Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain’s satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two naturally occurring hormonal peptides produced in gastrointestinal tract, knowns as incretins. Together, they orchestrate a crucial hormonal regulation known as the incretin effect. The concept of incretin effect was first proposed by Creutzfeldt in the 1970s, based on the early observations that insulin secretion was two to three times higher after oral glucose intake than that after an isocaloric intravenous glucose administration. The incretin effect was estimated to account for approximately 50% - 70% of the postprandial insulin responses in healthy individuals and may be substantially reduced to 20% – 30% in individuals with type 2 diabetes mellitus (T2DM), a complex disorder arising from inadequate compensation of insulin secretion by pancreas to counter peripheral insulin resistance. Consequently, researchers have devoted decades to studying incretins, postulating that incretin-based therapies could potentially reverse this diminished incretin effect and restore insulin secretion in patients with T2DM. This review presents a concise history of the discoveries of GIP and GLP-1, explores the physiology and pharmacology of incretins and their synthetic mimetics, and discusses the therapeutic applications of the USA FDA-approved GLP-1 and dual GIP/GLP-1 receptor agonists.
The first incretin, GIP, was purified from canine intestinal extracts in the late 1960s and initially named gastric inhibitory polypeptide because the peptide inhibited gastrin-stimulated H+ secretion. In the early 1970s, Dupre et al. discovered that infusion of GIP purified from porcine duodenojejunal mucosa, when combined with glucose, led to enhanced insulin secretion and improved glucose intolerance in humans. As a result, GIP was designated as the first incretin. In normal subjects, both fat and carbohydrate stimulate GIP secretion from enteroendocrine K cells, which are dispersed in the upper portion of the gastrointestinal tract (duodenum and jejunum). Interestingly, fat appears to be a stronger stimulator of GIP secretion than carbohydrate. Most intestinal K cells secrete a biologically active form of GIP consisting of 42 amino acids, GIP (1–42), which is derived from a 153 amino acid preprohormone precursor distinct from preproglucagon. GIP is conserved across mammalian species; purification and sequencing of porcine and bovine GIP revealed only minor differences (two amino acids in porcine and one in bovine) compared to the human GIP peptide.
The discovery of the second incretin, GLP-1, originated from observations in 1982 that anglerfish proglucagon mRNA contained coding sequences of glucagon-related peptide, flanked by pairs of basic amino acids characteristic of the sites cleaved during post-translational processing of prohormones. In 1983, Bell et al. reported the human and hamster GLP-1 gene and the deduced peptide sequences using cDNA hybridization technology and analysis of the human preproglucagon gene. In 1986, Mojsov et al. utilized rabbit anti-serum generated from synthetic peptide to identify GLP-1 peptide in both human pancreatic and intestinal tissues. Meanwhile, Holst et al. employed hydrophobic gel permeation and HPLC technique to isolate GLP-1 from pig ileal mucosa. Subsequently, these two groups independently reported that the synthetic GLP-1 peptide acted as a potent stimulator of insulin secretion in isolated perfused rat pancreas and isolated perfused pig pancreas, respectively, thus implicating GLP-1 as the second incretin. This second incretin is produced by enteroendocrine L cells, which are diffusedly distributed in the distal gut mucosa of ileum and colon. GLP-1 exists in two equipotent circulating peptides: GLP-1 (7–37) and GLP-1 (7–36) amide, with GLP-1 (7–36) amide being more abundant in the circulation after a meal. The complete conservation of GLP-1 across all mammalian species underscores its critical physiological role.
GIP and GLP-1 concentrations appear to be highly variable among individuals, both with and without T2DM. Interestingly, the mean values remain relatively normal in most T2DM groups, suggesting that the impaired incretin releases are not a typical prerequisite for the development of T2DM. The fasting plasma levels of GIP typically range between 10 – 20 pM with the peak values reaching around 80 – 150 pM after a meal. On the other hand, fasting plasma levels of bioactive GLP-1 typically fall within the ranges of 5 - 15 pM and could increase 3 – 5 fold postprandially. Under physiological conditions, postprandial GIP levels are approximately 3 – 4 times higher in molar concentration compared to GLP-1, irrespective of diabetic status.
Shortly after food intake, these incretins are released into body circulation and bind to their receptors. The physiological effects of GIP and GLP-1 are closely tied to the distribution of their respective receptors in various tissues and organs. Among the tissues and organs crucial in regulating glucose and lipid metabolism, pancreas, brain, and adipocytes express GIP receptors (GIPRs), while pancreas, brain, and gastrointestinal tract are rich in GLP-1 receptors (GLP-1Rs). GIPR was first cloned in rats, identifying a 455-amino acid glycoprotein with a predicted molecular weight of approximately 59 kDa. Distinct from GIPR, GLP-1R consists of 463 amino acids and has a molecular weight of 62 kDa. Both GIPR and GLP-1R belong to the class B family of 7-transmembrane G protein-coupled receptors (GPCR) within the glucagon receptor superfamily. The C-terminal of hormone binds to the extracellular domain, while the N-terminal interacts with the transmembrane domain of the receptor. Notably, a study by Finan et al. reported that the half-maximal effective concentrations (EC50) of GIP with GIPR and of GLP-1 with GLP-1R are 20 pM and 28 pM, respectively, without exhibiting cross-reactivity.
The hormonal binding at the extracellular domain is communicated to the intracellular receptor side, leading to G protein engagement and activation. The differential insulinotropic potency and other physiological effects of GIP and GLP-1 in both healthy individuals and those with T2DM may be linked to their distinct receptors and the downstream G proteins that transmit signals intracellularly. These pathways exhibit both overlapping function, such as stimulation of adenylate cyclase/cAMP pathway, and unique signaling transduction cascades. Notably, in murine pancreatic β-cells, GLP-1 can activate both G proteins Gαs and Gαq, whereas GIP selectively activates Gαs. Despite extensive research into the mo
