Using a lab-designed protein to regulate blood glucose levels

Researchers at the Indiana University School of Medicine have discovered a new way to regulate blood glucose levels using a lab-designed protein, possibly opening the door to a new treatment avenue for people with Type 1 diabetes.

The findings, published in ACS Pharmacology and Translational Science, showed improvement in rats treated with the substance, which combines insulin and glucagon into one molecule.

Insulin is a hormone that lowers blood sugar levels, while another hormone, glucagon, does the opposite. People with Type 1 diabetes struggle to create enough insulin because their immune systems attack the cells in the pancreas that produce insulin, requiring them to inject a synthetic version of the hormone to manage blood sugar levels.

Patients must constantly balance blood sugar levels in this way, as too much glucose (hyperglycemia) or too little (hypoglycemia) can each lead to significant health risks including death.

The research team's new protein works by mimicking the two hormones and in turn signaling the liver, which naturally responds to insulin and glucagon depending on the body's needs.

The effort was spearheaded by IU School of Medicine Distinguished Professor Michael A. Weiss, MD, PhD, and compliments his previous research on similar "smart insulins." Previously, Weiss created a synthetic hinge that could react to such a substance and more accurately regulate body blood sugar levels.

For the past century, coping with hypoglycemia (the lows) has been an ever-present challenge in Type 1 diabetes. This has made creating glucose-responsive insulins (smart insulins) a major goal. Our approach simplifies such design by exploiting an endogenous 'smart' switch in the liver, how the body naturally adjusts relative hormonal responses based on whether the blood glucose level is high or low: Too high, insulin wins; too low, glucagon wins."

Michael A. Weiss, MD, PhD, Distinguished Professor, IU School of Medicine 

Many Type 1 diabetes patients must currently inject insulin and glucagon separately. Stress, diet, hormonal fluctuations and physical activity levels further complicate the balancing act.

In addition to the treatment results, the new form of insulin remained stable for weeks without refrigeration prior to being opened. This would make it easier to produce and store than currently available insulin, which typically requires refrigeration.

Though the results are promising, Weiss cautioned the research is still early in development. Many steps remain before the hybrid medication is cleared for public use.

The researchers hope to develop two types of a "smart insulin": One meant for injection once per week, and the other a short-acting variety for use in insulin pumps.

This research was funded by a variety of grants, including the IU Precision Health Initiative, the IU School of Medicine INCITE Fund of the Lilly Foundation, the Type 1 Diabetes "Grand Challenge" program of Breakthrough T1D UK and Steve Morgan Foundation UK.

Other IU School of Medicine contributors to this researcher were: former graduate student Nicolas Varas; research faculty members Mark A. Jarosinski, Yen-Shan Chen and Yanwu Yang; and post-doctoral fellow Chun-Lun Ni.

Rat studies were formed in collaboration with Dr. Raimund Herzog of the Yale School of Medicine.