From the Guidelines
GLP-1 receptor agonists function primarily as insulin secretagogues in the management of type 2 diabetes mellitus. These medications, including exenatide, liraglutide, semaglutide, and dulaglutide, work by binding to GLP-1 receptors on pancreatic beta cells, stimulating insulin release in a glucose-dependent manner, as described in the 2018 consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 1. This means they increase insulin secretion only when blood glucose levels are elevated, which reduces the risk of hypoglycemia. GLP-1 receptor agonists also suppress glucagon secretion from pancreatic alpha cells, slow gastric emptying, and promote satiety through central nervous system effects, leading to reduced food intake and weight loss, as further explained in the 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease 2.
Some key points about GLP-1 receptor agonists include:
- They have a glucose-dependent mechanism of action, which minimizes the risk of hypoglycemia
- They promote weight loss and have beneficial effects on cardiovascular outcomes, as highlighted in a 2024 systematic review and network meta-analysis for the American College of Physicians 3
- They are effective tools for glycemic control, offering additional benefits beyond just lowering blood glucose levels
- Unlike inhibitors of intestinal carbohydrate absorption or insulin sensitizers, GLP-1 receptor agonists directly enhance the body's natural insulin response to meals.
Overall, the primary mechanism of action of GLP-1 receptor agonists is as insulin secretagogues, making them a valuable treatment option for patients with type 2 diabetes mellitus.
From the FDA Drug Label
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.
The mechanism of action of GLP-1 receptor agonists used in the management of type 2 diabetes mellitus is as a stimulator of insulin production.
- Key points: + GLP-1 receptor agonists enhance glucose-dependent insulin secretion + They increase insulin release in the presence of elevated glucose concentrations + Insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia [4] [5]
From the Research
Mechanism of Action of GLP-1 Receptor Agonists
The mechanism of action of GLP-1 receptor agonists used in the management of type 2 diabetes mellitus includes:
- Augmentation of hyperglycemia-induced insulin secretion 6, 7, 8, 9, 10
- Suppression of glucagon secretion at hyper- or euglycemia 6, 7, 8, 9, 10
- Deceleration of gastric emptying preventing large post-meal glycemic increments 6, 7, 8, 9, 10
- Reduction in calorie intake and body weight 6, 7, 8, 9, 10
Classification of GLP-1 Receptor Agonists
GLP-1 receptor agonists can be classified as:
- Short-acting agents (exenatide b.i.d., lixisenatide) 6, 8
- Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) 6, 8, 9
Effects on Insulin Secretion
GLP-1 receptor agonists stimulate insulin secretion in a glucose-dependent manner, making them effective in reducing HbA1c levels and lowering postprandial blood glucose levels 7, 8, 9, 10