GLP-1 & GIP: The Science, the Hype, and the Dietary Connection

In the world of weight loss and metabolic health, GLP-1 receptor agonists—such as Ozempic, Wegovy, and Mounjaro—have taken centre stage. These drugs promise remarkable weight loss and better blood sugar control, but at what cost?

While some see them as a breakthrough in obesity treatment, others worry about the unintended consequences of their long-term use. Understanding how GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Polypeptide) work can help us assess whether these drugs are truly a sustainable solution—or whether they come with hidden trade-offs that deserve more attention.

What Are GLP-1 & GIP Hormones?

GLP-1 and GIP are incretin hormones—chemical messengers released in the gut after eating. They play a key role in:

• Regulating blood sugar by enhancing insulin release

• Suppressing appetite by acting on the brain’s hunger centres

• Slowing digestion to increase feelings of fullness

These hormones are naturally produced, but people with obesity often have a blunted GLP-1 response, particularly to carbohydrates. This could help explain why processed carbs are so easy to overeat—they don’t properly trigger the satiety signals that tell the body to stop eating.

GLP-1 receptor agonists mimic the effects of GLP-1 but last much longer in the body, extending its appetite-suppressing and glucose-lowering effects. Some newer drugs, like Tirzepatide (Mounjaro/Zepbound), target both GLP-1 and GIP, potentially enhancing weight loss further.

The Science of GLP-1 & GIP: How These Gut Hormones Control Appetite and Blood Sugar

GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Peptide) are incretin hormones—chemical messengers released in response to food intake. They play a critical role in digestion, appetite control, and blood sugar regulation. These hormones are the foundation of many modern weight-loss drugs like Ozempic, Wegovy, and Mounjaro.

However, before diving into these medications, it's essential to understand how these hormones naturally function in the body. Let's take a deep dive into their mechanisms.

General Mechanisms

• Both GLP-1 and GIP exert their effects by binding to their specific receptors (GLP-1R and GIPR), which are G-protein-coupled receptors.   

• This binding activates intracellular signaling pathways, notably increasing cyclic adenosine monophosphate (cAMP) levels.   

• This increase in cAMP mediates many of their downstream effects.   

The Tiny Sensors in Your Digestive System: L Cells & K Cells

Inside your intestines, there are specialized cells that act as nutrient sensors:

• L cells – Found mainly in the lower small intestine (ileum) and colon, these cells secrete GLP-1 when they detect food.

• K cells – Located in the upper small intestine (duodenum and jejunum), these cells primarily release GIP.

When food—whether carbohydrates, proteins, or fats—enters the digestive tract, these cells sense the nutrients and release their respective incretin hormones into the bloodstream. This triggers a cascade of physiological effects designed to slow digestion, regulate hunger, and control blood sugar levels.

GLP-1’s First Task: Slowing Digestion (Gastric Emptying)

Once GLP-1 is released, its first major action is to slow down how quickly food leaves your stomach and enters the small intestine. This process, known as gastric emptying, has two key benefits:

1. Prolonged Fullness – Food stays in the stomach longer, increasing the feeling of satiety and reducing overall food intake.

2. Steady Blood Sugar – Slower digestion prevents rapid spikes in blood sugar after meals.

In addition to slowing gastric emptying, GLP-1 also stimulates stomach distension, physically expanding the stomach walls. This further amplifies signals to the brain that you're full—one reason why people feel extremely satiated after a large meal.

How GIP differs: While GLP-1 slows gastric emptying, GIP does not. Instead, GIP helps store excess energy as fat—which is why some believe targeting GLP-1 alone (without GIP activation) may be more beneficial for weight loss.

The Gut-Brain Axis: How GLP-1 Suppresses Appetite

GLP-1 doesn’t just act locally in the gut—it also communicates directly with the brain via the gut-brain axis.

• Vagus Nerve – This nerve connects the gut to the brain and carries GLP-1 signals to the hypothalamus, the brain’s hunger control centre.

• Hypothalamus – When GLP-1 levels rise, the hypothalamus gets the message: "We're full, stop eating."

This mechanism is why GLP-1 receptor agonist drugs (like Ozempic and Wegovy) are so effective at reducing appetite—they mimic this natural satiety signal but in a prolonged and amplified way.

