Abstract
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.
Introduction
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.
Conclusion and challenges
GLP-1RAs have been used to treat T2DM since 2005 and gained approval for weight management in 2014. In studies on cardiovascular diseases, GLP-1RAs have shown potential benefits. Notably, in high-quality large RCTs, tirzepatide demonstrated greater effectiveness than GLP-1R mono agonists in reducing serum glucose, fat mass, and body weight. Ongoing clinical trials will provide clarity on the presumed cardiovascular benefits of tirzepatide. However, the global supply of these medications remains limited, often resulting in a first-come, first-served distribution. To address this, there have been proposals to prioritize individuals at higher risk of premature death, aligning with ethical principles of equitable care. Nevertheless, it is crucial to consider the potential adverse effects of weight fluctuation after discontinuing these medications, particularly the increased risk of cardiovascular and all-cause mortality in patients with obesity or overweight.
For all their promise, GLP-1 and dual GIP/GLP-1 receptor agonists have raised more questions, particularly regarding their long-term safety implications. Clinical trials have provided limited insight into the long-term effects, as the longest trials spanned less than six years in adults and about one year in adolescents. Given the natural fluctuations in hormone levels and the intricate rhythms of human physiology throughout the day and over a person’s lifetime, there is concern about the uncertain health ramifications of sustained elevation of incretin activity over decades of treatment. Like virtually all medications, incretin mimetics come with side-effects, leading some patients to abandon treatment. Common adverse effects include nausea and vomiting, as well as increased hazards of gastroparesis and small bowel obstruction. The next generation of regimens may involve combining GLP-1 or dual GIP/GLP-1 receptor agonists with other nutrient-based hormone receptor agonists or antagonists that offer equal or greater effectiveness with fewer gastrointestinal adverse effects.