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Paradoxical stimulation of glucagon secretion by high glucose concentrations

Salehi, S Albert LU orcid ; Vieira, Elaine and Gylfe, Erik (2006) In Diabetes 55(8). p.2318-2323
Abstract
Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25-30 mmol/l and In-R1-G9 cells at 12-20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for... (More)
Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25-30 mmol/l and In-R1-G9 cells at 12-20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the a-cells. Studies of isolated mouse a-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia. (Less)
Please use this url to cite or link to this publication:
author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
55
issue
8
pages
2318 - 2323
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000239468300019
  • pmid:16873696
  • scopus:33749347851
  • pmid:16873696
ISSN
1939-327X
DOI
10.2337/db06-0080
language
English
LU publication?
yes
id
e38e7b72-ed4a-4a9b-b972-ad4ba7daf261 (old id 686336)
date added to LUP
2016-04-01 15:59:30
date last changed
2021-08-25 02:57:20
@article{e38e7b72-ed4a-4a9b-b972-ad4ba7daf261,
  abstract     = {Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25-30 mmol/l and In-R1-G9 cells at 12-20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the a-cells. Studies of isolated mouse a-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia.},
  author       = {Salehi, S Albert and Vieira, Elaine and Gylfe, Erik},
  issn         = {1939-327X},
  language     = {eng},
  number       = {8},
  pages        = {2318--2323},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Paradoxical stimulation of glucagon secretion by high glucose concentrations},
  url          = {http://dx.doi.org/10.2337/db06-0080},
  doi          = {10.2337/db06-0080},
  volume       = {55},
  year         = {2006},
}