Ca2+-secretion coupling is impaired in diabetic Goto Kakizaki rats
Rose, Tobias ; Efendić, Suad ; Rupnik, Marjan
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 ß cells in acute pancreatic tissue slices by assessing exocytosis with high time-resolution membrane capacitance measurements. We found that ß cells of GK rats respond to glucose stimulation with a normal increase in the cytosolic Ca2+ concentration. Duringtrains of depolarizing pulses, the secretory activity from GK rat ß cells was defective in spite of upregulated cell size and doubled voltage-activated Ca2+ currents. In GK rat ß 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 stimulationwith two successive trains of depolarizing pulses led to a prominent activity-dependent facilitation of release in GK rat ß cells, whereas secretion in controls was unaffected. Broad-spectrum inhibition of PKCsensitized Ca2+-dependent exocytosis, whereas it prevented the activity-dependent facilitation in GK rat ß cells. We conclude that a decreasein the sensitivity of the GK rat ß-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 ormore PKC isoenzymes in diabetic rat ß cells.
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