Ghrelin's Role in Hunger:

• Ghrelin is primarily produced by the stomach and signals to the brain (specifically the hypothalamus) to stimulate appetite.

• Ghrelin levels typically rise before meals and fall after meals, reflecting the body's hunger-satiety cycle.

GLP-1 and Ghrelin:

• Ghrelin Suppression: GLP-1 has been shown to suppress ghrelin secretion. This is a key mechanism by which GLP-1 reduces appetite and promotes satiety.

• Central Effects: GLP-1 also acts directly on the brain to reduce hunger signals, further contributing to its appetite-suppressing effects.

• Delayed Gastric Emptying: GLP-1 slows down gastric emptying, which prolongs the feeling of fullness and reduces the desire to eat. This indirect effect also contributes to decreased ghrelin.

How GIP differs: Interestingly, GIP does not strongly suppress appetite like GLP-1 does. Instead, its role is more focused on glucose metabolism (discussed next).

GLP-1 and the Reward System: The Double-Edged Sword

Beyond its effects on digestion, appetite, and blood sugar, GLP-1 also interacts with the brain’s reward system. This is why GLP-1 analogues (like Ozempic and Wegovy) have been shown to reduce cravings for not just food, but also alcohol and other addictive substances. However, blunting the brain’s reward response is a double-edged sword.

GLP-1’s Role in Dopamine & Reward Processing

• The brain’s reward system (dopaminergic pathways) is responsible for feelings of pleasure and reinforcement, encouraging behaviours essential for survival, such as eating.

• GLP-1 receptors are present in key brain regions, including the ventral tegmental area (VTA) and nucleus accumbens, both of which regulate dopamine release.

• When GLP-1 levels rise, they dampen dopamine activity, reducing the perceived reward from food, alcohol, and even other pleasurable activities.

  
  

💡 This is why people on GLP-1 drugs report reduced cravings for food, alcohol, and other addictive substances.

GLP-1 & GIP in Blood Sugar Regulation

Beyond appetite control, GLP-1 and GIP are also essential regulators of glucose metabolism.

• GLP-1’s Role in Blood Sugar Control:

  • Stimulates the pancreas to release insulin, helping move glucose into cells for energy.

  • Suppresses glucagon, a hormone that tells the liver to release stored glucose into the bloodstream.

  • Results in lower blood sugar levels and improved insulin sensitivity.

• GIP’s Role in Blood Sugar Control:

  • Also stimulates insulin release but is more potent than GLP1 and is released after a mixed meal (proteins, fats and carbohydrates).

  • Encourages fat storage in adipose tissue, which can be beneficial or harmful depending on energy balance.

Because of its ability to increase both insulin and fat storage, GIP has historically been seen as less useful for weight loss. However, new research suggests that when GIP is combined with GLP-1, it may enhance overall metabolic benefits—this is the principle behind Mounjaro (tirzepatide), a dual GLP-1/GIP receptor agonist.

The Natural Rise and Fall of GLP-1 Throughout the Day

In a healthy person, GLP-1 levels naturally fluctuate:

1. Rise after eating – Peaking about 45–60 minutes post-meal, suppressing appetite and boosting insulin release.

2. Gradual decline – As food is digested, GLP-1 levels fall, allowing hunger to return.

3. Baseline fasting levels – Remain low but still present to support glucose regulation.

This natural cycle prevents excessive hunger while maintaining stable energy levels.

How Drugs Like Ozempic and Wegovy Work:These medications mimic GLP-1 but with a much longer half-life. Instead of lasting for an hour or two, they persist for days or even a week, continuously suppressing appetite and slowing digestion. While this leads to dramatic weight loss, it also causes side effects like nausea, muscle loss, and even mental health concerns due to prolonged appetite suppression.

Key Takeaways

• GLP-1 and GIP are incretin hormones released by the gut in response to food.

• GLP-1 slows digestion, suppresses appetite, and enhances insulin release.

• GIP boosts insulin secretion but also promotes fat storage, making its effects more complex.

• Modern drugs like Ozempic (GLP-1 agonists) mimic these hormones but with longer-lasting effects.

