In Vivo Stimulation of Insulin Secretion by Guanidine Derivatives in the Rat

Abstract. The ability of the cholinergic agonist carbachol to sensitize islets to the action of combined glucose, cholecystokinin and gastric inhibitory polypeptide was determined in isolated rat islets. In response to this combination, peak first phase insulin secretion from control islets averages 85 ± 5 pg · islet−1 · min−1 (mean ± sem) and the insulin secretory rates measured 35–40 min after the onset of stimulation averages 127 ± 34 pg · islet−1 · min−1. A prior 20 min exposure to 1 mmol/l carbachol potentiates the modest insulin stimulatory response to this combination of stimulants: peak first phase release is 354 ± 61 pg · islet−1 · min−1, and release measured 35–40 min after the onset of stimulation is 179 ± 34 pg · islet−1 · min−1. This sensitizing effect of carbachol lasts for at least 40 min and can be duplicated by the natural in vivo agonist acetylcholine. These results demonstrate that cholinergic stimulation of isolated islets primes them to the subsequent stimulatory effect of a moderate increase in the circulating glucose level and to several postulated incretin factors. If operative in vivo, this communications network between cephalic and enteric factors represents a remarkable control system to ensure the release of insulin in amounts commensurate to meet the anticipated and actual insulin requirements for insulin-mediated fuel disposition.

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Hyperinsulinemia of preobese and obese fa/fa rats is partly vagus nerve mediated

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1983.244.4.e317 ◽

1983 ◽

Vol 244 (4) ◽

pp. E317-E322 ◽

Cited By ~ 7

Author(s):

F. Rohner-Jeanrenaud ◽

A. C. Hochstrasser ◽

B. Jeanrenaud

Keyword(s):

Electrical Stimulation ◽

Insulin Secretion ◽

B Cells ◽

Vagus Nerve ◽

Zucker Rats ◽

Glucose Load ◽

Parasympathetic System ◽

Enhanced Sensitivity ◽

Stimulation Of

In vivo glucose-induced insulin secretion was greater in preweaned preobese 17-day-old Zucker rats than in the corresponding controls. This hypersecretion of insulin was reversed to normal by acute pretreatment with atropine. A short-lived (30 s) electrical stimulation of the vagus nerve preceding a glucose load potentiated the in vivo glucose-induced insulin release in adult animals (6-9 wk) and more so in obese Zucker (fa/fa) than in lean rats. This suggested the existence of enhanced sensitivity and/or responsiveness of the B cells of obese animals to the parasympathetic system. That the parasympathetic tone was increased in adult obese Zucker (fa/fa) rats was corroborated by the observation that acute vagotomy of these animals resulted in a significant decrease in glucose-induced insulin secretion, whereas no such effect was seen in lean rats. Also, perfused pancreases from adult obese (fa/fa) rats oversecreted insulin during a stimulation by arginine when compared with controls, an oversecretion that was restored toward normal by superimposed infusion of atropine. It is concluded that a) the increased insulin secretion of preobese Zucker fa/fa rats is an early abnormality that is mediated by the vagus nerve, and b) increased secretion of insulin in adult obese fa/fa rats continues to be partly vagus-nerve mediated, although a decreased sympathetic tone and other unknown defects could conceivably play a role as well.

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GPRC6A Mediates the Effects of l-Arginine on Insulin Secretion in Mouse Pancreatic Islets

Endocrinology ◽

10.1210/en.2012-1301 ◽

2012 ◽

Vol 153 (10) ◽

pp. 4608-4615 ◽

Cited By ~ 53

Author(s):

Min Pi ◽

Yunpeng Wu ◽

Nataliya I Lenchik ◽

Ivan Gerling ◽

L. Darryl Quarles

Keyword(s):

Insulin Secretion ◽

Pancreatic Islets ◽

Ex Vivo ◽

Β Cells ◽

Direct Role ◽

Mouse Pancreatic Islets ◽

Islet Size ◽

G Protein Coupled ◽

Stimulation Of

Abstract l-Arginine (l-Arg) is an insulin secretagogue, but the molecular mechanism whereby it stimulates insulin secretion from β-cells is not known. The possibility that l-Arg regulates insulin secretion through a G protein-coupled receptor (GPCR)-mediated mechanism is suggested by the high expression of the nutrient receptor GPCR family C group 6 member A (GPRC6A) in the pancreas and TC-6 β-cells and the finding that Gprc6a−/]minus] mice have abnormalities in glucose homeostasis. To test the direct role of GPRC6A in regulating insulin secretion, we evaluated the response of pancreatic islets derived from Gprc6a−/]minus] mice to l-Arg. We found that the islet size and insulin content were decreased in pancreatic islets from Gprac6a−/]minus] mice. These alterations were selective for β-cells, because there were no abnormalities in serum glucagon levels or glucagon content of islets derived from Gprac6a−/]minus] mice. Significant reduction was observed in both the pancreatic ERK response to l-Arg administration to Gprc6a−/]minus] mice in vivo and l-Arg-induced insulin secretion and production ex vivo in islets isolated from Gprc6a−/]minus] mice. l-Arg stimulation of cAMP accumulation in isolated islets isolated from Gprc6a−/]minus] mice was also diminished. These findings suggest that l-Arg stimulation of insulin secretion in β-cells is mediated, at least in part, through GPRC6A activation of cAMP pathways.

