Incretin receptor agonist

Incretin receptor agonists are a class of medications used primarily in the management of type 2 diabetes. They work by mimicking the effects of incretin hormones, which are naturally occurring hormones that help regulate blood sugar levels. Here’s an overview of how they function and their role in diabetes management:

What Are Incretin Hormones? Incretins: These are hormones released by the gut in response to food intake. The two main incretin hormones are:

Glucagon-like peptide-1 (GLP-1) Gastric inhibitory peptide (GIP) Functions:

Increase Insulin Secretion: Incretins stimulate the pancreas to release insulin in response to meals. Decrease Glucagon Secretion: They reduce the secretion of glucagon, a hormone that raises blood sugar levels. Slow Gastric Emptying: They slow down the emptying of the stomach, which helps in controlling postprandial blood sugar spikes. Reduce Appetite: They can help with weight management by reducing appetite. Incretin Receptor Agonists Mechanism of Action: Incretin receptor agonists are designed to mimic the effects of natural incretins, specifically GLP-1, by binding to and activating GLP-1 receptors on pancreatic beta cells. This action increases insulin secretion and reduces blood glucose levels in a glucose-dependent manner.

Types of Incretin Receptor Agonists:

Exenatide (Byetta, Bydureon): An injectable medication that mimics GLP-1. Bydureon is a long-acting version of Exenatide. Liraglutide (Victoza, Saxenda): Another GLP-1 mimetic with a longer duration of action. Saxenda is a higher-dose form used for weight management. Dulaglutide (Trulicity): A once-weekly injectable that also mimics GLP-1. Semaglutide (Ozempic, Wegovy): A newer and more potent GLP-1 receptor agonist, with Ozempic used for diabetes management and Wegovy for weight management. Benefits:

Effective Glycemic Control: They help lower blood sugar levels effectively, particularly postprandial glucose levels. Weight Loss: Many of these medications lead to weight loss, which is beneficial for patients with type 2 diabetes who are overweight or obese. Cardiovascular Benefits: Some GLP-1 receptor agonists have been shown to provide cardiovascular benefits, such as reducing the risk of heart attack and stroke. Side Effects:

Gastrointestinal Issues: Common side effects include nausea, vomiting, and diarrhea. Pancreatitis: There is a potential risk of pancreatitis, though this is relatively rare. Thyroid Tumors: Some studies suggest a potential link to thyroid tumors, though this risk is still being evaluated. Administration: Most incretin receptor agonists are administered via subcutaneous injection. Some newer formulations offer once-weekly dosing, which can be more convenient for patients.

Clinical Use Incretin receptor agonists are typically used when oral medications (like metformin) are insufficient in managing type 2 diabetes. They may be used alone or in combination with other diabetes medications, depending on individual patient needs and treatment goals.

Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder ¹⁾.