• Overuse of GLP-1 drugs can lead to side effects like nausea, lean mass loss, and diminishing effectiveness over time.

Understanding these mechanisms allows us to explore natural strategies to enhance GLP-1 function without relying on medications—through diet, exercise, and other lifestyle changes.

Image Credit: Trends in Endocrinology

How Processed & Ultra-Processed Foods Disrupt GLP-1 & GIP Mechanisms

In a world where ultra-processed foods (UPFs) make up the majority of daily calorie intake, the natural mechanisms of GLP-1 and GIP are overridden, blunted, and hijacked, leading to overeating, metabolic dysfunction, and insulin resistance.

These foods are specifically engineered to be hyper-palatable, rapidly digestible, and nutrient-poor, which disrupts the delicate balance of gut-brain signalling, blood sugar control, and appetite regulation. Here’s how they interfere with each step of the incretin system:

Ultra-Processed Foods Flood the Gut Too Quickly - Cause Rapid Gastric Emptying

Ultra-processed foods—like refined grains, sugary snacks, and fast food—are designed for rapid digestion and absorption. They are often:

• Lack of fibre and protein – These are key nutrients that naturally slow digestion and trigger satiety (removing natural digestion-slowing properties).

• High glycemic index – Refined sugars and white flour rapidly break down into glucose, pushing food through the stomach too quickly.

• Liquid calories – Soft drinks, juices, and shakes empty from the stomach at an accelerated rate, preventing GLP-1 from delaying gastric emptying.

• High in simple sugars & refined starches (which break down into glucose almost instantly).

• Highly processed to require minimal chewing, making them easier to over-consume.

  
  

💡 How This Disrupts GLP-1 & GIP:

• L cells (GLP-1) and K cells (GIP) require time to sense nutrients and respond appropriately. When food is rapidly absorbed, these gut sensors don’t have a chance to properly activate.

• GLP-1 release is diminished, leading to weaker satiety signals.

• This rapid delivery of nutrients to the upper portion of the small intestine (K Cells) can lead to a quick and substantial release of GIP

• GIP gets overstimulated, promoting fat storage instead of balanced energy use.

This is one reason why people consuming high-processed diets often feel hungry again soon after eating, even after large meals. This contributes to a cycle of overeating and increased fat accumulation, especially around the visceral organs.

The Gut-Brain Axis Gets Overridden by Hyper-Palatable Foods

Ultra-processed foods hijack the gut-brain axis by artificially stimulating reward pathways in the brain. This effect is driven by:

• High sugar + fat combinations – Rare in nature, but common in UPFs, these combinations (e.g., doughnuts, ice cream, crisps) trigger excessive dopamine release.

• Artificial flavours & additives – These amplify taste without nutritional benefits, tricking the brain into craving more.

• Soft textures & emulsifiers – These reduce the need for chewing, speeding up intake and delaying satiety signals.

  
  

💡 How This Disrupts GLP-1 & GIP:

• GLP-1 signalling is weakened, meaning the brain doesn’t receive the "we’re full" message effectively.

• Ultra-processed foods disrupt the normal GLP-1 response (by, for example, causing a rapid and excessive release of insulin that then quickly drops blood sugar), this could lead to less ghrelin suppression and increased hunger.

• Hunger hormones (ghrelin) stay elevated, making it harder to stop eating.

• The brain rewires to seek out ultra-processed foods, leading to addictive-like eating behaviours.

The net result? People over-consume energy-dense, nutrient-poor foods while still feeling unsatisfied.

Processed Foods Spike Blood Sugar & Disrupt Insulin Signalling

One of GLP-1’s primary roles is to regulate blood sugar by enhancing insulin release and reducing liver glucose output. However, a diet high in ultra-processed foods causes:

• Frequent, excessive glucose spikes, forcing the pancreas to overproduce insulin.

• Insulin resistance, as cells become desensitised to insulin’s effects.

• Compensatory glucagon release, worsening blood sugar instability.

  
  

💡 How This Disrupts GLP-1 & GIP:

• GLP-1 becomes less effective over time, leading to weaker insulin responses.

• GIP contributes to excessive fat storage, worsening metabolic dysfunction.