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EFFECTS OF GASTRIN ON THE RELEASE OF INSULIN IN VITRO

Journal of Endocrinology ◽

10.1677/joe.0.0430371 ◽

1969 ◽

Vol 43 (3) ◽

pp. 371-375 ◽

Cited By ~ 22

Author(s):

A. LERNMARK ◽

B. HELLMAN ◽

H. G. COORE

Keyword(s):

Insulin Secretion ◽

Pancreatic Islets ◽

Glucose Concentration ◽

Gastrointestinal Hormones ◽

Mouse Pancreas ◽

Low Glucose ◽

Isolated Pancreas ◽

Stimulation Of

SUMMARY Several investigations in vivo and in vitro have shown that gastrointestinal hormones stimulate insulin secretion. Whether gastrin also has such an effect was tested both with the isolated mouse pancreas and with micro-dissected pancreatic islets from obese-hyperglycaemic mice. A fairly low concentration of human synthetic gastrin I (0·15 μg./ml.) was found to inhibit the stimulation of insulin release normally obtained with increasing glucose concentrations. However, when a higher concentration of gastrin was tested on the isolated pancreas in the presence of a low glucose concentration there was a stimulation of insulin secretion.

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Increase of gap junctions between pancreatic B-cells during stimulation of insulin secretion.

The Journal of Cell Biology ◽

10.1083/jcb.82.2.441 ◽

1979 ◽

Vol 82 (2) ◽

pp. 441-448 ◽

Cited By ~ 109

Author(s):

P Meda ◽

A Perrelet ◽

L Orci

Keyword(s):

Insulin Secretion ◽

B Cells ◽

Gap Junctions ◽

Freeze Fracture ◽

Secretory Activity ◽

Isolated Rat Islets ◽

Pancreatic B Cells ◽

Stimulation Of

The development of gap junctions between pancreatic B-cells was quantitatively assessed in freeze-fracture replicas of isolated rat islets under different conditions of insulin secretion. The results show that in resting B-cells, gap junctions are small and scarce but that these junctions increase when insulin secretion is stimulated. Both a short (90 min) stimulation by glucose in vitro and a prolonged (2.5 d) stimulation by glibenclamide in vivo raise the number of gap junctions; in addition, the glibenclamide stimulation causes an increase in the size of individual gap junctions. As a consequence, the total area occupied by gap junctions on the B-cell membrane and the ratio of this area to the cell volume were found significantly increased in the latter condition. The slight increase of these values observed after the glucose stimulation did not reach significance. These data indicate a change of gap junctions during the secretory activity of the pancreatic B-cells. The possibility that the coupling of the cells is affected by the treatment is discussed.

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[Ala6]gastrin-releasing peptide-10: an analogue with dissociated biological activities

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.257.2.e235 ◽

1989 ◽

Vol 257 (2) ◽

pp. E235-E240

Author(s):

H. Mukai ◽

K. Kawai ◽

S. Suzuki ◽

H. Ohmori ◽

K. Yamashita ◽

...

Keyword(s):

Insulin Secretion ◽

Biological Activities ◽

Glucagon Secretion ◽

Gastrin Releasing Peptide ◽

Gastrin Secretion ◽

Insulin And Glucagon Secretion ◽

Mammalian Tissues ◽

Stimulation Of

COOH-terminal decapeptide of gastrin-releasing peptide (GRP-10) is a bombesin-like peptide, which has bioactivities to stimulate gastrin, insulin, and glucagon secretion. We have synthesized an analogue of GRP-10 that inhibits GRP-10's stimulation of insulin secretion both in vivo and in vitro and glucagon secretion in vivo, while potentiating the stimulation of gastrin secretion. The amino acid sequence of this peptide is H-Gly-Asn-Trp-Ala-Ala-Gly-His-Leu-Met-NH2 ([Ala6]GRP-10). Because the stimulation of insulin and gastrin secretion by GRP-10 has been ascribed to a direct effect on B- and G-cells, these findings suggest that there are two subtypes of receptors for bombesin-like peptides in mammalian tissues.

