People with type 1 or type 2 diabetes who take insulin have a higher risk of developing hypoglycemia, or low blood sugar. Now, a study of how a protein works in the pancreas could lead to new treatments for protecting against the potentially life-threatening condition.
Dr. Gina L. C. Yosten, who is an assistant professor of pharmacology and physiology at Saint Louis University in Missouri, and her team discovered the protein, which has the name neuronostatin, in earlier work.
They found that neuronostatin could prevent hypoglycemia by getting the pancreas to raise blood sugar in two ways. One way is to make less insulin, which is a hormone that reduces blood sugar, and the other is to produce more glucagon, a hormone that increases blood sugar.
In the more recent investigation, the scientists showed that injecting rats with neuronostatin raised the animals' blood sugar levels.
They also found that low blood sugar causes human pancreatic tissue to release more neuronostatin and that treatment with glucagon triggers more neuronostatin release.
The team says that, with more research, these findings could lead to neuronostatin becoming a target for drugs to prevent and treat hypoglycemia in people with type 1 and type 2 diabetes.
The study has featured at the annual meeting of the American Physiological Society during the Experimental Biology 2019 interdisciplinary meeting, which is taking place from April 6–9 in Orlando, FL.
"There are very few options," says Stephen Grote, a doctoral student in Dr. Yosten's group, "for preventing hypoglycemia or treating hypoglycemia unawareness other than avoiding low blood sugar as much as possible."
"Understanding what neuronostatin does and how it works will provide valuable information for preventing hypoglycemia and provide more complete knowledge into how the pancreas manages blood sugar normally," he adds.
Diabetes and the pancreas
Diabetes arises because the body has problems making or using insulin, which is a hormone that helps cells to take in glucose, or blood sugar, and use it for energy.
There are two main types of diabetes: type 1 and type 2. The vast majority of people with diabetes have type 2.
In type 1 diabetes, the body does not make enough insulin, and so people with this type need to take insulin every day to stop their blood sugar rising to dangerous levels.
In type 2 diabetes, the cells of the body cannot use insulin effectively. The pancreas tries to make up for it by making even more insulin, but, eventually, this is not enough, and people need to take extra insulin to control their blood sugar.
According to the World Health Organization (WHO), the number of people worldwide with diabetes rose from 108 to 422 million during 1980–2014.
In the United States, there are around 30 million people with diabetes of which 90–95 percent have type 2.
A need for better treatments
People with diabetes who take too much insulin may experience low blood sugar that can leave them dizzy and sleepy. If their sugar levels continue to drop, there is a high risk that more severe symptoms will follow, including seizures and loss of consciousness.
There is also a risk that episodes of hypoglycemia can develop into a vicious cycle of increasing severity, as the condition can reduce people's ability to notice the symptoms and, consequently, the chance to intervene.
There is a need, therefore, for improved treatments and a deeper understanding of how hypoglycemia develops in diabetes.
In the new study, Dr. Yosten and her team showed how neuronostatin increased glucagon by interacting with certain types of receptor proteins in the pancreatic alpha cells that release the hormone.
In addition, they demonstrated that, in response to higher glucose levels, neuronostatin reduced insulin production by pancreatic beta cells.
In a meeting abstract about the study, the team notes that this suggested that neuronostatin "is a pancreatic component of the counterregulatory response to hypoglycemia."
To confirm this, the researchers then showed that infusing male rats with neuronostatin for 30 minutes "substantially increased" their blood glucose levels.
Also, treatment with neuronostatin slowed down the clearance of glucose and reduced the production of insulin in response to hyperglycemia.
Further tests also revealed that pancreatic cells exposed to low glucose released neuronostatin, and that fasting blood glucose raised blood levels of neuronostatin in rats.
Potential to protect against hypoglycemia
The researchers say that scientists need to do further studies now to confirm that neuronostatin can prevent or reverse hypoglycemia, and to find out which mechanisms and signaling pathways the body uses.
"We propose," they note, "that [neuronostatin] could represent a novel therapeutic target for the treatment and prevention of hypoglycemia in diabetes."
The team is carrying on with its work to find out how the body controls neuronostatin and how it interacts with mechanisms of insulin and glucagon release in the pancreas.
"Neuronostatin is a truly novel factor," Grote explains, "and everything we find about it pushes our knowledge of its therapeutic potential just a bit further."
"We believe that studying neuronostatin could ultimately reveal a way to use it to help prevent and reverse vicious cycles of hypoglycemia by helping the body respond appropriately to the low blood sugar with more glucagon."