Ca2+–Secretion Coupling Is Impaired in Diabetic Goto Kakizaki rats
Open Access
- 29 May 2007
- journal article
- Published by Rockefeller University Press in The Journal of general physiology
- Vol. 129 (6), 493-508
- https://doi.org/10.1085/jgp.200609604
Abstract
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 Ca2+-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 Ca2+–secretion coupling of healthy and GK rat β cells in acute pancreatic tissue slices by assessing exocytosis with high time-resolution membrane capacitance measurements. We found that β cells of GK rats respond to glucose stimulation with a normal increase in the cytosolic Ca2+ concentration. During trains of depolarizing pulses, the secretory activity from GK rat β cells was defective in spite of upregulated cell size and doubled voltage-activated Ca2+ currents. In GK rat β cells, evoked Ca2+ 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 β cells, whereas secretion in controls was unaffected. Broad-spectrum inhibition of PKC sensitized Ca2+-dependent exocytosis, whereas it prevented the activity-dependent facilitation in GK rat β cells. We conclude that a decrease in the sensitivity of the GK rat β-cell to depolarization-evoked Ca2+ 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 β cells.Keywords
This publication has 108 references indexed in Scilit:
- Cx36-Mediated Coupling Reduces β-Cell Heterogeneity, Confines the Stimulating Glucose Concentration Range, and Affects Insulin Release KineticsDiabetes, 2007
- Programmed disorders of β-cell development and function as one cause for type 2 diabetes? The GK rat paradigmDiabetes/Metabolism Research and Reviews, 2005
- KATP-channels in beta-cells in tissue slices are directly modulated by millimolar ATPMolecular and Cellular Endocrinology, 2005
- Synaptotagmin V and IX isoforms control Ca2+-dependent insulin exocytosisJournal of Cell Science, 2004
- Some precautions in using chelators to buffer metals in biological solutionsCell Calcium, 2004
- Down-Regulated Expression of Exocytotic Proteins in Pancreatic Islets of Diabetic GK RatsBiochemical and Biophysical Research Communications, 2002
- Short-Term Synaptic PlasticityAnnual Review of Physiology, 2002
- Delayed Ca2+Response to Glucose in Diabetic GK RatBiochemical and Biophysical Research Communications, 1997
- Insulin secretion from islets of GK rats is not impaired after energy generating stepsMolecular and Cellular Endocrinology, 1995
- Analysis and use of the perforated patch technique for recording ionic currents in pancreaticβ-cellsThe Journal of Membrane Biology, 1991