Human pancreatic islets release many signal molecules including neurotransmitters like γ-aminobutyric acid (GABA) (1, 2). In the present study, the native GABAA receptors (GABAARs) in intact human pancreatic islets from nondiabetic (ND) and type 2 diabetic (T2D) donors were studied and used as biological sensors for GABA. We examined the biophysical properties of the GABAARs in the β cells and then, the functional implications of their activation. By using the patch-clamp technique in the whole-cell configuration, we identified distinct patterns of GABAAR-mediated currents in human islet α, β and δ cells. Based on single-channel current distributions registered in β cells, GABAARs can be divided into two groups that were termed islet-GABAA receptor I and II (iGABAARI and iGABAARII) with the single-channel conductance (as a mean ± S.E.M.) of 30 ± 3 pS (n = 11) and 72 ± 2 pS (n = 9), respectively. Current-voltage relationships, open probability (Po) and mean current (Imean) as function of the membrane potential were analysed for the iGABAARs. We also compared the Po and Imean for the iGABAARs in β cells as a function of GABA concentrations from ND and T2D donors. The results showed that the frequency of iGABAAR single-channel openings was highest in 100 to 1000 nM GABA. The kinetics of iGABAARs were temperature sensitive for both ND and T2D. Modelling the data revealed significantly lower GABA apparent affinity (Ka values) for β cell iGABAARs from T2D donors as compared to ND donors at room temperature as well as 34°C. The iGABAARs in T2D β cells are thus supersensitive to GABA. At the level of insulin-containing single vesicles, 100 nM GABA decreased the rate of exocytosis in β cells. On the other hand, the effect of GABA on glucose-stimulated insulin secretion from groups of 10-15 islets was more variable. We examined the effects of several commonly used medicines. The results demonstrate that the benzodiazepine diazepam and the anaesthetics propofol and pentobarbital but, interestingly, not the hypnotic zolpidem, significantly increased Imean and the frequency of iGABAAR single-channel openings. Further, the incretin glucagon-like peptide-1 (GLP-1) significantly enhanced the frequency of channel openings by a factor of 3.3 ± 1.1 (Mann-Whitney rank sum test, P<0.05, n=7). However, although the frequency decreased after GLP-1 washout, it remained significantly higher than before the GLP-1 application. In summary, in human islets GABA activates β cell-specific GABAARs that become highly sensitive to GABA in T2D. GABA modulates rate of insulin granule exocytosis and glucose-stimulated insulin secretion. iGABAAR activity in β cells is enhanced by diazepam, anaesthetics, GLP-1 but not zolpidem (3).