Glucagon-like peptide-1 (GLP-1)

Glucagon-like peptide-1 (GLP-1) is a biologically active peptide hormone that plays a critical role in glucose homeostasis and appetite regulation. It is synthesized and released by the enteroendocrine L cells primarily located in the ileum and colon of the gastrointestinal tract in response to nutrient ingestion, particularly carbohydrates. These L-cells are also found in the brain, in the nucleus tractus solitarius of the dorsal medulla.

GLP-1 exerts its effects through interactions with specific receptors, namely the GLP-1 receptor (GLP-1R), which is expressed in various tissues, including pancreatic β-cells, where it mediates its primary actions:

1. Insulin Release: GLP-1 enhances glucose-dependent insulin secretion from pancreatic β-cells, promoting the uptake of glucose into cells and thus reducing blood glucose levels. This action makes GLP-1 a crucial player in glucose regulation.
2. Glucagon Inhibition: GLP-1 suppresses the release of glucagon from pancreatic α-cells, further helping to lower blood sugar levels.
3. Satiety and Weight Regulation: GLP-1 has anorexigenic effects, meaning it induces a feeling of fullness and reduces food intake by acting on the hypothalamus. This effect makes it relevant in appetite control and weight management.
4. Slowed Gastric Emptying: GLP-1 delays gastric emptying, which can lead to a more gradual absorption of nutrients, including glucose, from the digestive tract into the bloodstream.

The role of GLP-1 in glucose metabolism and appetite regulation has led to its therapeutic use in managing type 2 diabetes and obesity. GLP-1 receptor agonists, such as semaglutide and liraglutide, are medications designed to mimic the actions of GLP-1. They can improve blood glucose control and aid in weight loss for patients with these conditions.

How is GLP-1 released in the body in response to food intake?

GLP-1 is released in the body in response to food intake, primarily as a part of the enteroendocrine response within the gastrointestinal tract. Here’s an explanation of how this process works:

1. Stimulus of Food Ingestion: The release of GLP-1 is initiated by the presence of food, particularly carbohydrates and nutrients, in the digestive system. When a person consumes a meal, the nutrients are broken down in the stomach and small intestine.
2. Stimulation of L Cells: Specialized cells known as enteroendocrine L cells, located primarily in the ileum and colon of the small intestine, are responsible for producing and releasing GLP-1. These cells have specialized nutrient sensors and receptors that detect the presence of nutrients in the digestive tract.
3. Nutrient Sensing: When nutrients from the ingested food reach the lower part of the small intestine and the upper part of the colon, the L cells in these regions are stimulated by the nutrients. This nutrient sensing triggers the release of GLP-1.
4. Hormone Secretion: In response to this nutrient stimulation, the L cells secrete GLP-1 into the bloodstream. GLP-1 is initially released in its biologically inactive form, known as GLP-1 (1-37).
5. Conversion to Active Form: Once in the bloodstream, GLP-1 (1-37) undergoes rapid enzymatic degradation by dipeptidyl peptidase-4 (DPP-4) and is converted to its active form, GLP-1 (7-37), which is responsible for most of its physiological effects.
6. Action on Target Tissues: Active GLP-1 (7-37) then circulates in the blood and exerts its effects on various target tissues. It interacts with GLP-1 receptors, particularly in the pancreas (on β-cells to stimulate insulin release and α-cells to inhibit glucagon release), the brain (to induce feelings of satiety and control appetite), and the gastrointestinal tract (to slow down gastric emptying).

This process ensures that GLP-1 is released in a nutrient-dependent manner and acts to regulate blood sugar levels and appetite in response to food intake. It is an important part of the enteroendocrine system’s role in maintaining glucose homeostasis and energy balance.

The process of GLP-1 breakdown in the body

GLP-1 is rapidly broken down in the body and has a short half-life. The half-life of active GLP-1 (7-37) is estimated to be approximately 1-2 minutes in humans. This rapid degradation is primarily due to the enzymatic activity of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, converting it into its inactive form, GLP-1 (9-37). This inactivation prevents GLP-1 from exerting its effects on target tissues for an extended period.

GLP-1 receptor agonists are engineered to be more stable and resistant to DPP-4 degradation, resulting in an extended half-life. The extended half-life ensures their effects on blood sugar control, appetite reduction, and weight loss are consistent and sustained over time. In contrast, endogenous GLP-1’s short duration of action can lead to fluctuations in its effects throughout the day.

Metabolic effects of GLP-1

GLP-1 receptor agonists were developed to overcome the limitations of native GLP-1, offering greater stability, efficacy, and convenience. They provide a therapeutic option that can help manage blood sugar levels, induce weight loss, and improve overall metabolic control in individuals with type 2 diabetes and obesity, making them a valuable addition to the treatment armamentarium.

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