Periodic Reporting for period 1 - ISLET GABA (Beta cell GABA secretion: route, physiological function, and potential for pharmacological modulation in diabetes therapy)
Reporting period: 2021-10-11 to 2023-10-10
Background:
Diabetes is a serious disease characterized by increased glucose levels in the blood. Blood glucose levels are normally maintained through the actions of the hormone insulin which is released when blood glucose increases and tells the body to take action to reduce glucose levels. Diabetes arises when either insulin production or insulin effectiveness are decreased. The two main types of diabetes are type 1 diabetes, which results from the autoimmune destruction of insulin-producing beta cells in the pancreas, and type 2 diabetes, which involves insulin resistance and subsequent progressive loss of insulin secretion capacity from beta cells.
Recent research has uncovered a potential role for the chemical messenger γ-aminobutyric acid (GABA) in normal beta cell function and diabetes pathogenesis. GABA, primarily known for its role in transferring messages within the brain, is also produced and secreted by beta cells. Evidence suggests that GABA may also play a critical role in regulating beta cell survival, proliferation, and function. Studies in animal models have also shown that GABA administration can reverse diabetes progression, sparking significant interest in exploring its therapeutic potential for diabetes treatment.
GABA is stored within the beta cell in small structures called vesicles. Vesicles function as sealed packages within the cell which can fuse with the outer membrane of the cell and rupture, releasing their contents into the space outside. The fusion and release of vesicle contents is termed exocytosis and is the major process by which many chemicals and hormones, such as GABA and insulin, are secreted to carry out their functions within the body. In the beta cell, detection of increased blood glucose is the major trigger for vesicle release. This process underlies insulin secretion and thereby maintains normal blood glucose levels. It is currently unclear what regulates the production, storage, and release of GABA containing vesicles from beta cells and how these factors are affected during development of diabetes.
Unlike insulin which is stored in a class of vesicles termes secretory granules, GABA is thought to be stored in smaller vesicles named Synaptic-like microvesicles. These microvesicles appear to be somewhat similar to those involved in transmitting messages in the brain. However, we do not fully understand how much GABA these contain and how important they are for beta cell function and blood glucose control.
Aims:
The primary aim of this research proposal is to explain the how GABA is packaged, stored, and secreted from pancreatic beta cells, with a specific focus on the involvement of synaptic-like microvesicles. This project also explores the effects of interfering with this route of GABA secretion on beta cell function
Potential therapeutic implications:
• Targeting genes involved in vesicle trafficking pathways or GABA signaling may offer potential therapeutic strategies for treating diabetes.
• Modulating vesicle secretion or GABA release from beta cells could be a way to enhance insulin secretion and improve blood glucose maintenance in individuals with diabetes.
• Identifying genetic variants associated with diabetes risk could help personalize treatment approaches and develop precision medicine strategies for managing the disease.
Conclusions
I have identified the genes and cellular pathways responsible for SLMV biogenesis and establiched the tolls required to directly assess the physiological significance of this pathway in blood glucose management and the development of diabetes.
Diabetes is a serious disease characterized by increased glucose levels in the blood. Blood glucose levels are normally maintained through the actions of the hormone insulin which is released when blood glucose increases and tells the body to take action to reduce glucose levels. Diabetes arises when either insulin production or insulin effectiveness are decreased. The two main types of diabetes are type 1 diabetes, which results from the autoimmune destruction of insulin-producing beta cells in the pancreas, and type 2 diabetes, which involves insulin resistance and subsequent progressive loss of insulin secretion capacity from beta cells.
Recent research has uncovered a potential role for the chemical messenger γ-aminobutyric acid (GABA) in normal beta cell function and diabetes pathogenesis. GABA, primarily known for its role in transferring messages within the brain, is also produced and secreted by beta cells. Evidence suggests that GABA may also play a critical role in regulating beta cell survival, proliferation, and function. Studies in animal models have also shown that GABA administration can reverse diabetes progression, sparking significant interest in exploring its therapeutic potential for diabetes treatment.
GABA is stored within the beta cell in small structures called vesicles. Vesicles function as sealed packages within the cell which can fuse with the outer membrane of the cell and rupture, releasing their contents into the space outside. The fusion and release of vesicle contents is termed exocytosis and is the major process by which many chemicals and hormones, such as GABA and insulin, are secreted to carry out their functions within the body. In the beta cell, detection of increased blood glucose is the major trigger for vesicle release. This process underlies insulin secretion and thereby maintains normal blood glucose levels. It is currently unclear what regulates the production, storage, and release of GABA containing vesicles from beta cells and how these factors are affected during development of diabetes.
Unlike insulin which is stored in a class of vesicles termes secretory granules, GABA is thought to be stored in smaller vesicles named Synaptic-like microvesicles. These microvesicles appear to be somewhat similar to those involved in transmitting messages in the brain. However, we do not fully understand how much GABA these contain and how important they are for beta cell function and blood glucose control.
Aims:
The primary aim of this research proposal is to explain the how GABA is packaged, stored, and secreted from pancreatic beta cells, with a specific focus on the involvement of synaptic-like microvesicles. This project also explores the effects of interfering with this route of GABA secretion on beta cell function
Potential therapeutic implications:
• Targeting genes involved in vesicle trafficking pathways or GABA signaling may offer potential therapeutic strategies for treating diabetes.
• Modulating vesicle secretion or GABA release from beta cells could be a way to enhance insulin secretion and improve blood glucose maintenance in individuals with diabetes.
• Identifying genetic variants associated with diabetes risk could help personalize treatment approaches and develop precision medicine strategies for managing the disease.
Conclusions
I have identified the genes and cellular pathways responsible for SLMV biogenesis and establiched the tolls required to directly assess the physiological significance of this pathway in blood glucose management and the development of diabetes.
This project has involved carrying out genetic manipulation of beta cell lines and other cell systems. By mutating genes in beta cells, the project has identified those responsible for the formation of GABA secreting vesicles. Further experiments have identified and validated new functional partners for the identified genes.
The project has also developed the tools and assays required to assess the roles of SLMV in native pancreatic islet tissue. This approach preserves the complex interactions between different cell types within the islets.
The results from this project will be published in two peer reviewed journal articles which are currently in preparation.
The project has also developed the tools and assays required to assess the roles of SLMV in native pancreatic islet tissue. This approach preserves the complex interactions between different cell types within the islets.
The results from this project will be published in two peer reviewed journal articles which are currently in preparation.
By identifying the pathways and genes responsible for SLMV biogenesis and secretion this project has revealed new information abut the cellular processes which operate to control blood glucose levels. These genes and pathways may prove to be targets for therapeutic intervention aimed at maintaining or restoring blood glucose control during the development of diabetes.