How GLP-1 Drugs Work for Weight Loss

Ozempic, Wegovy, Mounjaro and more: The GLP-1 Drugs – A Scientific Overview

Let’s start with some basics: what is a Hormone?

Hormones are biochemical messengers, secreted by specialised cells in the endocrine glands, directly into the bloodstream. They help control various physiological processes within our body including metabolism, growth, reproduction, and homeostasis. (Homeostasis is the very tight control of the environment inside our cells and in our body)

Hormones bind to specific receptors on target cells (a bit like a key within a lock) initiating a cascade of cellular responses. Examples include insulin, cortisol and oestrogen.

Which Hormones Influence Weight, Satiety, and Hunger?

Weight, satiety, and hunger are regulated by a complex interplay of hormones, primarily:

• Ghrelin: Known as the “hunger hormone,” ghrelin is secreted by ghrelin-producing cells in the fundus of the stomach. It stimulates the hypothalamus of the brain to increase appetite and food intake. Ghrelin levels rise before meals (making us feel hungry) and fall after eating.
• Leptin: Often referred to as the “satiety hormone,” leptin is secreted by adipocytes (fat cells) located in adipose tissue. It communicates with the hypothalamus to suppress appetite and increase energy expenditure. Leptin resistance (the cells start to ignore the leptin signal) is common in obesity. The knock on effect of leptin resistance disrupts this elegant feedback loop.
• Insulin: Secreted by beta cells in the islets of Langerhans of the pancreas, insulin facilitates glucose uptake into cells for energy storage. It also plays a role in appetite regulation by acting on brain regions such as the hypothalamus. Actually insulin has numerous other actions but that’s a discussion for another day!
• Glucagon: Produced by alpha cells in the islets of Langerhans of the pancreas, glucagon increases blood glucose levels by stimulating glycogen breakdown and gluconeogenesis. It has a minor role in appetite regulation but significantly impacts energy balance. Glucagon is the Yin to Insulin’s Yang. Glucagon wants to elevate blood sugar levels while insulin has the reverse effect
• Peptide YY (PYY): Secreted by L-cells located in the distal ileum and colon, PYY reduces appetite by acting on the hypothalamus and slowing gastric motility. Its levels are proportional to calorie intake.
• Cholecystokinin (CCK): Released by I-cells in the mucosa of the small intestine (particularly the duodenum and jejunum) in response to fat and protein consumption, CCK promotes satiety by stimulating digestion and sending signals to the brain to reduce appetite. It also slows gastric emptying.
• Glucagon-Like Peptide-1 (GLP-1): A key incretin hormone, GLP-1 is secreted by L-cells in the small intestine and colon after eating. It enhances insulin secretion, suppresses glucagon release, delays gastric emptying, and reduces appetite by acting on the hypothalamus. The overall effects are to lower blood sugar levels and increase feelings of fullness after eating
• Glucose-Dependent Insulinotropic Polypeptide (GIP): Secreted by K-cells in the duodenum and proximal jejunum if the small intestine , GIP stimulates insulin secretion in a glucose-dependent manner. It also influences fat metabolism by promoting lipid storage in adipose tissue and enhancing triglyceride synthesis. In other words it’s a fat storage hormone as well as lowering blood sugar. So  GLP1 and GIP act synergistically in the presence of food.

 

What Are Incretins?

Incretins are hormones secreted by the gastrointestinal tract in response to nutrient ingestion. So-called because they both INCrease The secretion of Insulin. The two primary incretins are:

• Glucagon-Like Peptide-1 (GLP-1): Enhances insulin secretion, suppresses glucagon release, delays gastric emptying, and reduces appetite.
• Glucose-Dependent Insulinotropic Polypeptide (GIP): Stimulates insulin secretion and plays a role in fat metabolism.

Interestingly Roux-en-Y gastric bypass (RYB) surgery significantly alters hormone secretion and metabolic responses by bypassing most of the stomach and upper small intestine. Bit it preserves the function of both K-cells and L-cells in the gut, leading to enhanced secretion of GIP and GLP-1. The result is improved glycaemic (blood sugar) control and weight loss.

What Role Do Incretins Play in Hunger, Satiety, and Weight Regulation?

Incretins regulate glucose homeostasis (blood glucose control) and appetite. GLP-1 slows gastric emptying, prolonging feelings of fullness. It also acts on the hypothalamus (an area of the brain) to suppress hunger, aiding in weight loss. GIP complements the action of GLP-1 by influencing fat storage and energy expenditure.

