Ca2+-secretion coupling is impaired in diabetic Goto Kakizaki rats

The Goto Kakizaki (GK) rat is a widely used animal model to study defective glucose-stimulated insulin release in type-2 diabetes (T2D). As in T2D patients, the expression of several proteins involved in Ca(2+)-dependent exocytosis of insulin-containing large dense-core vesicles is dysregulated in t...

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Bibliographic Details
Published in:The Journal of general physiology 2007-06, Vol.129 (6), p.493-508
Main Authors: Rose, Tobias, Efendic, Suad, Rupnik, Marjan
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Calcium
Calcium Channels - metabolism
Calcium Signaling - drug effects
Cell Enlargement
Diabetes
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - pathology
Diabetes Mellitus, Type 2 - physiopathology
Disease Models, Animal
Electric Capacitance
Electric Stimulation
Exocytosis
Glucose - metabolism
In Vitro Techniques
Indoles - pharmacology
Insulin
Insulin - metabolism
Insulin Secretion
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - metabolism
Insulin-Secreting Cells - pathology
Islets of Langerhans - drug effects
Islets of Langerhans - metabolism
Islets of Langerhans - pathology
Islets of Langerhans - physiopathology
Male
Maleimides - pharmacology
Membrane Potentials
Molecular biology
Patch-Clamp Techniques
Protein Kinase C - antagonists & inhibitors
Protein Kinase C - metabolism
Protein Kinase Inhibitors - pharmacology
Rats
Rats, Wistar
Rodents
Secretory Vesicles - drug effects
Secretory Vesicles - metabolism
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Summary:The Goto Kakizaki (GK) rat is a widely used animal model to study defective glucose-stimulated insulin release in type-2 diabetes (T2D). As in T2D patients, the expression of several proteins involved in Ca(2+)-dependent exocytosis of insulin-containing large dense-core vesicles is dysregulated in this model. So far, a defect in late steps of insulin secretion could not be demonstrated. To resolve this apparent contradiction, we studied Ca(2+)-secretion coupling of healthy and GK rat beta cells in acute pancreatic tissue slices by assessing exocytosis with high time-resolution membrane capacitance measurements. We found that beta cells of GK rats respond to glucose stimulation with a normal increase in the cytosolic Ca(2+) concentration. During trains of depolarizing pulses, the secretory activity from GK rat beta cells was defective in spite of upregulated cell size and doubled voltage-activated Ca(2+) currents. In GK rat beta cells, evoked Ca(2+) entry was significantly less efficient in triggering release than in nondiabetic controls. This impairment was neither due to a decrease of functional vesicle pool sizes nor due to different kinetics of pool refilling. Strong stimulation with two successive trains of depolarizing pulses led to a prominent activity-dependent facilitation of release in GK rat beta cells, whereas secretion in controls was unaffected. Broad-spectrum inhibition of PKC sensitized Ca(2+)-dependent exocytosis, whereas it prevented the activity-dependent facilitation in GK rat beta cells. We conclude that a decrease in the sensitivity of the GK rat beta-cell to depolarization-evoked Ca(2+) influx is involved in defective glucose-stimulated insulin secretion. Furthermore, we discuss a role for constitutively increased activity of one or more PKC isoenzymes in diabetic rat beta cells.
ISSN:0022-1295
1540-7748
DOI:10.1085/jgp.200609604