationship

Abstract. Pertussis vaccine, pertussis toxin, and the α-adrenoceptor blocking drug phentolamine augment glucose-induced insulin secretion. The present study was carried out to determine the relationship between this action and the ability of these agents to prevent the inhibitory actions of adrenaline. Pertussis vaccine augmented glucose-induced insulin secretion in rat islets ex vivo and prevented the inhibitory actions of adrenaline and clonidine. Incubation of islets with phentolamine or the irreversible α-adrenoceptor blocking agent benextramine also augmented glucose-induced insulin secretion. However, the α-adrenoceptor blocking drugs idazoxan, yohimbine or phenoxybenzamine, in concentrations that prevented the inhibitory effects of adrenaline and/or clonidine, did not modify glucose-induced insulin release in vitro. Benextramine (1 × 10−5 mol/l) blocked the inhibitory effect of clonidine, whilst having no significant effect on the response to adrenaline. It is concluded that stimulation of insulin secretion by certain α-adrenoceptor blocking drugs can be dissociated from their α-adrenoceptor properties. The ability of pertussis vaccine, phentolamine or benextramine to augment glucose-induced insulin release in vitro is unlikely to be due to the prevention of the inhibitory action of endogenous catecholamines.

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.

Sign in / Sign up

Export Citation Format

Share Document