Targeting glucagon pathway may offer a new approach to treating diabetes

April 12, 2012 in Diabetes

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.

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

Provided by Columbia University Medical Center search and more info website

not rated yet  

Rank not rated yet
Relevant PhysicsForums posts

More news stories

Rise in type 2 diabetes amongst young

The number of young people diagnosed with type 2 diabetes has seen the sharpest rise over the last twenty years compared to a background of a general increase across the board, new University research has ...

Diabetes created 40 minutes ago | popularity not rated yet | comments 0

Research uncovers a potential role of two proteins in diabetes

(Medical Xpress)—Flinders University researchers are breaking new ground in a decade-long journey to pinpoint the function of two closely related proteins.

Diabetes created 1 hour ago | popularity not rated yet | comments 0 | with audio podcast

Exercise prevents fructose-induced hypertriglyceridemia

(HealthDay)—Moderate aerobic exercise prevents fructose-induced hypertriglyceridemia in healthy males, according to a study published online May 14 in Diabetes.

Diabetes created May 17, 2013 | popularity 5 / 5 (1) | comments 0 | with audio podcast

DNA variant affects diabetes risk and treatment response

A DNA variant near a digestive enzyme does not only affect risk of developing diabetes but also affects the response to treatment, an international consortium of researchers including the University of Dundee has found.

Diabetes created May 17, 2013 | popularity not rated yet | comments 0 | with audio podcast

The artificial pancreas that keeps tabs on sugar

(Medical Xpress)—Development of a sophisticated artificial pancreas holds potential to transform the lives of patients with Type 1 diabetes.

Diabetes created May 16, 2013 | popularity 5 / 5 (1) | comments 0 | with audio podcast


Pre-proceedings process fails to reduce length of care proceedings, but can help divert cases from court

A major new report on a procedure that aims to reduce the duration of care proceedings for children has found it made no significant difference to what happened in court, and cases lasted just as long regardless of whether ...

Report reveals impact of public injecting

New research undertaken on the streets of Richmond and Abbotsford has revealed increasing health risks for people who inject drugs and significant community concern over the impact of injecting in public ...

Wireless ultrasound transducers help physicians

Siemens has presented the world's first ultrasound system with wireless transducers. The system's transducers, which can be easily operated with one hand, transmit ultrasound images via radio waves to the ...

Vitamin D could provide new and effective treatments for asthma

(Medical Xpress)—Scientists at King's College London have discovered that Vitamin D has the potential to significantly reduce the symptoms of asthma. The study, led by Professor Catherine Hawrylowicz from ...

Immune protein could stop diabetes in its tracks

Melbourne researchers have identified an immune protein that has the potential to stop or reverse the development of type 1 diabetes in its early stages, before insulin-producing cells have been destroyed.

Lymphatic fluid takes detour

When tumours metastasise, they can block lymphatic vessels, as researchers from ETH Zurich have discovered using a new method. The lymphatic fluid subsequently has to find a new path through the tissue. Such ...