• The pancreas gets overworked, increasing the risk of type 2 diabetes.

This is why individuals consuming diets high in processed carbs and sugars often develop insulin resistance—the body stops responding to normal incretin signals.

GLP-1 & GIP Become Chronically Dysregulated

In a natural diet, GLP-1 and GIP levels rise and fall in sync with meal patterns. However, with ultra-processed foods:

• GLP-1 is blunted – Leading to constant hunger, poor satiety, and increased food intake.

• GIP becomes overstimulated – Promoting weight gain and fat storage.

• Insulin resistance develops, making it harder to regulate blood sugar.

Over time, this leads to metabolic syndrome, obesity, and type 2 diabetes—the very conditions that new GLP-1 drugs (like Ozempic) are now being used to treat.

The Processed Food Trap & GLP-1 Dysfunction

• Ultra-processed foods bypass natural gut-brain mechanisms, leading to overeating, disrupted satiety, and metabolic dysfunction.

• GLP-1 function is weakened, preventing proper appetite control and blood sugar regulation.

• GIP is overstimulated, encouraging excess fat storage and insulin resistance.

• Natural food-based approaches (high-fibre, protein-rich, whole foods) help restore normal GLP-1 & GIP function without needing medications.

Mechanism	Natural GLP-1/GIP Function	Altered Response Due to Ultra-Processed Foods
Sensing Nutrients (L Cells Activation)	L cells in the gut detect whole foods (proteins, fats, complex carbs) and release GLP-1/GIP appropriately.	Rapid digestion of ultra-processed foods overwhelms L cells, leading to dysregulated GLP-1/GIP release.
Gastric Emptying	GLP-1 slows gastric emptying, allowing gradual nutrient absorption and sustained satiety.	Ultra-processed foods are digested too quickly, leading to rapid gastric emptying and post-meal hunger.
Satiety & Fullness	GLP-1 signals the brain via the vagus nerve and hypothalamus to suppress appetite.	Hyper-palatable foods override satiety signals, leading to overconsumption.
Blood Sugar Regulation	GLP-1 enhances insulin release and reduces glucose output from the liver, keeping blood sugar stable.	Ultra-processed carbs cause rapid blood sugar spikes, leading to insulin resistance over time.
Dopamine & Reward System	GLP-1/GIP contribute to balanced reward signalling, reinforcing normal eating behaviours.	Ultra-processed foods trigger excessive dopamine release, reinforcing cravings and compulsive eating.
GLP-1/GIP Cycling Throughout the Day	Incretin levels rise post-meal and decline gradually, promoting natural hunger-satiety rhythms.	Frequent snacking on processed foods leads to erratic incretin signalling, contributing to metabolic dysfunction.

This contrast highlights how ultra-processed foods hijack natural metabolic pathways, leading to disrupted appetite control, insulin resistance, and compulsive overeating—all key drivers of obesity and metabolic disease.

Evolutionary Role of GLP-1 and GIP: Designed for Survival, Not Overabundance

The GLP-1 and GIP incretin systems evolved as part of a finely tuned mechanism to ensure survival in an environment where food was scarce and intermittent. Our ancestors did not have the luxury of frequent meals or easy access to calorie-dense foods. Instead, they relied on whole, fibrous, and nutrient-dense foods obtained through hunting, foraging, and seasonal availability.

In such an environment, the primary functions of GLP-1 and GIP made perfect sense:

• Efficient Nutrient Absorption: Slowing gastric emptying allowed the body to extract as much nutrition as possible from each meal, which was essential when food was not always guaranteed.

• Energy Storage for Famine Resistance: By promoting insulin release and fat storage, GIP played a crucial role in helping humans build energy reserves for times of scarcity.

• Controlled Eating Behaviour: The gut-brain axis ensured that eating behaviour was self-regulating—hunger was triggered when energy was needed, and satiety signals ensured we stopped eating when sufficient nutrients were obtained.

• Balanced Reward System: A moderate release of dopamine in response to eating helped reinforce survival-driven behaviours without fostering addiction to food.

