“lotte bjerre knudsen” & GLP-1: Hormone Science Breakthroughs

Lotte Bjerre Knudsen has played a key role in advancing GLP-1 research, contributing to therapies that have transformed diabetes and obesity treatment. Her work has refined how we harness this hormone’s potential for improving metabolic health.

Scientific breakthroughs in GLP-1-based treatments have led to more effective ways to manage blood sugar and body weight. Understanding these advancements provides insight into their biological mechanisms and therapeutic applications.

Biological Functions in Glucose Regulation

Glucagon-like peptide-1 (GLP-1) maintains glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and slowing gastric emptying. Secreted by intestinal L-cells in response to food intake, it enhances insulin release from pancreatic β-cells in a glucose-dependent manner, reducing the risk of hypoglycemia. This property makes GLP-1 receptor agonists a preferred option for type 2 diabetes, improving glycemic control while minimizing the adverse effects of traditional insulinotropic agents.

GLP-1 also suppresses glucagon secretion from pancreatic α-cells, preventing excessive hepatic glucose production, a major contributor to hyperglycemia. Studies show GLP-1 receptor activation lowers fasting plasma glucose and postprandial glucose levels, improving HbA1c over time. Clinical trials, such as the LEADER study, have demonstrated that long-acting GLP-1 receptor agonists not only reduce blood sugar but also lower the risk of major cardiovascular events in type 2 diabetes patients.

Additionally, GLP-1 delays gastric emptying, moderating postprandial glucose spikes by slowing nutrient absorption. This effect helps maintain a stable glycemic profile, particularly in individuals with impaired glucose tolerance. However, it can also contribute to gastrointestinal side effects, such as nausea, which are common when initiating GLP-1-based therapies.

Receptor Binding and Molecular Interactions

GLP-1 exerts its effects by binding to the GLP-1 receptor (GLP-1R), a class B G protein-coupled receptor (GPCR) found in pancreatic β-cells, the central nervous system, the gastrointestinal tract, and cardiovascular tissues. Ligand binding triggers a conformational change in GLP-1R, activating intracellular signaling proteins, primarily Gαs, which increases cyclic adenosine monophosphate (cAMP) levels. This rise in cAMP enhances insulin secretion through protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), ensuring insulin release is tightly regulated and minimizing hypoglycemia risk.

Cryo-electron microscopy studies have revealed the two-step binding mechanism between GLP-1 and its receptor. The receptor’s extracellular domain initially binds GLP-1’s C-terminal region before full engagement within the transmembrane domain, stabilizing its active conformation. This insight has guided the development of therapeutics with prolonged receptor engagement and improved pharmacokinetics.

Beyond insulin secretion, GLP-1R activation supports β-cell survival and proliferation by engaging the PI3K and ERK pathways. This reduces apoptosis and promotes β-cell regeneration, as observed in preclinical models where prolonged GLP-1R activation correlates with increased β-cell mass and improved pancreatic function. These findings highlight the potential for GLP-1 analogs to modify disease progression in type 2 diabetes.

Effects on Appetite and Digestive Processes

GLP-1 also influences appetite and gastrointestinal function. It acts on the central nervous system, binding to receptors in the hypothalamus and brainstem to regulate satiety. In the arcuate nucleus, it enhances pro-opiomelanocortin (POMC) neuron activity, which promotes fullness, while inhibiting neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons, which stimulate hunger. Clinical trials have shown that GLP-1 receptor agonists significantly reduce caloric intake in individuals with obesity and type 2 diabetes.

GLP-1 receptor activation in the nucleus tractus solitarius (NTS) enhances vagal afferent signaling, amplifying the sensation of fullness after meals. This neural pathway also slows gastric motility, prolonging nutrient absorption. While this helps with postprandial glucose control, it also contributes to common side effects such as nausea and early satiety.

GLP-1 further modulates gut hormone secretion by increasing peptide YY (PYY) levels, reinforcing satiety and slowing intestinal transit. It also reduces ghrelin secretion, lowering hunger and supporting long-term weight loss benefits seen with GLP-1 therapies.

Formulation Approaches for Enhanced Stability

The clinical effectiveness of GLP-1 receptor agonists depends on their stability. Native GLP-1 has a short half-life of 1–2 minutes due to rapid enzymatic degradation by dipeptidyl peptidase-4 (DPP-4) and renal clearance. To extend its duration of action, structural modifications have been made, such as substituting amino acids at DPP-4 cleavage sites. For example, replacing alanine at position 8 with glycine significantly prolongs GLP-1’s half-life without affecting receptor affinity.

Other strategies include conjugation with albumin-binding moieties, which slow renal filtration and extend circulation time. Semaglutide, for instance, incorporates a C18 fatty acid chain, achieving a half-life of about one week, enabling once-weekly dosing. PEGylation has also been explored to enhance solubility and reduce immunogenicity while maintaining prolonged activity.

Interplay With Other Endocrine Factors

GLP-1 interacts with multiple endocrine pathways that influence metabolism and pancreatic function. By modulating hormone secretion, it contributes to a coordinated metabolic response relevant to diabetes and obesity treatment.

GLP-1 enhances insulin secretion while suppressing glucagon release, stabilizing glycemia in individuals with impaired pancreatic function. It also interacts with glucose-dependent insulinotropic polypeptide (GIP), another incretin hormone involved in insulin modulation. The development of dual GLP-1/GIP receptor agonists, such as tirzepatide, underscores the importance of these hormonal interactions, as they offer superior glycemic control and weight loss compared to GLP-1 receptor agonists alone.

Additionally, GLP-1 influences cortisol and catecholamine levels, particularly in response to stress and energy demands. Studies suggest GLP-1 receptor activation in the central nervous system may modulate the hypothalamic-pituitary-adrenal (HPA) axis, affecting cortisol secretion. This could impact metabolic flexibility, as cortisol regulates gluconeogenesis and fat metabolism. GLP-1 also affects leptin and adiponectin secretion, suggesting a broader role in energy homeostasis with potential benefits for lipid metabolism and insulin sensitivity. These hormonal interactions highlight why GLP-1 therapies extend beyond glycemic control, offering broader metabolic benefits.