Team provides insight into glucagon's role in diabetic heart disease

February 21, 2018 by Patrick Wascovich, UT Southwestern Medical Center
Touchstone Center provides insight into glucagon's role in diabetic heart disease
Findings by Touchstone Center for Diabetes Research may advance the understanding of how diabetes drugs benefit heart function. Credit: UT Southwestern Medical Center

A UT Southwestern study reveals 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, from the Touchstone Center for Diabetes Research, may advance understanding of how 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 potent negative effects that fats have on tissues," said Dr. Philipp Scherer, Director of the Touchstone Center and Professor of Internal Medicine and Cell Biology at UT Southwestern, which is recognizing its 75th anniversary this year.

The study, published in Cell Reports, builds on decades of discoveries at the Touchstone Center, first directed by Dr. Roger Unger, Professor of Internal Medicine and holder of the Touchstone/West Distinguished Chair in Diabetes Research.

"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. He received the 2014 Rolf Luft Award from the Karolinska Institutet for that finding. A UTSW faculty member since 1956 and Director of the Touchstone Center from 1986 to 2007, 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 U.S. 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.

Using Type 2 diabetic mice models, the researchers investigated the metabolic effects of the drug REMD 2.59, a human antibody and competitive glucagon receptor antagonist. The antibody improved glucose levels in the blood and enhanced insulin action in liver and skeletal muscle. Also, nondiabetic mice with cardiac-specific challenges showed improvements in contractile function with REMD 2.59 treatment.

"Particularly exciting is that diabetes-related cardiomyopathy - diseases of heart muscle - dramatically declined," said author Dr. Zhao Wang, Assistant Professor of Internal Medicine in the Division of Cardiology. "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."

The study showed that elevated levels promote the accumulation of harmful bioactive lipids, which in turn stunt insulin signaling and decrease ventricular function, added co-first author Ankit Sharma, a Research Technician II in the Touchstone Center.

Future studies will be needed to investigate whether the demonstrated anti-lipotoxic effects in different tissues translate into the clinical setting, while the functional improvements in the heart need further definition, said Dr. Scherer, who has directed the Touchstone Center for more than a decade and holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research.

Explore further: Research elucidates hormone ghrelin's role in blood glucose regulation

More information: Ankit X. Sharma et al. Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice, Cell Reports (2018). DOI: 10.1016/j.celrep.2018.01.065

Related Stories

Research elucidates hormone ghrelin's role in blood glucose regulation

May 9, 2017
UT Southwestern research investigating the blood glucose-regulatory actions of the hormone ghrelin may have implications for development of new treatments for diabetes.

High insulin levels tied to obesity pathway, research shows

August 25, 2014
UT Southwestern Medical Center researchers have identified a crucial link between high levels of insulin and pathways that lead to obesity, a finding that may have important implications when treating diabetes.

Double advantage of potential new diabetes treatment

April 19, 2016
Blocking the hormone that raises sugar levels in the blood could increase insulin levels while keeping blood sugar levels down.

Researchers uncover potential 'cure' for type 1 diabetes

January 26, 2011
Type 1 diabetes could be converted to an asymptomatic, non-insulin-dependent disorder by eliminating the actions of a specific hormone, new findings by UT Southwestern Medical Center researchers suggest.

Similar defects ID'd for T2DM, chronic pancreatitis and diabetes

August 2, 2017
(HealthDay)—Patients with type 2 diabetes and those with diabetes secondary to chronic pancreatitis have similarly impaired α-cell responses to oral glucose ingestion and hypoglycemia, according to a study published online ...

Low-carb diet cuts tx effect of glucagon in hypoglycemia

November 7, 2016
(HealthDay)—For patients with type 1 diabetes, a low-carbohydrate diet (LCD) results in lower incremental rises in plasma glucose (PG) after mild hypoglycemia compared with an isocaloric high-carbohydrate diet (HCD), according ...

Recommended for you

High gluten diet in pregnancy linked to increased risk of diabetes in children

September 19, 2018
A high gluten intake by mothers during pregnancy is associated with an increased risk of their child developing type 1 diabetes, suggests a study published by The BMJ today.

Anti-inflammatory protein promotes healthy gut bacteria to curb obesity

September 19, 2018
Scientists from the UNC School of Medicine discovered that the anti-inflammatory protein NLRP12 normally helps protect mice against obesity and insulin resistance when they are fed a high-fat diet. The researchers also reported ...

Study reveals the current rates of diagnosed type 1 and type 2 diabetes in American adults

September 18, 2018
A new study from the University of Iowa finds that type 2 diabetes remains overwhelmingly the most common type of diabetes diagnosed in American adults who have the disease.

Research reveals link between immunity, diabetes

September 14, 2018
When it comes to diet-induced obesity, your immune system is not always your friend.

BPA exposure in U.S.-approved levels may alter insulin response in non-diabetic adults

September 14, 2018
In a first study of its kind study, researchers have found that a common chemical consumers are exposed to several times a day may be altering insulin release. Results of the study, led by scientists at the University of ...

High blood sugar during pregnancy ups risk of mother's type 2 diabetes, child's obesity

September 11, 2018
Mothers with elevated blood glucose during pregnancy—even if not high enough to meet the traditional definition of gestational diabetes—were significantly more likely to have developed type 2 diabetes a decade after pregnancy ...

0 comments

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.