Liraglutide (GLP-1 Analogue)

The Incretin Effect of GLP-1

Dr. Holst emphasizes the pivotal role of GLP-1 in the “incretin effect,” a phenomenon driven by metabolic hormones released by the gastrointestinal tract. These hormones, known as incretins, work to lower blood glucose levels. In rodent models, GLP-1, alongside GIP, emerges as one of the key hormones responsible for stimulating the incretin effect, despite GIP circulating at levels approximately ten times higher than GLP-1. Notably, when blood glucose levels are elevated, GLP-1 exhibits greater potency.

Furthermore, researchers have identified a GLP-1 receptor on the surface of pancreatic beta cells, indicating that GLP-1 directly triggers insulin release from the pancreas. When combined with sulfonylurea drugs, GLP-1 demonstrates the ability to enhance insulin secretion, resulting in mild hypoglycemia in up to 40% of subjects. This increased insulin secretion carries several beneficial effects, including heightened protein synthesis, reduced protein breakdown, and greater amino acid uptake by skeletal muscles.

GLP-1 and Beta Cell Protection

Studies conducted in animal models suggest that GLP-1 fosters the growth and proliferation of pancreatic beta cells. Additionally, it appears to promote the differentiation of new beta cells from progenitors residing in the pancreatic duct epithelium. Notably, GLP-1 also inhibits beta cell apoptosis, tilting the balance between beta cell growth and death in favor of growth. These findings suggest the potential utility of GLP-1 in treating diabetes and safeguarding pancreatic beta cells from harm.

In a compelling trial, GLP-1 was found to counteract the death of beta cells induced by elevated levels of inflammatory cytokines. In mouse models of type 1 diabetes, GLP-1 protects islet cells from destruction, offering promise as a preventive measure against the onset of type 1 diabetes.

GLP-1 and Appetite

In mouse models, administering GLP-1, along with its close relative GLP-1, directly into the brains of mice has shown the ability to reduce the drive to eat and suppress food intake. This effect stems from GLP-1’s potential to enhance feelings of satiety, leading to a sense of fullness and a reduction in hunger. Recent clinical studies in mice have demonstrated that twice-daily administration of GLP-1 receptor agonists results in gradual, consistent weight loss. Over time, this weight loss correlates with significant improvements in cardiovascular risk factors and reduced hemoglobin A1C levels, indicating improved diabetes management.

Potential Cardiovascular Benefits of GLP-1

Research has unveiled the presence of GLP-1 receptors throughout the heart, enhancing cardiac function under specific circumstances by increasing heart rate and decreasing left ventricular end-diastolic pressure. This latter effect, although seemingly modest, plays a critical role in countering left ventricular hypertrophy, cardiac remodeling, and eventual heart failure.

Emerging evidence suggests that GLP-1 may contribute to limiting damage caused by heart attacks. GLP-1 appears to enhance glucose uptake in cardiac muscle cells, providing essential nutrition to ischemic heart muscle cells, which can stave off programmed cell death. Importantly, this increase in glucose uptake occurs independently of insulin.

Large infusions of GLP-1 in dogs have shown improvements in left ventricular performance and a reduction in systemic vascular resistance. This reduction in vascular resistance helps lower blood pressure, easing the strain on the heart. Consequently, this can mitigate the long-term consequences of high blood pressure, such as left ventricular remodeling, vascular thickening, and heart failure. Dr. Holst notes that administering GLP-1 following cardiac injury consistently enhances myocardial performance in both experimental animal models and patients.

GLP-1 and the Brain

Evidence suggests that GLP-1 may enhance learning and protect neurons against neurodegenerative diseases like Alzheimer’s. Studies have shown that GLP-1 can improve associative and spatial learning in mice, even mitigating learning deficits in mice with specific gene defects. In rats with overexpressed GLP-1 receptors in certain brain regions, both learning and memory significantly outperform normal controls.

Additionally, research in mice indicates that GLP-1 can protect against excitotoxic neuron damage, offering complete protection against glutamate-induced apoptosis in rat models of neurodegeneration. GLP-1 can also stimulate neurite outgrowth in cultured cells, raising hopes for its potential in halting or reversing neurodegenerative diseases.

Notably, GLP-1 and its analogue exendin-4 have demonstrated the ability to reduce amyloid-beta levels in the brain, as well as beta-amyloid precursor protein in neurons. These are key components of the plaques observed in Alzheimer’s disease, which, while not definitively causative, are associated with disease severity. While the prevention of amyloid-beta accumulation’s impact on Alzheimer’s disease remains to be determined, this research provides valuable insights into potential interventions for mild cognitive impairment progressing to full Alzheimer’s disease.

Please note that GLP-1 has minimal to moderate side effects, excellent subcutaneous bioavailability in mice, and dosage in mice does not scale to humans. It is available for research purposes only and not intended for human consumption.