Three hormones, three receptors
GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon are hormones produced in the gastrointestinal tract and pancreas in response to eating. Each acts through a distinct G protein-coupled receptor (GPCR). Together, they regulate blood glucose, appetite, energy expenditure, and body composition. Triple receptor agonism - activating all three simultaneously - has emerged as one of the most studied approaches in metabolic research.
GLP-1: the satiety and insulin signal
GLP-1 is an incretin hormone released from L-cells in the small intestine in response to nutrient ingestion. Its primary actions include stimulating insulin secretion from pancreatic beta cells in a glucose-dependent manner (only when blood glucose is elevated), suppressing glucagon from alpha cells, slowing gastric emptying, and signalling satiety through hypothalamic and vagal pathways.
The glucose-dependency of GLP-1's insulin stimulus is significant: it substantially reduces the risk of hypoglycaemia compared to insulin itself. Native GLP-1 has a half-life of approximately 2 minutes due to rapid cleavage by dipeptidyl peptidase-4 (DPP-4). GLP-1 receptor agonists developed for research and pharmaceutical use are engineered with resistance to DPP-4 degradation, extending activity from minutes to hours or weeks.
Published trials of GLP-1 receptor agonists (such as semaglutide, NEJM 2021) have shown substantial reductions in body weight and cardiovascular event rates in participants with obesity and type 2 diabetes.
GIP: the forgotten incretin
GIP (glucose-dependent insulinotropic polypeptide) is released from K-cells in the proximal small intestine. Like GLP-1, it stimulates insulin secretion in a glucose-dependent manner. GIP also acts on adipose tissue to promote energy storage, and has direct effects on bone metabolism and possibly the brain.
GIP was historically considered less therapeutically useful than GLP-1 because GIP receptors become down-regulated in type 2 diabetes, reducing the hormone's effectiveness. However, combined GLP-1 and GIP receptor agonism appears to produce greater weight loss than GLP-1 agonism alone - a synergistic effect seen in trials of tirzepatide (Lancet 2021, SURMOUNT-1 trial), suggesting GIP adds meaningful activity when the two pathways are co-activated.
Glucagon: the counterbalance
Glucagon is produced by pancreatic alpha cells and raises blood glucose by stimulating glycogen breakdown and gluconeogenesis in the liver - the physiological opposite of insulin. Adding glucagon receptor agonism to a metabolic compound might seem counterproductive for glucose management, but the picture is more complex.
Glucagon receptor activation increases energy expenditure, promotes fat oxidation in the liver (reducing hepatic steatosis), and may increase basal metabolic rate. When co-administered with GLP-1 receptor agonism (which offsets glucagon's glucose-raising effect through insulin stimulation and glucagon suppression), the net result in research models has been weight loss beyond what GLP-1 alone achieves, with manageable effects on glucose control.
Triple agonism in research
Retatrutide (LY3437943), developed by Eli Lilly, is a single peptide molecule that acts as an agonist at all three receptors - GLP-1R, GIPR, and GCGR. Phase 2 clinical trial results published in the New England Journal of Medicine (Jastreboff et al., 2023) showed mean weight reductions of approximately 17% over 24 weeks and up to 24% over 48 weeks in participants with obesity. These results represented the largest weight reductions observed in a pharmaceutical trial at that time.
Understanding triple agonism requires understanding what each component contributes - the combined effect is greater than any single receptor pathway, which is why this mechanism has attracted significant research attention.
References: Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018. Jastreboff AM et al. Triple-hormone-receptor agonist retatrutide for obesity. N Engl J Med. 2023. Frias JP et al. Tirzepatide versus semaglutide. Lancet. 2021.
Three hormones, three receptors
GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon are hormones produced in the gastrointestinal tract and pancreas in response to eating. Each acts through a distinct G protein-coupled receptor (GPCR). Together, they regulate blood glucose, appetite, energy expenditure, and body composition. Triple receptor agonism - activating all three simultaneously - has emerged as one of the most studied approaches in metabolic research.
GLP-1: the satiety and insulin signal
GLP-1 is an incretin hormone released from L-cells in the small intestine in response to nutrient ingestion. Its primary actions include stimulating insulin secretion from pancreatic beta cells in a glucose-dependent manner (only when blood glucose is elevated), suppressing glucagon from alpha cells, slowing gastric emptying, and signalling satiety through hypothalamic and vagal pathways.
The glucose-dependency of GLP-1's insulin stimulus is significant: it substantially reduces the risk of hypoglycaemia compared to insulin itself. Native GLP-1 has a half-life of approximately 2 minutes due to rapid cleavage by dipeptidyl peptidase-4 (DPP-4). GLP-1 receptor agonists developed for research and pharmaceutical use are engineered with resistance to DPP-4 degradation, extending activity from minutes to hours or weeks.
Published trials of GLP-1 receptor agonists (such as semaglutide, NEJM 2021) have shown substantial reductions in body weight and cardiovascular event rates in participants with obesity and type 2 diabetes.
GIP: the forgotten incretin
GIP (glucose-dependent insulinotropic polypeptide) is released from K-cells in the proximal small intestine. Like GLP-1, it stimulates insulin secretion in a glucose-dependent manner. GIP also acts on adipose tissue to promote energy storage, and has direct effects on bone metabolism and possibly the brain.
GIP was historically considered less therapeutically useful than GLP-1 because GIP receptors become down-regulated in type 2 diabetes, reducing the hormone's effectiveness. However, combined GLP-1 and GIP receptor agonism appears to produce greater weight loss than GLP-1 agonism alone - a synergistic effect seen in trials of tirzepatide (Lancet 2021, SURMOUNT-1 trial), suggesting GIP adds meaningful activity when the two pathways are co-activated.
Glucagon: the counterbalance
Glucagon is produced by pancreatic alpha cells and raises blood glucose by stimulating glycogen breakdown and gluconeogenesis in the liver - the physiological opposite of insulin. Adding glucagon receptor agonism to a metabolic compound might seem counterproductive for glucose management, but the picture is more complex.
Glucagon receptor activation increases energy expenditure, promotes fat oxidation in the liver (reducing hepatic steatosis), and may increase basal metabolic rate. When co-administered with GLP-1 receptor agonism (which offsets glucagon's glucose-raising effect through insulin stimulation and glucagon suppression), the net result in research models has been weight loss beyond what GLP-1 alone achieves, with manageable effects on glucose control.
Triple agonism in research
Retatrutide (LY3437943), developed by Eli Lilly, is a single peptide molecule that acts as an agonist at all three receptors - GLP-1R, GIPR, and GCGR. Phase 2 clinical trial results published in the New England Journal of Medicine (Jastreboff et al., 2023) showed mean weight reductions of approximately 17% over 24 weeks and up to 24% over 48 weeks in participants with obesity. These results represented the largest weight reductions observed in a pharmaceutical trial at that time.
Understanding triple agonism requires understanding what each component contributes - the combined effect is greater than any single receptor pathway, which is why this mechanism has attracted significant research attention.
References: Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018. Jastreboff AM et al. Triple-hormone-receptor agonist retatrutide for obesity. N Engl J Med. 2023. Frias JP et al. Tirzepatide versus semaglutide. Lancet. 2021.