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Glucose-induced oscillatory insulin secretion in perifused rat pancreatic islets and clonal beta-cells (HIT)

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.4.e702 ◽

1996 ◽

Vol 271 (4) ◽

pp. E702-E710 ◽

Cited By ~ 16

Author(s):

B. A. Cunningham ◽

J. T. Deeney ◽

C. R. Bliss ◽

B. E. Corkey ◽

K. Tornheim

Keyword(s):

Insulin Secretion ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Basal Secretion ◽

Oscillation Pattern ◽

Glucose Stimulation ◽

High Concentrations ◽

Perifused Islets ◽

Stimulation Of

Normal insulin secretion is oscillatory in vivo and from groups of perifused islets. Stimulation of rat islets with different glucose concentrations gave insulin oscillations of similar period (5-8 min) but increasing amplitude. It has been assumed that oscillatory secretion is due to oscillations in intracellular free Ca2+, as seen in single islets and single pancreatic beta-cells. However, when islets were perifused with diazoxide and high KCl to maintain high intracellular free Ca2+, insulin oscillations of similar amplitude and period still occurred on glucose stimulation, although superimposed on elevated basal secretion. Several likely possibilities for a diffusible synchronizing factor were tested, including pyruvate, lactate, ATP, and insulin itself; nevertheless, perifusion with high concentrations of these did not prevent insulin oscillations. Clonal pancreatic beta-cells (HIT) and dissociated islets also exhibited oscillatory insulin secretion, but with the 5- to 8-min period oscillations superimposed on 15- to 20-min period oscillations. These results indicate that the mechanisms for generating and synchronizing insulin oscillations reside in the beta-cell, although the structure of the islet may modulate the oscillation pattern.

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In Vivo Stimulation of Insulin Secretion by Novel Esters of Succinic Acid

Hormone and Metabolic Research ◽

10.1055/s-2007-979950 ◽

1995 ◽

Vol 27 (05) ◽

pp. 251-252 ◽

Cited By ~ 4

Author(s):

T.-M. Zhang ◽

F. Björkling ◽

W. Malaisse

Keyword(s):

Insulin Secretion ◽

Succinic Acid ◽

Stimulation Of

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An inhibitory role for polyamines in protein kinase C activation and insulin secretion in mouse pancreatic islets

Biochemical Journal ◽

10.1042/bj2370131 ◽

1986 ◽

Vol 237 (1) ◽

pp. 131-138 ◽

Cited By ~ 40

Author(s):

P Thams ◽

K Capito ◽

C J Hedeskov

Keyword(s):

Protein Kinase C ◽

Insulin Secretion ◽

Protein Kinase ◽

Pancreatic Islets ◽

Kinase C ◽

Mouse Pancreatic Islets ◽

Mouse Islets ◽

Protein Kinase C Activation ◽

Stimulation Of

The occurrence and function of polyamines in protein kinase C activation and insulin secretion in mouse pancreatic islets were studied. Determination of polyamines in mouse islets revealed 0.9 +/- 0.3 (mean +/- S.E.M., n = 6) pmol of putrescine, 11.7 +/- 3.2 (8) pmol of spermidine and 3.7 +/- 0.6 (8) pmol of spermine per islet, corresponding to intracellular concentrations of 0.3-0.5 mM-putrescine, 3.9-5.9 mM-spermidine and 1.2-1.9 mM-spermine in mouse islets. Stimulation of insulin secretion by glucose, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) or the sulphonylurea glibenclamide did not affect these polyamine contents. In accordance with a role for protein kinase C in insulin secretion, TPA stimulated both protein kinase C activity and insulin secretion. Stimulation of insulin secretion by TPA was dependent on a non-stimulatory concentration of glucose and was further potentiated by stimulatory concentrations of glucose, glibenclamide or 3-isobutyl-1-methylxanthine, suggesting that protein kinase C activation, Ca2+ mobilization and cyclic AMP accumulation are all needed for full secretory response of mouse islets. Spermidine (5 mM) and spermine (1.5 mM) at concentrations found in islets inhibited protein kinase C stimulated by TPA + phosphatidylserine by 55% and 45% respectively. Putrescine (0.5 mM) was without effect, but inhibited the enzyme at higher concentrations (2-10 mM). Inhibition of protein kinase C by polyamines showed competition with Ca2+, and Ca2+ influx in response to glucose or glibenclamide prevented inhibition of insulin secretion by exogenous polyamines at concentrations where they did not affect glucose oxidation. It is suggested that inhibition of protein kinase C by polyamines may be of significance for regulation of insulin secretion in vivo and that Ca2+ influx may function by displacing inhibitory polyamines bound to phosphatidylserine in membranes.

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