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¹ European Neuroscience Institute-Göttingen, 37073 Göttingen, Germany
² Department of Molecular Medicine, Karolinska Hospital, 17176 Stockholm, Sweden

Correspondence to Marjan Rupnik: marjan.rupnik{at}uni-mb.si

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. During trains 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 stimulation with 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 PKC sensitized Ca²⁺-dependent exocytosis, whereas it prevented the activity-dependent facilitation in GK rat ß cells. We conclude that a decrease in 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 or more PKC isoenzymes in diabetic rat ß cells.

M. Rupnik's present address is Institute of Physiology, Faculty of Medicine, University of Maribor, Slomkov trg 15, 2000 Maribor, Slovenia.

Abbreviations used in this paper: BIS, bisindolylmaleimide I; ES, extracellular solution; GK, Goto Kakizaki; GSIS, glucose-stimulated insulin secretion; HVA, high-voltage activated; IRP, immediately releasable pool; LDCV, large dense-core vesicle; LVA, low-voltage activated; n.s., not significant; RP, release-ready pool; SNARE, N-ethylmaleimide–sensitive factor attachment protein receptor; T2D, type-2 diabetes; VACC, voltage-activated Ca²⁺ current.

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