The GLIA Monster: The Discovery of Exenatide

The discovery of exenatide, the first GLP-1 receptor agonist, was inspired by the salivary protein of the Gila monster (Heloderma suspectum). Researchers identified a compound similar to GLP-1 but with a longer half-life. Exenatide became a breakthrough therapy for type 2 diabetes, addressing both glycaemic control and weight management.

How Do GLP-1 Receptor Agonists Work?

GLP-1 receptor agonists mimic the action of natural (endogenous) GLP-1. These drugs bind to GLP-1 receptors, enhancing insulin secretion, suppressing glucagon release, slowing gastric emptying, and reducing appetite. Their effects improve glycaemic control and promote weight loss.

Tirzepatide: How Does It Differ?

Tirzepatide is a dual GIP and GLP-1 receptor agonist. Remember (from above) that the L-cells naturally (secrete GLP1) and K-cells (secrete GIP) in equal quantities.  Unlike traditional GLP-1 receptor agonists, tirzepatide targets both incretins, amplifying their combined effects. This dual action enhances glycaemic control and weight loss more effectively than single-target therapies.

Where Are GLP-1 Receptors Found, and How Does This Relate to the Drugs’ Actions?

GLP-1 receptors are widely distributed throughout the body, including:

• Pancreas: GLP-1 receptors in the pancreas enhance insulin secretion from beta cells and suppress glucagon release from alpha cells. These actions improve glucose homeostasis and reduce hyperglycaemia (high blood glucose) in individuals with type 2 diabetes.
• Brain: In the central nervous system, GLP-1 receptors are found in the hypothalamus and brainstem. They regulate appetite by reducing hunger signals and promoting satiety, making them effective in weight management.
• Gastrointestinal Tract: GLP-1 receptors in the stomach and intestines delay gastric emptying and reduce gastric motility. This prolongs the sensation of fullness after meals, contributing to reduced caloric intake. You feel fuller and eat less as a result
• Heart: Cardiac GLP-1 receptors mediate cardioprotective (heart-protecting) effects, including improved cardiac output, reduced inflammation, and enhanced endothelial function. These benefits lower the risk of cardiovascular complications in high-risk patients.
• Kidneys: In the kidneys, GLP-1 receptors influence sodium excretion and fluid balance. This can help lower blood pressure and reduce the risk of cardiovascular and renal diseases.
• Adipose (fat) Tissue: GLP-1 receptors in adipose tissue modulate lipid metabolism by promoting lipolysis (breaking down fats to use for energy and reducing fat storage. This contributes to improved insulin sensitivity and weight reduction.

The wide distribution of these receptors explains the systemic benefits of GLP-1 receptor agonists, including their ability to improve glucose control, promote weight loss, and protect against cardiovascular and renal complications. In fact, the GLP drugs are currently being investigated for a huge range of indications, but we’ll get to that later.

What Are GLP-1 Drugs Used For?

GLP-1 receptor agonists have emerged as powerful tools in managing metabolic and related disorders, offering both licensed and investigational uses. These drugs target multiple systems in the body, making them versatile but also requiring careful administration and monitoring.

Licensed Uses:

1. Type 2 Diabetes Management: GLP-1 receptor agonists are approved for glycaemic control in type 2 diabetes. By enhancing insulin secretion in a glucose-dependent manner, they reduce postprandial glucose spikes and improve overall glycaemic control. These drugs also suppress glucagon, further stabilising blood glucose levels. Remember insulin lowers blood sugar and glucagon has the opposite effect
2. Weight Loss in Obesity: Several GLP-1 receptor agonists, including liraglutide and semaglutide, are approved for weight management in individuals with obesity or overweight with comorbid conditions. They reduce appetite, increase satiety, and lead to significant and sustained weight loss when combined with lifestyle interventions.
3. Cardiovascular Risk Reduction: GLP-1 receptor agonists, such as liraglutide and dulaglutide, have demonstrated cardiovascular benefits in patients with type 2 diabetes and established cardiovascular disease. These include reductions in major adverse cardiovascular events (MACE), such as heart attacks and strokes.

