The activity of GLP-1 and GIP for Type 2 Diabetes and Obesity.

The mechanism of GLP-1 and GIP signaling at homeostasis.

Obesity and Type 2 Diabetes has an increasing prevalence worldwide, presenting a major health challenge. They are two of the most common noncommunicable diseases in the world, and estimates predict one billion people worldwide are affected by obesity while approximately 521million individuals globally live with diabetes. According to the CDC, as of 2021, 38.1 million adults (14.7%) in the United States had diabetes, with the incidence increasing with age. 30-53% of new cases are directly linked to obesity. 2023 Population data from the CDC shows that in 23 states more than 1 in 3 adults has obesity, with notable differences by race, age, ethnicity, and socioeconomic class. Many diabetes treatments also impact weight loss and obesity medication such as GLP-1 agonists, combined with healthy lifestyle interventions, can positively impact morbidities associated with diabetes and obesity.1

Patients with Type 2 diabetes have diminished responses of incretin hormones compared to healthy individuals. Glucagon-like peptide 1 agonists (GLP-1) and Gastric inhibitory polypeptide (GIP) have emerged as valuable therapeutic agents for managing obesity and type 2 diabetes. For patients, GLP-1 & GIP agonists can stimulate insulinotropic responses similar to individuals with normal glycemic responses. 2,3 Given the systemic benefits of GIP on macronutrient metabolism and energy consumption, partnering with GLP-1 can impact glycemic and weight loss goals for many patients. 2,4

GLP-1 and GIP signaling in homeostasis, refer to figure. Upon ingestion of glucose and nutrients, incretin hormones (GIP and GLP-1) are secreted by endocrine cells that are in the epithelium of the small intestine and stimulate insulin secretion from pancreatic β cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), and increasing the level of intracellular cyclic adenosine monophosphate (cAMP), in pancreatic β cells. This initiates a cascade that leads to the activation of protein kinase A (PKA), closing of potassium channels, depolarization, and release of calcium from the endoplasmic reticulum.3 An increase of intracellular calcium levels within the cell initiates insulin expression in the nucleus, stimulates energy (ATP) production in the mitochondria, and triggers the release of insulin into the blood stream in a glucose dependent manner (image adapted from Adipogen Life Sciences).4,5

Several commercially and prescribed agents are now available for the management of obesity and type 2 diabetes. Considered a short acting agent, Exenatide, administered by twice-daily subcutaneous injection, was the first GLP-1 RA in clinical use. Long-acting agents like Exenatide (once weekly), Liraglutide, Dulaglutide, Semaglutide, and several others have been favored for use based on data from comparative trails. Additional dual agents that target GLP-1 and GIP include Tirzepatide, which has shown to provide greater glycemic control compared to available single agonist agents. Dual GLP-1 RA and glucagon agonists as well as Triple GLP-1/GIP/glucagon RA are still ongoing clinical evaluations but have shown significant reduction in HbA1c levels and weight management. Given the availability of these agents for treating obesity and type 2 diabetes, along with the several agents in development, and current demand, trends in clinical practice have shifted towards personalized and tailored use of these agent for individual patient needs.6

GLP-1 and GIP agonist offer various benefits in managing obesity and type 2 diabetes. Additionally, benefits like lowering blood pressure, improving lipid disorders, improving fatty liver disease, reducing your risk of heart disease and kidney disease, and delaying the progression of diabetes-related nephropathy, have been documented. However, as expected with any drug agent, several adverse effects can occur. Common side effects include loss of appetite, nausea, vomiting, diarrhea, and gastrointestinal discomfort. Moderate adverse effects include dizziness, mild increased heart rate, infections, headaches, and indigestion. Severe but rare side effects can include pancreatitis, medullary thyroid cancer, acute kidney injury, and worsening diabetes related retinopathy. Although generally safe, risks to also consider are allergic reactions, use during pregnancy, and low blood sugar levels.7

The mechanism of GLP-1 & GIP agonist has offered a multifaceted approach to treating both type 2 diabetes and obesity. These agents play a crucial role in regulating blood glucose levels, enhancing insulin secretion, and improving insulin sensitivity. As many of their effects influence weight loss and management, the variety of formulations provide tailored treatment options for many individuals. Although there is no best way to manage type 2 diabetes or obesity, there are several options for individuals looking to make progress and changes to manage or improve their health.

References:

New CDC Data Show Adult Obesity Prevalence Remains High © CDC Newsroom 2024. https://www.cdc.gov/media/releases/2024/p0912-adult-obesity.html
Samms RJ, Coghlan MP, Sloop KW. How May GIP Enhance the Therapeutic Efficacy of GLP-1?. Trends Endocrinol Metab. 2020;31(6):410-421. doi:10.1016/j.tem.2020.02.006
Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018;20 Suppl 1:5-21. doi:10.1111/dom.13129
Parker VER, Robertson D, Wang T, et al. Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist. J Clin Endocrinol Metab. 2020;105(3):dgz047. doi:10.1210/clinem/dgz047
Alfaris N, Waldrop S, Johnson V, Boaventura B, Kendrick K, Stanford FC. GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review. EClinicalMedicine. 2024;75:102782. Published 2024 Aug 30. doi:10.1016/j.eclinm.2024.102782
GLP-1 agonist. Cleveland Clinic © 2025 https://my.clevelandclinic.org/health/treatments/13901-glp-1-agonists Assessed and Endorsed by the MedReport Medical Review Board