Do Glucagon-like peptide-1 (GLP-1) agonists cause persistent beta cell stimulation and increased insulin production?

From the Guidelines

GLP-1 agonists do not cause persistent beta cell stimulation and increased insulin production, instead, they work in a glucose-dependent manner, stimulating insulin secretion only when blood glucose levels are elevated. This glucose-dependent mechanism helps prevent hypoglycemia while improving glycemic control, as noted in a study published in 2024 1. GLP-1 agonists, including semaglutide, liraglutide, dulaglutide, and exenatide, actually preserve beta cell function over time by reducing glucotoxicity and lipotoxicity, potentially slowing the progressive decline in beta cell function seen in type 2 diabetes. They also suppress glucagon secretion from pancreatic alpha cells when glucose levels are high, reduce gastric emptying, and promote satiety through central nervous system effects.

The benefits of GLP-1 agonists are well-documented, with studies showing improved lipid profiles and reduced cardiovascular risk 1. The LEADER trial, which investigated the use of liraglutide in patients with type 2 diabetes at high cardiovascular risk, found a significant reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke 1. Similarly, the SUSTAIN 6 trial, which examined the use of semaglutide in patients with type 2 diabetes at high cardiovascular risk, found a significant reduction in the primary outcome of cardiovascular death, non-fatal myocardial infarction, or stroke 1.

Some key points to consider when using GLP-1 agonists include:

• They have a minimal risk of hypoglycemia, but may increase the hypoglycemic potential of insulin and sulfonylureas when combined with those medications 2
• They can cause gastrointestinal side effects, such as nausea, vomiting, and diarrhea, which are dose-dependent and more frequent with short-acting drugs 1
• They may have a beneficial effect on cardiovascular outcomes, with studies showing a reduction in cardiovascular death, non-fatal myocardial infarction, or stroke 1
• They can be used in the peri-operative management of hyperglycemia, with studies showing an insulin-sparing effect and significant decreases in plasma glucose 1

Overall, GLP-1 agonists are a beneficial treatment option for patients with type 2 diabetes, offering improved glycemic control, reduced cardiovascular risk, and a low risk of hypoglycemia. As noted in a study published in 2022, GLP-1 agonists should not be used with other GLP-1 receptor agonists or with dipeptidyl peptidase-4 inhibitors, and caution is advised when using them in combination with insulin or insulin secretagogues 3.

From the FDA Drug Label

Liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. 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 FDA drug label does not provide information on persistent beta cell stimulation and increased insulin production by GLP-1 agonists. The label only describes the glucose-dependent insulin secretion, which subsides as blood glucose concentrations decrease.

• Key points: + GLP-1 agonists, such as liraglutide, stimulate insulin secretion in a glucose-dependent manner. + Insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. + There is no information on persistent beta cell stimulation and increased insulin production. 4

From the Research

GLP-1 Agonists and Beta Cell Stimulation

• GLP-1 agonists increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner 5, 6, 7, 8
• They also promote β-cell proliferation and probably neogenesis, while reducing apoptosis in animal models 7
• GLP-1 receptor agonists appear to have a positive effect on β-cell function 7, 8

Effects on Insulin Production

• GLP-1 agonists stimulate insulin secretion, which can lead to increased insulin production 5, 6, 7, 8
• The increase in insulin production is glucose-dependent, reducing the risk of hypoglycemia 5, 6, 7, 8
• Long-acting GLP-1 RAs have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin 6

Persistent Beta Cell Stimulation

• GLP-1 agonists may improve pancreatic beta cell function, which may delay disease progression if maintained over the long term 8
• However, the long-term effects of GLP-1 agonists on beta cell stimulation are not fully understood and require further research 6
• Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment 6