Investigational Uses:

1. Parkinson’s Disease: Emerging evidence suggests that GLP-1 receptor agonists may offer neuroprotective effects, potentially slowing disease progression and improving motor symptoms in patients with Parkinson’s disease. Their anti-inflammatory and neuroprotective properties are being actively explored in clinical trials.
2. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH): GLP-1 receptor agonists show promise in reducing liver fat and inflammation, making them potential treatments for NAFLD and NASH. This is particularly relevant as these conditions often coexist with type 2 diabetes and obesity.
3. Alzheimer’s Disease: Research is underway to evaluate the cognitive benefits of GLP-1 receptor agonists, based on their potential to reduce neuroinflammation (inflammation in the brain and nerve cells generally) and amyloid plaque deposition. Early findings suggest they may slow cognitive decline.
4. Polycystic Ovary Syndrome (PCOS): Given their effects on insulin sensitivity and weight loss, GLP-1 receptor agonists are being investigated as a treatment for PCOS, a condition characterised by insulin resistance and metabolic dysfunction.
5. Postprandial Hypotension: By slowing gastric emptying, GLP-1 receptor agonists may mitigate postprandial hypotension, a condition where blood pressure drops after eating, leading to dizziness and fainting.
6. Other Applications: Preliminary studies are exploring the role of GLP-1 receptor agonists in treating chronic kidney disease (CKD), improving fertility outcomes, and addressing rare genetic disorders linked to metabolism.

While GLP-1 receptor agonists have shown immense potential across these diverse applications, their use must be carefully tailored to individual needs, considering both their benefits and limitations.

Side Effects of GLP-1 Drugs: Why They Are Not a Miracle Cure

• Weight Loss and Tissue Composition: Weight loss induced by GLP-1 receptor agonists is not solely due to fat reduction. Studies indicate that approximately 25% to 35% of the weight lost is lean tissue, including muscle and bone mass. The loss of muscle is particularly concerning as it can reduce metabolic rate and physical strength, while bone loss increases the risk of fractures, particularly in older adults.

The underlying mechanisms for these changes may include reductions in anabolic (protein-building) signals such as insulin and alterations in nutrient absorption due to delayed gastric emptying. Additionally, rapid weight loss itself can lead to muscle and bone catabolism (breakdown), especially if not accompanied by resistance exercise or adequate protein intake. This highlights the importance of combining GLP-1 therapy with lifestyle interventions to minimise adverse effects on body composition.GLP-1 receptor agonists have been hailed as groundbreaking for weight loss and glycaemic control, but they are not without limitations. Understanding their side effects and the consequences of discontinuation is essential to provide a balanced perspective.

• Gastrointestinal Issues: The most common side effects include nausea, vomiting, diarrhoea, and constipation. These effects often occur early in treatment and may diminish over time, but for some patients, they can persist or lead to treatment discontinuation.
• Gallbladder Complications: GLP-1 drugs are associated with an increased risk of gallstones and cholecystitis (inflammation of the gallbladder), possibly due to their impact on gastrointestinal motility and bile flow.
• Pancreatitis Risk: Although rare, there is a potential risk of pancreatitis.(Inflammation of the pancreas) Patients with a history of pancreatitis are generally advised against using these medications.
• Thyroid Concerns: Animal studies have linked GLP-1 receptor agonists to thyroid C-cell hyperplasia and medullary thyroid carcinoma, though this risk has not been conclusively demonstrated in humans.
• Hypoglycaemia: While GLP-1 agonists alone rarely cause hypoglycaemia, (low blood sugar) the risk increases when combined with other glucose-lowering agents like insulin or sulfonylureas.
• Cardiovascular Side Effects: Although these drugs have demonstrated cardioprotective benefits, some individuals may experience increased heart rate, which warrants careful monitoring.
• Psychological Effects: Emerging reports suggest that some users may experience changes in mood, such as anxiety or depression, potentially linked to alterations in appetite and metabolism. The mechanism behind these effects may involve GLP-1 receptor activity in the brain, particularly in regions such as the hypothalamus and brainstem, which are integral to regulating mood and appetite. GLP-1 drugs influence neurotransmitter systems, including dopamine and serotonin pathways, which are associated with mood regulation. Alterations in these systems may predispose certain individuals to mood changes or depressive symptoms. Additionally, rapid weight loss or significant lifestyle adjustments triggered by these drugs may exacerbate psychological stress. There is also evidence of an increased incidence of suicidal ideation in some users, although the exact cause remains unclear. It may relate to underlying vulnerabilities in mental health exacerbated by changes in neurochemical signalling and metabolic states.
• Discontinuation Effects: When GLP-1 drugs are stopped, patients often experience a rebound effect, including rapid weight regain and worsening of glycaemic control. This is due to the cessation of appetite suppression and metabolic benefits provided by the drug, necessitating a long-term management strategy for sustainable results.

