GABA signalling in human pancreatic islets

Abstract

The pancreatic islets are essential microorgans controlling the glucose level in the blood. The islets consist of different cell types which communicate with each other by means of auto- and paracrine interactions. One of the communication molecules produced by and released within the islets is γ-aminobutyric acid (GABA), a well-known inhibitor of neuronal excitability in the mammalian nervous system. Interestingly, GABA is also present in the blood in the nanomolar concentration range. Thus, GABA can affect not only islet function per se (e.g. hormone secretion) but also interactions between immune cells and the pancreatic islet cells in physiological conditions and in pathological states (particularly in type 1 diabetes). In the last decade the interest in GABA signalling in islets has increased. The broad research scope ranges from fundamental physiological studies at the molecular and cellular level to pathological implications and clinical trials. The aim of this mini-review is to outline the current status of the islet GABA field mostly in relation to human islets, to identify the gaps in the current knowledge and what clinical implications GABA signalling may have in islets.

Keywords: GABA tolerance; GABAA receptor; T1D mouse model; blood glucose; diabetes mellitus; insulin secretion; mixed-identity cell; β cell.

Figure 1

Intracellular cascades triggered by activation of GABA_A receptors in human β cells. Upon GABA binding to GABA_A receptors (GABA_ARs) chloride (Cl^–) leaves the cell along the driving force created by the difference between the membrane potential and Cl^– equilibrium potential (E_Cl), that depolarizes the cell membrane above the threshold of activation of voltage-gated calcium (Ca²⁺) channels (VGCCs). Ca²⁺ entrance through VGCCs stimulates insulin secretion which activates insulin receptor and subsequently – PI3K/Akt pathway. The influx of intracellular Ca²⁺ through VGCCs also activates PI3K/Akt cascade. Both routes eventually stimulate mechanisms of β cell proliferation and survival.

Figure 2

Hypothesis of controlled conversion of pancreatic cells with mixed identity. Conversion of the α/β cell with glucagon transcript (GCG) expression level higher than or similar to insulin transcript (INS) expression level, to the α/β cell with reciprocal expression pattern or to the cell with the β cell-like phenotype, respectively under the influence of molecules interacting with the GABA signalling system of the mixed-identity cell.