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Modulation of islet G-proteins, alpha-glucosidehydrolase inhibition and insulin release stimulated by various secretagogues

Salehi, S Albert LU and Lundquist, Ingmar LU (1996) In Bioscience Reports 16(1). p.23-34
Abstract
Guanine nucleotide-binding proteins (G-proteins) are known to act as important modulators of insulin release from the islets of Langerhans. We have recently found that the deoxynojirimycin-derivative emiglitate, a recognized inhibitor of intestinal alpha-glucosidehydrolase activity, is a powerful inhibitor of glucose-induced insulin release. With the use of isolated mouse islets the present investigation was performed in a primary attempt to elucidate whether this inhibitory mechanism in some way was linked to the beta-cell G-protein system. Treatment of freshly isolated islets with pertussis toxin (PTX), which is known to inactivate the G (i)-proteins, abolished the inhibitory effect of the alpha(2)-adrenoceptor agonist clonidine on... (More)
Guanine nucleotide-binding proteins (G-proteins) are known to act as important modulators of insulin release from the islets of Langerhans. We have recently found that the deoxynojirimycin-derivative emiglitate, a recognized inhibitor of intestinal alpha-glucosidehydrolase activity, is a powerful inhibitor of glucose-induced insulin release. With the use of isolated mouse islets the present investigation was performed in a primary attempt to elucidate whether this inhibitory mechanism in some way was linked to the beta-cell G-protein system. Treatment of freshly isolated islets with pertussis toxin (PTX), which is known to inactivate the G (i)-proteins, abolished the inhibitory effect of the alpha(2)-adrenoceptor agonist clonidine on insulin release stimulated by the phosphodiesterase inhibitor IBMX in the presence of the protein kinase C activator TPA and even changed it into an increase. Emiglitate did not display any inhibitory action on insulin release induced by these secretagogues. Similarly, clonidine-induced inhibition of glucose stimulated insulin release was reversed by PTX. However, PTX did not influence the suppressive action of emiglitate on glucose-induced insulin secretion. In contrast, the adenylate cyclase activator forskolin totally abolished the inhibitory effect of emiglitate, but not that of the glucose analogue mannoheptulose, on glucose-induced insulin release. Moreover, the stimulatory effect of forskolin and cholera toxin (CTX) (activator of G (s)-proteins) on the secretion of insulin was markedly enhanced in the presence of emiglitate. In conclusion, our results suggest that the inhibitory effect of emiglitate on glucose-induced insulin release is not directly related to the G(s)-proteins, but most likely exerted solely through the selective suppression of lysosomal aglucosidehydrolase activity, a step in between the proximal and the distal G(i)-proteins, in glucose induced stimulus-secretion mechanisms. Our data also suggests that the inhibitory action of emiglitate on glucose stimulated insulin release can be compensated for by an increased sensitivity of the cyclic AMP-protein kinase A pathway. Hence, emiglitate might indirectly elicit an increased activity of the G(s)-proteins to facilitate the secretory process. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Pancreatic islets, insulin secretion, pertussis toxin, cholera toxin, agr-glucosidehydrolase inhibition, insulin secretagogues
in
Bioscience Reports
volume
16
issue
1
pages
23 - 34
publisher
Kluwer
external identifiers
  • pmid:8861537
  • scopus:0029894259
ISSN
0144-8463
DOI
10.1007/BF01200998
language
English
LU publication?
yes
id
04d1901c-350f-443d-a183-2f32e5120c80 (old id 1110695)
date added to LUP
2008-07-29 10:35:28
date last changed
2017-01-01 07:13:02
@article{04d1901c-350f-443d-a183-2f32e5120c80,
  abstract     = {Guanine nucleotide-binding proteins (G-proteins) are known to act as important modulators of insulin release from the islets of Langerhans. We have recently found that the deoxynojirimycin-derivative emiglitate, a recognized inhibitor of intestinal alpha-glucosidehydrolase activity, is a powerful inhibitor of glucose-induced insulin release. With the use of isolated mouse islets the present investigation was performed in a primary attempt to elucidate whether this inhibitory mechanism in some way was linked to the beta-cell G-protein system. Treatment of freshly isolated islets with pertussis toxin (PTX), which is known to inactivate the G (i)-proteins, abolished the inhibitory effect of the alpha(2)-adrenoceptor agonist clonidine on insulin release stimulated by the phosphodiesterase inhibitor IBMX in the presence of the protein kinase C activator TPA and even changed it into an increase. Emiglitate did not display any inhibitory action on insulin release induced by these secretagogues. Similarly, clonidine-induced inhibition of glucose stimulated insulin release was reversed by PTX. However, PTX did not influence the suppressive action of emiglitate on glucose-induced insulin secretion. In contrast, the adenylate cyclase activator forskolin totally abolished the inhibitory effect of emiglitate, but not that of the glucose analogue mannoheptulose, on glucose-induced insulin release. Moreover, the stimulatory effect of forskolin and cholera toxin (CTX) (activator of G (s)-proteins) on the secretion of insulin was markedly enhanced in the presence of emiglitate. In conclusion, our results suggest that the inhibitory effect of emiglitate on glucose-induced insulin release is not directly related to the G(s)-proteins, but most likely exerted solely through the selective suppression of lysosomal aglucosidehydrolase activity, a step in between the proximal and the distal G(i)-proteins, in glucose induced stimulus-secretion mechanisms. Our data also suggests that the inhibitory action of emiglitate on glucose stimulated insulin release can be compensated for by an increased sensitivity of the cyclic AMP-protein kinase A pathway. Hence, emiglitate might indirectly elicit an increased activity of the G(s)-proteins to facilitate the secretory process.},
  author       = {Salehi, S Albert and Lundquist, Ingmar},
  issn         = {0144-8463},
  keyword      = {Pancreatic islets,insulin secretion,pertussis toxin,cholera toxin,agr-glucosidehydrolase inhibition,insulin secretagogues},
  language     = {eng},
  number       = {1},
  pages        = {23--34},
  publisher    = {Kluwer},
  series       = {Bioscience Reports},
  title        = {Modulation of islet G-proteins, alpha-glucosidehydrolase inhibition and insulin release stimulated by various secretagogues},
  url          = {http://dx.doi.org/10.1007/BF01200998},
  volume       = {16},
  year         = {1996},
}