Future Developments

Emerging research aims to optimise GLP-1-based therapies, focusing on several innovative areas:

Combination Therapies: Dual and triple agonists targeting GLP-1, GIP, and glucagon receptors are under development. These therapies aim to enhance efficacy for glycaemic control and weight loss while reducing side effects.

Oral Formulations: Innovations in oral GLP-1 drugs are progressing, improving bioavailability and offering non-injectable options for patients, making the therapy more accessible and convenient.

Personalised Medicine: Genetic and metabolic profiling may help tailor GLP-1 therapies to individual patients, maximising benefits and minimising risks.

Extended-Action Drugs: Research into molecules with longer half-lives aims to reduce the frequency of dosing, improving adherence for patients who struggle with frequent injections.

Neuroprotective Applications: Ongoing studies are exploring the role of GLP-1 drugs in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Their potential to reduce neuroinflammation and promote neuronal survival is a promising avenue.

Cardiovascular and Renal Therapies: GLP-1 receptor agonists with enhanced cardioprotective and nephroprotective properties are being investigated to expand their use beyond diabetes and obesity.

Microbiome Modulation: Exploring how GLP-1 therapies interact with the gut microbiome could pave the way for more effective treatments with fewer gastrointestinal side effects.12. Microdosing with GLP-1 Drug

MICRODOSING:

The practice of administering significantly smaller doses of a drug than typically prescribed, is being explored in the context of GLP-1 receptor agonists for specific patient populations and applications. This approach aims to harness the benefits of GLP-1 drugs while minimising side effects and costs.

Potential Applications:

1. Mild Metabolic Dysfunction: Microdosing may be suitable for individuals with prediabetes or mild insulin resistance who do not require full therapeutic doses.
2. Weight Maintenance: For individuals who have achieved weight loss using standard doses of GLP-1 drugs, microdosing could help maintain results without prolonged exposure to higher drug levels.
3. Combination Therapies: In combination with other treatments, microdosing could complement lifestyle interventions such as diet and exercise, enhancing their effectiveness without the burden of full-dose side effects.

Advantages:

• Reduced incidence of gastrointestinal and psychological side effects.
• Lower financial burden for patients.
• Potential for broader accessibility to the drugs in resource-limited settings.

Challenges and Limitations:

• Uncertainty about the optimal dosing regimen for microdosing.
• Lack of robust clinical trials demonstrating efficacy and safety.
• Variability in individual responses, which may complicate dosing adjustments.

Microdosing represents a promising area of research, offering a potential way to extend the benefits of GLP-1 drugs to more individuals while mitigating the risks and costs associated with higher doses.

Emerging research aims to optimise GLP-1-based therapies, focusing on:

• Combination Therapies: Dual and triple agonists targeting GLP-1, GIP, and glucagon receptors.
• Oral Formulations: Improving bioavailability for non-injectable options.
• Personalised Medicine: Tailoring therapies based on genetic and metabolic profiles.
• Extended Action Drugs: Developing molecules with longer half-lives for less frequent dosing.

Natural Ways to Increase GLP-1 and GIP

Table: Foods and Their Incretin-Stimulating Properties

Food	Incretin-Stimulating Properties	Examples
High-Fibre Foods	Slow gastric emptying, stimulate L-cells and K-cells	Whole grains, legumes, fruits, vegetables
Protein-Rich Foods	Increase GLP-1 and GIP levels, promote satiety	Eggs, fish, poultry, dairy, whey protein
Healthy Fats	Stimulate GLP-1 secretion, enhance nutrient absorption	Avocados, nuts, seeds, olive oil
Fermented Foods	Support a healthy gut microbiome, indirectly enhance incretin release	Yogurt, kefir, kimchi
Polyphenol-Rich Foods	Anti-inflammatory, gut microbiome modulation, enhance GLP-1 release	Berries, green tea, dark chocolate

Increasing the secretion of GLP-1 and GIP naturally through diet and lifestyle changes offers a promising alternative to pharmaceutical interventions. These natural approaches focus on stimulating the body’s own incretin production and maintaining a healthy metabolic state.

