Blocking the GLP-1 receptor with exendin(9-39) eliminates the improvements in insulin sensitivity and blood glucose control that result from liraglutide treatment in people with obesity and...
Mechanism
Synthesis from 1 study
Liraglutide works by turning on special receptors that tell the liver to make less sugar and help muscles absorb more sugar from the blood. When a blocker is given to turn off those receptors, the liver starts making sugar again and muscles stop absorbing it, so blood sugar rises. This proves the...
Most probable mechanism
Liraglutide binds to special receptors on liver and muscle cells, telling the liver to make less sugar and helping muscles take in more sugar from the blood. When a blocker is given to stop these receptors, the liver starts making more sugar again and muscles stop taking in as much, so blood sugar goes back up.
Liraglutide binds to GLP-1 receptors on hepatocytes and peripheral tissues including skeletal muscle and adipose tissue
GLP-1 receptor activation triggers intracellular signaling pathways (cAMP/PKA and/or ERK) that modulate metabolic gene expression and enzyme activity
Signaling reduces hepatic glucose production by suppressing gluconeogenesis and glycogenolysis
Signaling enhances glucose uptake in skeletal muscle and adipose tissue
GLP-1 receptor activation on pancreatic alpha cells suppresses glucagon secretion
Reduced glucagon levels further decrease hepatic glucose output
Lower blood glucose reduces the demand for insulin secretion, unmasking improved insulin sensitivity
GLP-1 receptor antagonism with exendin(9-39) reverses these effects by blocking receptor binding, restoring glucagon secretion and hepatic glucose output, and reducing peripheral glucose uptake
Evidence from Studies
Supporting (1)
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Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals with Obesity and Pre-Diabetes.
Contradicting (0)
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