6-Month Project Update

Several studies have demonstrated that, similar to brain activity, GABA also can modulate the pancreatic cells’ functions. As any alteration in the secretion of pancreatic hormones can affect blood glucose, understanding the mechanism by which GABA modulates pancreatic function is crucial to improving the understanding of and treatment for type 1 and type 2 diabetes. The exact role of GABA in pancreatic islets is unclear, so we aimed to evaluate how GABA affects beta and delta cell function. 

We incubated human and mouse islets with GABA and GABAA receptor agonist and antagonist, and we evaluated insulin and somatostatin secretion and intracellular calcium dynamics. We observed that in low glucose GABA increased both insulin and somatostatin secretion, and at high glucose, GABA decreased both hormones’ secretion. This behavior is consistent with the known function of the GABAA receptor in beta and delta cells. These results also indicate, for the first time, that GABA may have a diametric effect delta cells, depending on glucose concentration. 

Both insulin and somatostatin secretions are dependent on intracellular calcium concentration. Calcium signaling in islets presents an oscillatory behavior, which is crucial to properly regulate the secretion of pancreatic hormones. We next evaluated how GABA signaling affects calcium oscillations. In human islets, we observed that in low glucose concentrations GABA did not affect the intracellular calcium. On the other hand, in high glucose, GABA reduces intracellular calcium. 

GABA is synthesized by beta cells through GAD enzyme activity. To confirm the effect of GABA on pancreatic beta-cell function, we used a knockout mouse to GAD enzyme specifically in the beta cells (GAD-KO) that consequently inhibits the GABA production by beta cells. We observed that in high glucose, the islets from GAD-KO mice did not present calcium oscillations. However, when we incubated these islets with GABA and GABAA receptor agonist and antagonist, we could re-initiate proper calcium oscillatory behavior. The defective calcium oscillations in GAD-KO mice reflect similar observations in human islets from donors with type 1 and type 2 diabetes, which we have previously shown to be devoid of GABA.

The results allow us to conclude that GABA modulates the rhythm of islet calcium oscillations and thus pulsatile insulin and somatostatin secretion. This modulation happens via the GABAA receptor, reinforcing that the islet GABA signaling network could be a potential target for diabetes treatment. The data up to this point support continuation of our ongoing studies evaluating of the mechanisms by which GABA can modulate pancreatic hormone secretion. In particular, we aim to understand better the parameters under which GAD-KO islets fail to initiate calcium oscillations and if the observations can be replicated in human islets.

Project Description

Blood sugar levels are managed by micro-organs, so-called pancreatic islets, that are located in the pancreas. These micro-organs are small accumulations of different cell types named alpha, beta and delta. Each of these cell types is responsible for the production and release of different hormones called glucagon, insulin, and somatostatin, respectively. These hormones work together as a team to make sure our blood sugar levels stay stable. Simplified, glucagon can increase blood sugar if it drops too low and insulin can decrease it in case it reaches too high. Somatostatin makes sure that glucagon and insulin levels are appropriate. However, except for their action on blood sugar levels, all hormones can change the behavior of their surrounding islet cells. This is called paracrine control and is crucial for proper islet hormone release. This is exemplified by the role of somatostatin or beta-cell death in type 1 diabetes (T1D) leading to an increase in glucagon release, further contributing to increased blood sugar levels.

It has been found that islet cells are able to release other molecules in addition to their hormones. These molecules also change the behavior of the surrounding islet cells, engaging in paracrine action. One of these molecules is gamma-aminobutyric acid (GABA), which I focus on in my research.

GABA is commonly known as a substance produced by the central nervous system that regulates brain activity. There, it reduces neuron activity and affects mood and motor functions. A pathological reduction in the function of GABA in the central nervous system can cause anxiety, insomnia, or epilepsy. The only other place in the body, besides the central nervous system, that generates large amounts of GABA is the pancreatic islet. However, the role of GABA in the pancreatic islet or how GABA deficiency in the islet will affect blood sugar levels or diabetes is not yet understood. Therefore, we want to study how the pancreatic GABA system works and whether it could potentially be targeted as a treatment for type 1 or type 2 diabetes.

In line with GABA being a molecule of critical function within the central nervous system, our data indicates that altering GABA in the pancreas also affects insulin release. However, other studies have shown that GABA might also affect glucagon and somatostatin release. Changing the release of any of these hormones will influence blood sugar levels. Therefore, GABA seems to be critically altering the function of the pancreatic islet.

Click HERE to view Dr. Sandra Mara Ferreira’s video.