Foods That Stimulate Incretin Secretion:

1. High-Fibre Foods:
   • Fibre-rich foods, such as whole grains, legumes, fruits, and vegetables, slow gastric emptying and stimulate the secretion of GLP-1 and GIP. Soluble fibre, in particular, ferments in the gut, promoting the release of incretins by stimulating L-cells and K-cells in the intestine.
2. Protein-Rich Foods:
   • Dietary proteins, especially those from sources like eggs, fish, poultry, and dairy, are known to increase GLP-1 and GIP levels. Whey protein has been shown to be particularly effective.
3. Healthy Fats:
   • Unsaturated fats, such as those found in avocados, nuts, seeds, and olive oil, can stimulate GLP-1 secretion. However, moderation is key to avoiding excess calorie intake.
4. Fermented Foods:
   • Foods such as yogurt, kefir, and kimchi promote a healthy gut microbiome, which can indirectly influence incretin secretion by improving gut health.
5. Polyphenol-Rich Foods:
   • Foods rich in polyphenols, such as berries, green tea, and dark chocolate, have been linked to enhanced GLP-1 secretion due to their anti-inflammatory and gut microbiome-modulating effects.

Lifestyle Factors That Enhance Incretin Secretion:

1. Regular Physical Activity:
   • Exercise improves insulin sensitivity and enhances incretin response. Both aerobic activities and resistance training can stimulate GLP-1 secretion, improving glucose regulation.
2. Maintaining a Healthy Weight:
   • Excess visceral fat can impair incretin secretion. Weight loss through natural methods such as calorie control and increased physical activity can restore incretin function.
3. Intermittent Fasting and Meal Timing:
   • Time-restricted eating or intermittent fasting can optimise incretin responses by promoting insulin sensitivity and regulating postprandial glucose levels.
4. Adequate Sleep:
   • Poor sleep patterns are associated with impaired glucose metabolism and lower incretin levels. Prioritising sleep hygiene can positively influence hormone regulation.
5. Stress Management:
   • Chronic stress disrupts hormonal balance and may impair incretin secretion. Practices like mindfulness, yoga, and deep breathing can support healthy metabolic functioning.
6. Hydration:
   • Adequate hydration supports overall digestive health and may improve nutrient absorption, which indirectly supports incretin secretion.

Conclusion:

Natural methods to increase incretin secretion focus on holistic dietary and lifestyle changes that improve metabolic health and gut function. These strategies not only support GLP-1 and GIP levels but also provide broader health benefits without the side effects associated with pharmacological treatments. Combining these methods with medical advice can maximise long-term outcomes for individuals seeking to manage weight, blood sugar levels, or other metabolic conditions.

The ProLongevity Approach: we are all about identifying root-causes and addressing them with precision-nutrition and  step-wise lifestyle changes. Our founder Graham Phillips is (in)famous as “The Pharmacist who Gave Up Drugs” so you might assume we’d be completely opposed to using GLPs under ANY circumstances. NOT SO! After deep-diving into the evidence we’re convinced that GLPs have a place. Lifestyle changes based on root-causes will always be front-and-centre in our programs, but that isn’t always enough. The appalling food environment we all have to cope with means so many of us are food addicted at least to an extent, ending up both overweight and permanently hungry. GLPs can turn down the food noise and help us better-control our blood sugar. So we’re planning to use the GLPs where appropriate but not in the conventional way. Let’s call it “precision prescribing”. Instead of a one-size-fits-all escalating dose we plan to tailor both the dose AND the timing to the individual. That means better outcomes, fewer side-effects and lower costs for ProLongevity clients.

If all of this sounds appealing, who not book a free exploratory call with the ProLongevity team. It costs you nothing and we never apply any pressure.

References

1. Drucker, D. J. (2018). Mechanisms of Action and Therapeutic Application of Glucagon-Like Peptide-1. Cell Metabolism, 27(4), 740-756.
2. Nauck, M. A., & Meier, J. J. (2018). Incretin Hormones: Their Role in Health and Disease. Diabetes, Obesity & Metabolism, 20(S1), 5-21.
3. Rosenstock, J., et al. (2021). Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine, 385(6), 501-512.
4. Holst, J. J., & Gøtze, J. P. (2020). Glucagon and GLP-1 Receptor Signalling in Metabolic Diseases. Nature Reviews Endocrinology, 16(7), 390-407.