A 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.
"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 the senior author.
" Our studies suggest that glucagon also contributes to cardiac dysfunction by altering lipid utilization in the heart," said the lead author. "By blocking glucagon action [in mice], we revealed unexpected effects of glucagon, most notably on glucose uptake into skeletal and cardiac muscle."
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 current 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 another author. "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 glucagon levels promote the accumulation of harmful bioactive lipids, which in turn stunt insulin signaling and decrease ventricular function, added co-first author.
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 the senior author.
Glucagon's role in diabetic heart disease
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