The receptor
The glucagon receptor is a class B GPCR expressed mainly in liver, signalling through cyclic AMP. Glucagon mobilises stored glucose, opposing insulin.
The apparent contradiction
Adding glucagon agonism to a molecule intended to improve metabolic parameters seems self-defeating, since glucagon raises blood glucose. The research rationale is that glucagon receptor activation also increases energy expenditure and affects hepatic lipid handling.
The proposition being tested is that GLP-1 activity offsets the glycaemic effect while the energy-expenditure effect is retained. Whether that balance holds is exactly what triple-agonist research measures.
Why balance is the whole question
The ratio of activity across the three receptors determines the outcome. A molecule with the same three targets in different proportions is, functionally, a different compound.
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