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Developmental biology - Diabetes|
Diabetes highlighted in 2 new studies
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 impairs beta cell function and subsequently 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 now when it was shown that GABA is important in maintaining and — potentially — in making new beta cells.
The two current studies reinforce GABA's importance in both types of diabetes. Scientists used ion channels that GABA opens - GABAA receptors - to determine the physiologic GABA concentration levels in human pancreatic islet cells. These two ion channels became more sensitive to GABA in type 2 diabetes in order to regulate insulin secretion (Article 1).
The scientists then isolated immune cells from human blood to study the effects of GABA on those cells. They found that GABA inhibited immune cells and reduced the secretion of a large number of inflammatory molecules (Article 2).
This anti-inflammatory effect of GABA appears vital to pancreatic islet cells.
As long as GABA is present, toxic white blood cells can be inhibited, increasing the survival of insulin-secreting beta cells. When beta cells decrease and disappear from islets in Type 1 diabetes, GABA also decreases along with its protective shielding of beta cells. When inflammatory molecules increase in strength, it may weaken and even kill the remaining beta cells.
In future studies, scientists will focus on clarifying the GABA signaling mechanisms in immune cells and in human beta cells. They will also study how existing drugs can increase, decrease or mimic the effects of GABA, explains Bryndis Birnir.
• GABA regulates cytokine secretion in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) and CD4+ T cells.
• GABA inhibits secretion of 47 cytokines in PBMCs from type 1 diabetes patients.
• GABA regulates secretion of pro- and anti-inflammatory cytokines in a concentration-dependent manner.
GABA is a signal molecule in the brain, blood and pancreatic islets where it is secreted by the insulin-producing ? cells. GABA has many roles in human islets including optimizing function and survival of ? cells. Bhandage et al. now show that GABA is a potent regulator of secretion of both pro- and anti-inflammatory cytokines in stimulated immune cells. In type 1 diabetes the ?-cell mass is diminished and thus the protective effect of GABA in the islets although not in blood. Targeting GABA signaling in diabetes mellitus is likely to be a part of the solution when curing diabetes.
The neurotransmitter ?-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100 nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100 nM, 500 nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.
Authors: Amol K. Bhandage, Zhe Jin, Sergiy V. Korol, Qiujin Shen, Yu Pei, Qiaolin Deng, Daniel Espes, Per-Ola Carlsson, Masood Kamali-Moghaddam, Bryndis Birnir
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