Effects of over-stimulation by glucose on pancreatic beta-cell functioning : studies in vitro with diazoxide
Author: Björklund, Anneli
Date: 1999-12-17
Location: Magnus Huss föreläsningssal M4:00, Karolinska Sjukhuset
Time: 9.15
Department: Institutionen för molekylär medicin / Department of Molecular Medicine
Abstract
Long term hyperglycemia impairs pancreatic ß-cell function. In vivo
studies in rats have shown a decreased glucose-induced insulin response
in the perfused pancreas after high glucose infusions. If insulin
secretion was blocked by diazoxide in the presence of high glucose, the
subsequent insulin response to glucose was restituted, indicating that
overstimulation was an important factor behind the impairment.
Long term exposure of rat pancreatic islets to high glucose in vitro also
resulted in a decreased glucose-induced insulin response, which could be
prevented by previous exposure to diazoxide. The after-effect of
diazoxide was not present after low glucose culture and not tightly
coupled to its interaction with K+-ATP channels. Omitting Ca2+ during
cooling completely mimicked the effect of diazoxide indicating that
diazoxide acts on both the level of Ca2+ inflow and exocytosis.
Also in human islets cultured at 27 mM glucose for 48 h previous
diazoxide restituted a glucose-induced insulin response in final
incubations. Diazoxide also protected against specific [Ca2+]i
abnormalities seen after high glucose culture such as a rise in basal [Ca2+]i
and a loss of slow oscillations. On the other hand, diazoxide did not
restore a glucose-induced rise in [Ca2+ ]i.
Diazoxide protected against over-stimulation also with regard to the
adenylate cyclase-cAMP system.
Exposing pancreatic islets from GK rats and GK hybrids to diazoxide
increased intracellular insulin content. In contrast previous exposure to
diazoxide failed to improve an impaired insulin response to glucose
Culture of human pancreatic islets at high glucose increased intraislet
PI/I (proinsulin/insulin) ratios and PI/I ratios of secretion. Co-culture
with diazoxide normalized these parameters. The inclusion of palmitate
enhanced PI/I ratios of secretion. This effect was additive to that of
glucose.
In conclusion, over-stimulation by long term elevated glucose induces
several effects that may be harmful to the ß-cell, indicating that
inducing "ß-cell rest" may offer a new approach in the treatment of type
2 diabetes.
List of papers:
I. Björklund A, Grill V (1993). "B-cell insensitivity in vitro: reversal by diazoxide entails more than one event in stimulus-secretion coupling. " Endocrinology 132(3): 1319-1328
Pubmed
II. Björklund A, Lansner A, Grill VE (2000). "Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation. " Diabetes 49(11): 1840-1848
Pubmed
III. Björklund A, Grill V. (1970). "Protection by diazoxide against B-cell insensitivity includes effects on the adenylate cyclase-cAMP system." (Manuscript)
IV. Björklund A, Östenson CG, Grill VE (1997). "Defective insulin secretion in the GK rat is not linked to excessive B-cell stimulation. " Pancreas 14(2): 212-214
Pubmed
V. Björklund A, Grill V. (1999). "Enhancing effects of long-term elevated glucose and palmitate on stored and secreted proinsulin-to-insulin ratios in human pancreatic islets. " Diabetes 48(7): 1409-1414
Pubmed
I. Björklund A, Grill V (1993). "B-cell insensitivity in vitro: reversal by diazoxide entails more than one event in stimulus-secretion coupling. " Endocrinology 132(3): 1319-1328
Pubmed
II. Björklund A, Lansner A, Grill VE (2000). "Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation. " Diabetes 49(11): 1840-1848
Pubmed
III. Björklund A, Grill V. (1970). "Protection by diazoxide against B-cell insensitivity includes effects on the adenylate cyclase-cAMP system." (Manuscript)
IV. Björklund A, Östenson CG, Grill VE (1997). "Defective insulin secretion in the GK rat is not linked to excessive B-cell stimulation. " Pancreas 14(2): 212-214
Pubmed
V. Björklund A, Grill V. (1999). "Enhancing effects of long-term elevated glucose and palmitate on stored and secreted proinsulin-to-insulin ratios in human pancreatic islets. " Diabetes 48(7): 1409-1414
Pubmed
Issue date: 1999-11-26
Publication year: 1999
ISBN: 91-628-3943-8
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