Why This System Works Against Us Today

While this system worked well in an environment of scarcity and physical exertion, it is now maladapted to our modern food environment in several ways:

1. Constant Food Availability

   • Unlike our ancestors, we live in a world of constant food access, where we rarely experience true hunger. The frequent availability of hyper-palatable foods disrupts the natural incretin cycles, leading to dysregulated hunger and satiety signals.

2. Ultra-Processed Foods Bypass Natural Controls

   • Whole foods require time to digest, allowing the incretin system to function properly. However, ultra-processed foods are engineered to be rapidly digested and absorbed, causing dysregulated GLP-1/GIP signalling. This results in:

     • Faster gastric emptying, leading to frequent hunger.

     • Impaired satiety response, causing overeating.

     • Excess insulin stimulation, promoting fat storage and insulin resistance.

3. Excessive Reward Signalling Leads to Overconsumption

   • Processed foods are designed to override natural satiety signals by stimulating excessive dopamine release. This leads to compulsive eating, reinforcing cravings even in the absence of true hunger. Over time, the brain becomes desensitised to normal satiety cues, making it harder to regulate food intake.

4. Insulin Resistance and Metabolic Dysfunction

   • Frequent insulin spikes due to ultra-processed food consumption lead to insulin resistance, reducing the effectiveness of GLP-1 and GIP over time. This creates a vicious cycle where the body requires even more food to trigger satiety, further driving weight gain and metabolic disease.

The Mismatch Between Evolution and Modern Diets

Our GLP-1/GIP systems evolved to help us survive in a world of scarcity, not abundance. Today, we live in an environment where food is:

• Excessively available

• Stripped of fibre and essential nutrients

• Highly processed and engineered for overconsumption

This mismatch between our ancient biology and modern diets is one of the key drivers of obesity, metabolic syndrome, and other chronic diseases. Instead of helping us regulate food intake, our natural incretin system is being hijacked by ultra-processed foods, making it increasingly difficult to maintain a healthy weight and metabolic function.

To restore balance, we need to align our diet with our evolutionary biology—focusing on whole, nutrient-dense foods that allow our natural incretin systems to function as they were designed to.

Conclusion: The Real Science Behind Weight Gain and Loss

Losing weight is hard—far harder than many realise. The common advice of “just eat less and move more” fails to address the underlying biological drivers of weight gain. The reality is that biochemistry determines behaviour, not the other way around. Overeating in individuals with obesity is not simply a failure of willpower; it is the result of a biochemical or hormonal imbalance.

We readily acknowledge that hormones dictate vertical growth during childhood and adolescence. Yet, when it comes to horizontal growth (weight gain), we default to blaming personal choices rather than recognising the role of hormonal regulation—particularly insulin, GLP-1, and other key metabolic signals.

Weight gain is a slow, cumulative process that unfolds over months and years, often without conscious intent. And the heavier a person becomes, the easier it is to gain even more weight, because the very hormones that regulate appetite and metabolism become dysregulated. GLP-1, a hormone designed to promote satiety and blood sugar control, becomes impaired by the very foods that dominate modern diets—ultra-processed, hyper-palatable, refined carbohydrates.

Ultra-processed foods hijack the body's natural hunger and reward systems, leading to:

• Excessive dopamine-driven cravings, reinforcing compulsive eating behaviours.

• Impaired GLP-1 signalling, making it harder to feel full.

• Chronic insulin resistance, keeping the body in a fat-storage mode.

In response to this, GLP-1 analogues (like Ozempic, Mounjaro and Wegovy) have emerged as powerful tools for appetite suppression, but they come with potential downsides. By blunting the brain’s reward response, these drugs not only reduce cravings but may also diminish overall enjoyment of life, leading to emotional flatness or even depression in some cases.

The key takeaway? Weight gain and loss are not just about calories; they are fundamentally controlled by hormones and metabolic signals. Addressing the obesity epidemic requires a deeper understanding of how modern diets disrupt these systems—and why restoring metabolic balance through diet and lifestyle is the most sustainable solution.

Rather than simply treating the symptoms with medication, preventing metabolic dysfunction in the first place is far easier than reversing it later. This is why understanding the role of hormones/neurotransmitters like GLP-1, insulin, and dopamine is critical—not just for weight management, but for overall health and longevity.