Pharmacology of Gut Hormone Mimetics for Obesity and Diabetes

Amplifying the antidiabetic actions of glucagon‐like peptide‐1: Potential benefits of new adjunct therapies

“…Indeed, such metabolic benefits are typified by the endogenously produced hormone oxyntomodulin that co-activates GLP-1 and glucagon receptors, and similar to GLP-1, it is also encoded by the proglucagon gene. 12 In this regard, a number of GLP-1/glucagon dual-acting peptides have been developed and assessed in preclinical models. In diet-induced obese mice, AstraZeneca's dual agonist cotadutide increased energy expenditure and satiety resulting in up to 30% greater weight loss than liraglutide, a long-acting GLP-1 receptor agonist clinically approved for type 2 diabetes and obesity.…”

“…Glucose-dependent insulinotropic peptide is a 42-amino-acid peptide secreted from intestinal K-cells upon nutrient absorption. 12 Once released, this hormone acts on pancreatic beta-cell GIP receptors to enhance glucose-stimulated insulin secretion, similar to GLP-1 (Table 1). Likewise, the activation of hypothalamic neuronal GIP receptors may reduce food intake, 23 with GIP receptor expressing neurons distinct from GLP-1, increasing potential for co-agonist therapy benefits.…”

“…Peptide tyrosine-tyrosine is a 36-amino acid hormone secreted from the GIT in response to nutrient absorption. 12 PYY(1-36) is believed to improve long-term betacell function via activation of islet cell Y1 receptors and resulting benefits of beta-cell turnover. 39 Notably, in the acute setting, Y1 receptor activation by PYY(1-36) inhibits glucose-induced insulin release, with this beta-cell rest effect thought to contribute to the enduring beta-cell benefits.…”

“…Cholecystokinin is a gut hormone secreted from I-cells within the GIT following nutrient intake. 12 The full-length hormone is cleaved by processing enzymes to produce several bioactive fragments, the smallest and most druggable, being CCK-8. Collectively, these CCK peptides act on CCK1 and CCK2 receptors, the latter almost exclusively expressed within the CNS.…”

“…Structurally similar to CCK, gastrin is a hormone secreted from G cells located on the pyloric antral mucosa and duodenum, which preferentially acts on CCK2 receptors. 12 Within the pancreas, gastrin and its target CCK2 receptor are produced and expressed in mouse islets, respectively (52), with gastrin monotherapy shown to increase betacell mass via transdifferentiation of exocrine ductal cells (62). When given in combination with GLP-1, gastrin significantly augments beta-cell mass both in diabetic db/db (63) and in non-obese diabetic (64) mice.…”