Semaglutide (GLP-1 Analogue)

The Incretin Effect of GLP-1 One of the most significant effects of GLP-1, as highlighted by Dr. Holst, is its role in the “incretin effect.” Incretins are hormones released by the gastrointestinal (GI) tract that lower blood glucose levels. In rodent models, GLP-1 is one of the two key hormones (the other being GIP) responsible for stimulating the incretin effect. Despite GIP’s higher circulating levels, GLP-1 appears to be more potent, especially when blood glucose levels are elevated.

A GLP-1 receptor has been identified on pancreatic beta cells, indicating that GLP-1 directly triggers the release of insulin from the pancreas. When combined with sulfonylurea drugs, GLP-1 can enhance insulin secretion, leading to mild hypoglycemia in up to 40% of individuals. Increased insulin secretion has various positive effects, including promoting protein synthesis, reducing protein breakdown, and enhancing amino acid uptake by skeletal muscles.

GLP-1 and Beta Cell Protection Research conducted in animal models suggests that GLP-1 can stimulate the growth and proliferation of pancreatic beta cells. It may also encourage the differentiation of new beta cells from progenitor cells in the pancreatic duct epithelium. Additionally, GLP-1 has been shown to inhibit beta cell apoptosis. Cumulatively, these effects shift the balance of beta cell growth and death toward growth, suggesting that GLP-1 may have potential therapeutic value in treating diabetes and protecting the pancreas from damage that could harm beta cells.

In a notable trial, GLP-1 was found to prevent beta cell death caused by elevated levels of inflammatory cytokines. Mouse models of type 1 diabetes have also demonstrated that GLP-1 can safeguard islet cells from destruction and may serve as a preventive measure against the onset of type 1 diabetes.

GLP-1 and Appetite Studies conducted in mouse models indicate that administering GLP-1, along with its counterpart GLP-1, directly into the brains of mice can reduce the urge to eat and suppress food intake. It appears that GLP-1 may enhance feelings of fullness, indirectly reducing hunger. Recent clinical studies in mice have shown that twice-daily administration of GLP-1 receptor agonists leads to gradual and consistent weight loss. Over time, this weight loss is associated with significant improvements in cardiovascular risk factors and a reduction in hemoglobin A1C levels, which is a marker for diabetes severity and blood sugar control.

Potential Cardiovascular Benefits of GLP-1 GLP-1 receptors are distributed throughout the heart and can enhance cardiac function under specific conditions. They increase heart rate and reduce left ventricular end-diastolic pressure, which is significant in preventing left ventricular hypertrophy, cardiac remodeling, and eventual heart failure.

Recent evidence suggests that GLP-1 may help reduce damage caused by heart attacks. GLP-1 improves glucose uptake in cardiac muscle cells, aiding ischemic heart muscle cells in obtaining the nutrition they need to continue functioning and avoid programmed cell death. This increase in glucose uptake appears to be independent of insulin.

In dog studies, large infusions of GLP-1 have been shown to enhance left ventricular performance and decrease systemic vascular resistance. This reduction in blood pressure and relief on the heart can help mitigate the long-term consequences of high blood pressure, such as left ventricular remodeling, vascular thickening, and heart failure. According to Dr. Holst, administering GLP-1 following cardiac injury consistently improves myocardial performance in both experimental animal models and patients.