Targeting glucagon pathway may offer a new approach to treating diabetes

April 12, 2012

Maintaining the right level of sugar in the blood is the responsibility not only of insulin, which removes glucose, but also of a hormone called glucagon, which adds glucose.

For decades, treatments for type II have taken aim at , but a new study suggests that a better approach may be to target glucagon's sweetening effect.

The findings were published today in the online edition of .

"What we've found is a way to reduce glucagon's influence on without the side effects of global ," said Ira Tabas, MD, PhD, Richard J. Stock Professor and Vice Chair of Research in the Department of Medicine and professor of Anatomy & Cell Biology (in Physiology and Cellular Biophysics), who led the study with Lale Ozcan, PhD, associate research scientist.

Though glucagon was discovered at the same time as insulin, research on it has languished compared with that of its cousin, and treatments have almost exclusively targeted the latter.

In the last decade, the success of incretins, a new class of drugs for type II diabetes, has sparked a renaissance in glucagon research. When they were first introduced, incretins were known to stimulate insulin secretion. But recent studies show that a significant part of their clinical success can be attributed to previously unsuspected inhibiting effects on glucagon secretion.

The experience with incretin has led to a renewed search for other drugs that act against glucagon, including compounds that block glucagon in the liver, where it acts to free glucose. Drugs that block the glucagon receptor in the liver have been tested, but glucagon has multiple roles, and recent early clinical trials show that it can raise cholesterol and lead to fat accumulation in the liver.

The new study shows how glucagon's effect on glucose could be disrupted without disturbing glucagon's other duties, raising prospects for a safer anti-glucagon diabetes treatment.

Drs. Tabas and Ozcan found that once glucagon binds to its receptor, glucose is fully released only after an enzyme called CaMKII is activated. When activated, CaMKII sends a protein called FoxO1 into the cell nucleus, where it turns on the genes needed for secretion. A related pathway, working in parallel to this one, sends a FoxO1 helper protein into the cell nucleus, as reported in a paper on which Dr. Tabas is a co-author, published online on April 8 in Nature (embargoed until that time).

"Even when their disease is well controlled, most patients with have excess glucagon action, so blocking CaMKII could potentially be a new way to lower blood sugar and better treat the disease," said Dr. Tabas.

When the researchers blocked CaMKII in obese, diabetic mice, the animals' blood sugar went down, with no negative side effects. Instead, cholesterol declined, insulin sensitivity improved, and the liver became less fatty.

"Until now, it has been difficult to block glucagon's effect on blood sugar without interfering with glucagon's other functions," said Dr. Tabas, "but we think CaMKII is different."

Dr. Tabas is now working on the possibility of developing a CaMKII inhibitor to treat diabetes.

Explore further: Research reveals hormone action that could lead to treatments for type 2 diabetes

More information: Drs. Ozcan's and Tabas' paper is titled, "Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity."

Related Stories

Recommended for you

Drug prevents type 1 diabetes in mice, study finds

September 14, 2015

The buildup of a substance in the pancreas during the pre-symptomatic stage of Type 1 diabetes is essential to the development of the disease, Stanford University School of Medicine researchers have shown.

Bacteria may cause type 2 diabetes

June 1, 2015

Bacteria and viruses have an obvious role in causing infectious diseases, but microbes have also been identified as the surprising cause of other illnesses, including cervical cancer (Human papilloma virus) and stomach ulcers ...

Engineered hot fat implants reduce weight gain in mice

August 20, 2015

Scientists at the University of California, Berkeley, have developed a novel way to engineer the growth and expansion of energy-burning "good" fat, and then found that this fat helped reduce weight gain and lower blood glucose ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.