Revelation of glucagon's role in diabetic heart disease

A new study has provided insight into glucagon's role in diabetic heart disease.

The UT Southwestern-led study revealed the hormone glucagon's importance to the development of insulin resistance and cardiac dysfunction during Type 2 diabetes, presenting opportunities to develop new therapies for diabetic diseases of the heart muscle.

These findings might provide an advanced understanding of how diabetes drugs benefit heart function, especially considering cardiovascular disease is the leading cause of death in diabetics.

"This investigation found that inhibiting glucagon action has potent anti-diabetic effects. This treatment reduces the potential negative effects that fats have on tissues," said Dr Philipp Scherer, Director of the Touchstone.

The study built on decades of discoveries at the Touchstone Center, first directed by Dr Roger Unger.

"Dr Unger's work established an important role for glucagon as a driving force for hyperglycemia, or excess glucose in the bloodstream, during the onset of diabetes. Our studies suggest that glucagon also contributes to cardiac dysfunction by altering lipid utilization in the heart," said Dr William Holland, former Assistant Professor of Internal Medicine who completed and published the work while a member of the Touchstone Center.

"By blocking glucagon action [in mice], we revealed unexpected effects of glucagon, most notably on glucose uptake into skeletal and cardiac muscle."

Dr Unger first identified glucagon as a pancreatic hormone that raises blood sugar levels, having the opposite effect of insulin. A UTSW faculty member since 1956, Dr Unger developed a test in the mid-1950s to measure concentrations of glucagon.

The Centers for Disease Control and Prevention (CDC) estimated that about 30.3 million people - or 9.4 percent of the American population - had diabetes in the latest reported year, 2015. That included 7.2 million undiagnosed or unreported adult cases. That same year, diabetes was the seventh-leading cause of death in the U.S., with more than 79,500 fatalities.

The latest investigation tackled a conundrum in the field of diabetes research. Glucagon-containing agonists have been studied as a diabetes treatment in animal models, as they enhance weight loss. Similarly, weight loss also is seen by blocking glucagon action.

The UTSW study in mice suggests that this discrepancy can be mediated by access to the brain. The study's drug still allows high glucagon levels to get to the brain, which decreases appetite and weight gain.

"Particularly exciting is that diabetes-related cardiomyopathy - diseases of heart muscle - dramatically declined", said author Dr Zhao Wang

"Since more than two out of every three diabetic patients develop heart failure, these findings shed new light on glucagon-based therapies and may set the stage for using glucagon blockers to treat diabetes, diabetic cardiomyopathy, and potentially other forms of heart disease", continued Dr Wang.

The study showed that elevated glucagon levels promote the accumulation of harmful bioactive lipids, which in turn stunt insulin signalling and decrease ventricular function, added co-first author Ankit Sharma.

The findings are from 'Touchstone Center for Diabetes Research' and are published in journal Cell Reports.