New Breakthrough in Diabetes Control: Pancreatic Key Protein
After each meal, glucose levels in the body rise. This stimulates our pancreatic machinery to function and, through a complex physiological mechanism, produce the right amount of insulin to control blood glucose levels and keep us healthy. However, when a person consumes high-fat foods for long periods of time, their pancreas is continually overstimulated, eventually causing it to become damaged and impairing its function. This increases the risk of developing type 2 diabetes, in which the mechanisms for controlling glucose levels become unbalanced.
Today, high-fat foods have become commonplace, as has diabetes. The need to design new treatment strategies for diabetes is on the rise. However, to find effective treatments, the cellular mechanisms of causality must be fundamentally elucidated. Now, a group of Japanese researchers led by Dr. Shoon Kume at Tokyo Institute of Technology has uncovered a key mechanism that regulates pancreatic function. Their findings were published in the American Diabetes Association's journal Diabetes.
The pancreas contains "beta cells" that secrete excessive amounts of insulin in response to excess glucose and fatty acids in the diet. When too much insulin is produced, dopamine, or the well-known "pleasure" hormone that controls insulin levels, causes feelings of pleasure. In the pancreas, a protein called VMAT2 transports dopamine into a sac called a "vesicle" to protect it from degradation by monoamine oxidase (MAO). The dopamine stored in the vesicle is then released with insulin into the extracellular space of the beta cell, where it binds to specific receptors on the beta cell plasma membrane and acts as a brake for insulin secretion. Thus, by regulating dopamine, VMAT2 also regulates pancreatic insulin levels.
At the same time, the degradation of dopamine by MAO produces a chemical called "reactive oxygen species" that, when produced in excess, can damage beta cells.
Dr. Kume said, "We wanted to understand the exact mechanisms by which VMAT2 and dopamine signaling regulate beta cell function and glucose homeostasis." To do this, Dr. Kume and his team created a genetically mutated mouse model of a beta cell that lacks the VMAT2 protein: the "betaVmat2KO" mouse. They then conducted experiments feeding these and wild-type mice a conventional diet and a high-fat diet, and monitored subsequent changes in their β-cell structure and function over the following weeks. As expected, shortly after feeding, βVmat2KO mice showed increased insulin secretion. However, chronic consumption of the high-fat diet led to impaired glucose and insulin tolerance as well as β-cell depletion.
This prompted the researchers to deduce the following: a high-sugar and high-fat diet increases both insulin and dopamine production. But when VMAT2 is absent from the beta cells, dopamine is still exposed to and degraded by MAO. However, as the amount of dopamine increases, its reaction with MAO rapidly produces reactive oxygen hydrogen peroxide. With the passage of time, this constant oxidative stress leads to beta cell loss and depletion. Thus, a high-fat diet accelerates β-cell depletion and may lead to the development of diabetes in βVmat2KO mice as they age.
In this case, VMAT2 protects β cells from oxidative stress induced by a high-fat diet in diabetics.
"We are pleased to find that VMAT2 protein also plays a critical role in the cellular response to excess nutrition, such as a high-fat diet, and our findings highlight the possibility of using VMAT2 as a target for novel therapeutic approaches against diabetes."
