Dynamic interactions between the nervous system, hormones and the immune system are normally on-going but in diabetes the balance is disturbed. The two studies published in EBioMedicine  highlight the importance of the neurotransmitter gamma-aminobutyric acid (GABA) in both Type 1 and Type 2 diabetes.

GABA is synthesized by an enzyme called GAD from the amino acid glutamate in nerve cells but also, importantly, in the insulin-producing beta cells in pancreatic islets. GAD has two forms, GAD65 and GAD67. In type 1 diabetes, beta cells are destroyed while type 2 diabetes is associated with impaired beta cell function and insulin resistance.

Patients with type 1 diabetes often have antibodies to GAD65. However, there has been no strong link between GABA and type 2 diabetes until recently when it was shown that GABA is important for maintaining and potentially also in the making of new beta cells.

The two current studies, now published in EBioMedicine, reinforce the image of GABA's importance, for both types of diabetes. The scientists used ion channels that GABA opens, the GABAA receptors, as a biological sensor for GABA, and were able to determine the effective, physiological GABA concentration levels in human pancreatic islets. They also showed that these ion channels became more sensitive to GABA in type 2 diabetes and that GABA helps regulate insulin secretion (Article 1).

Authors show that 100–1000 nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working.

GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors.

The scientists then isolated immune cells from human blood and studied the effects GABA had on these cells. They show that GABA inhibited the cells and reduced the secretion of a large number of inflammatory molecules (Article 2).

The anti-inflammatory effect of GABA may be vital in the pancreatic islets since as long as GABA is present, toxic white blood cells can be inhibited, thus increasing the survival of the insulin-secreting beta cells. When the beta cells decrease in number and disappear from the islets as happens in Type 1 diabetes, then GABA consequently is also decreased and, thereby, the GABA protective shielding of the beta cells. When inflammatory molecules increase in strength, it may weaken and even kill the remaining beta cells.

In ongoing studies, the scientists now focus on clarifying the GABA signaling mechanisms in the immune cells and in the human beta cells. They will also study how existing drugs can increase, decrease or mimic the effects of GABA, says the author.

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http://www.ebiomedicine.com/article/S2352-3964(18)30098-7/fulltext

http://www.ebiomedicine.com/article/S2352-3964(18)30103-8/fulltext