'Smart' insulin could reduce dangerous complications of diabetes treatment

Zhen Gu, PhD (front) & John Buse, MD, PhD

A study supported by the North Carolina Translational and Clinical Sciences (NC TraCS) Institute has developed a "smart" insulin that could reduce dangerous complications in people who use the drug to manage diabetes. This new type of insulin, called i-insulin, is released for action when the blood sugar or glucose levels rise and blocks its own activity when glucose levels fall.

The findings, generated in mice, appeared this week in the Proceedings of the National Academy of Sciences. The research was led by former University of North Carolina at Chapel Hill researcher Zhen Gu, PhD, now a professor of bioengineering at UCLA.

More pre-clinical tests and subsequent clinical trials in humans will be required before the smart insulin will be available to patients, according to study co-author John Buse, MD, PhD, co-PI of NC TraCS. "However, the vision, if realized, would be one of the most exciting advances in diabetes care," he said.

Diabetes affects more than 400 million people worldwide, and that number is expected to grow to 592 million by the year 2035. Patients with type 1 and advanced type 2 diabetes try to keep their blood sugar levels in check with regular finger pricks and repeated insulin shots, a process that is prone to human error. Injecting too much medication can lead to hypoglycemia and significant consequences such as seizures, brain damage, and even death. According to the International Diabetes Federation, diabetes caused 4.9 million deaths in 2014 alone.

According to Gu and his team at UCLA, insulin acts like a key that helps sugar or glucose gain entry into cells from the bloodstream. When the insulin key docks with its lock, called a receptor, it opens doors on fat and muscle cells that allow sugar to enter to be stored for future energy between meals. The doors are called glucose transporters. In this study, the researchers engineered a new type of insulin they called i-insulin by adding a glucose transporter inhibitor that plugs transporter molecules. What happens is that at low glucose levels, the i-insulin is bound to the glucose transporter and inactive. When glucose levels rise such as after a meal, the higher glucose competes with the i-insulin for glucose transporter sites and as a result insulin is released into the blood stream to dock with its lock and lower glucose levels.

"Our new i-insulin works like a 'smart' key," said Gu. "The insulin lets glucose into the cell, but the added inhibitor molecule prevents too much from going in when blood sugar is normal. This keeps blood sugar at normal levels and reduces the risk of hypoglycemia."

The team tested the smart insulin on a mouse model of type 1 diabetes. They found that a single injection if i-insulin kept blood sugar levels within the normal range for up to 10 hours, compared to only four hours in mice treated with traditional insulin. The mice treated with i-insulin did not become hypoglycemic, even after a second injection.

"The new insulin has the potential to be optimized for response times and how long it could last in the body before another dose would be required," said Gu. "And it could be delivered in other methods, such as a skin patch that automatically monitors blood sugar levels, or in pills."

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and NC TraCS. NC TraCS is the integrated hub for the Clinical and Translational Science Awards (CTSA) program at UNC-Chapel Hill. The CTSA program is led by the NIH's National Center for Advancing Translational Sciences (NCATS). NC TraCS combines the research strengths, resources, and opportunities of UNC and its partners to accelerate clinical and translational research from health science discovery to dissemination to patients and communities.

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