What is the mechanism of action of Glucose Transporter 1 (GLT1) agonists in treating diabetes?

Mechanism of Action of GLT-1 Agonists in Treating Diabetes

GLT-1 (Glucose Transporter 1) agonists are not a recognized class of diabetes medications. The evidence provided does not describe GLT-1 agonists as a treatment for diabetes. There appears to be confusion with GLP-1 (Glucagon-Like Peptide-1) receptor agonists, which are an established class of medications for treating type 2 diabetes.

Mechanism of Action of GLP-1 Receptor Agonists

GLP-1 receptor agonists work through multiple mechanisms to improve glycemic control:

1. Enhanced Insulin Secretion:

   • Stimulate glucose-dependent insulin release from pancreatic β-cells 1, 2
   • The glucose-dependency is crucial - insulin is only released when blood glucose levels are elevated, minimizing hypoglycemia risk 2

2. Suppression of Glucagon Secretion:

   • Inhibit glucagon release at hyperglycemic or euglycemic states 3
   • Reduce hepatic glucose output 4

3. Delayed Gastric Emptying:

   • Slow the rate of gastric emptying, preventing large post-meal glucose spikes 3
   • Short-acting GLP-1 RAs maintain this effect during long-term treatment, while long-acting agents develop tachyphylaxis 3

4. Central Nervous System Effects:

   • Reduce appetite through effects on GLP-1 receptors in the CNS 3, 1
   • Promote satiety and reduce caloric intake 3

5. Weight Reduction:

   • Promote significant weight loss, with newer agents like tirzepatide achieving up to 20.9% weight reduction at higher doses 5

Clinical Relevance and Effectiveness

GLP-1 receptor agonists have demonstrated:

• Significant reductions in HbA1c levels 3
• Cardioprotective effects with reduction in major adverse cardiovascular events (MACE) 6, 5
• Renoprotective effects 3
• Weight loss benefits in patients with and without diabetes 7

The American College of Physicians recommends GLP-1 receptor agonists as they reduce all-cause mortality and major adverse cardiovascular events compared with usual care (high certainty of evidence) 6.

Available GLP-1 Receptor Agonists

Several GLP-1 receptor agonists are available with different administration schedules:

• Twice daily: Exenatide b.i.d. 3
• Once daily: Lixisenatide, Liraglutide 3
• Once weekly: Exenatide once weekly, Dulaglutide, Albiglutide, Semaglutide 3
• Oral preparation: Semaglutide (daily) 3
• Dual GLP-1/GIP receptor agonist: Tirzepatide (once weekly) 5

Important Considerations

• GLP-1 receptor agonists are now preferred as first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment 3
• They can be combined with basal insulin in either free- or fixed-dose preparations 3
• Common adverse effects include gastrointestinal issues, which are typically transient and less common with long-acting formulations 3, 1
• Risk of hypoglycemia is low when used as monotherapy due to their glucose-dependent mechanism of action 7, 2
• Caution should be exercised when combining with sulfonylureas, as this may increase hypoglycemia risk 2

Clarification on GLT-1 vs. SGLT-2

It's important to note that the question may be confusing GLT-1 with SGLT-2 (Sodium-Glucose Cotransporter-2) inhibitors, which are a different class of diabetes medications. SGLT-2 inhibitors work by preventing glucose reabsorption in the kidneys, leading to increased urinary glucose excretion 6.

SGLT-2 is expressed in the brain at lower levels than SGLT-1, and both are present in various areas of the central nervous system 6. However, these are targets for inhibitors, not agonists, in diabetes treatment.