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Amylin Function and Effects
Amylin, also known as islet amyloid polypeptide (IAPP), is a natural peptide released alongside insulin from beta cells in the pancreas. It acts as an important signal in the brain, creating feelings of fullness. Amylin starts as a longer propeptide with 89 amino acids, released at about a 100:1 ratio compared to insulin. Like insulin, it is processed into a smaller, active form that is 37 amino acids long.
Amylin has several key effects: it slows down how quickly food moves through the stomach, promotes a sense of fullness in the brain, and prevents sharp rises in blood sugar after eating. By slowing the increase in blood sugar, amylin helps the body use sugar as energy rather than turning it into fat.
Amylin also plays a role in bone health, working similarly to calcitonin and CGRP (calcitonin gene-related peptide). These peptides lower blood calcium levels by encouraging its storage in bones. Amylin may also affect how much calcium is lost through the kidneys, though it’s not clear how significant this is.
In animal studies where the amylin gene was turned off, animals ate less and consumed fewer calories. Amylin is broken down by the same enzymes that degrade insulin, but cagrilintide, a synthetic version of amylin, is designed to resist these enzymes, making it last longer and have stronger, more sustained effects.
There’s also a possible connection between amylin and Alzheimer’s disease, though it’s not fully proven. High levels of amylin, often seen in people with insulin resistance or diabetes, can lead to clumping of the protein into fibrils. These fibrils may interact with beta amyloid in the brain, potentially contributing to the formation of amyloid plaques associated with Alzheimer’s, but a direct cause hasn’t been confirmed.
Cagrilintide Design and Function
Cagrilintide is a man-made version of amylin, a protein naturally produced by the pancreas. It is designed to resist breakdown by enzymes in the blood, giving it a longer-lasting effect compared to natural amylin. Cagrilintide isn’t the first amylin-based drug; that title goes to pramlintide, developed in the early 2000s. Pramlintide was used alongside insulin to help control blood sugar in people with diabetes, reducing the sharp rise in blood sugar after meals and allowing less insulin to be used. What makes cagrilintide different is its much longer half-life.
Beyond lasting longer, cagrilintide also solves a problem with natural amylin: protein clumping. When amylin levels in the blood are too high, it can clump together, making it ineffective. These clumps, called amyloid fibrils, can harm insulin-producing beta cells in the pancreas and may contribute to type 2 diabetes. The idea is that eating too much food triggers the release of extra insulin and amylin, leading to high amylin levels that cause these toxic clumps. These clumps are similar to the amyloid beta tangles seen in Alzheimer’s disease and can damage beta cells, reducing the pancreas’s ability to produce enough insulin.
Cagrilintide is a carefully designed drug that overcomes the limitations of natural amylin. While amylin works well when released naturally by the pancreas, it’s not ideal for use as a drug. To prevent clumping, scientists added proline residues to one end of the amylin molecule. They also added an amide residue to improve how it binds to receptors. Additionally, a fatty acid residue was added to the other end to help it cross into the brain more effectively. These changes allow cagrilintide to bind better to specific receptors called RAMP-1 and RAMP-3.
RAMP receptors (receptor activity-modifying proteins) are a group of proteins that work with other receptors to change how they function. RAMP-1 and RAMP-3 interact with receptors like the calcitonin-like receptor, calcitonin receptor, and calcium-sensing receptor, while RAMP-3 also interacts with the secretin receptor. The exact roles of these interactions are not fully understood, but problems with RAMP receptors have been linked to diseases like heart disease, diabetes, and cancer.
Cagrilintide Mechanisms of Action
Cagrilintide works in several ways to help with weight loss and blood sugar control. In the stomach and intestines, it slows down how quickly food moves through the digestive system. This signals the brain to feel full, which reduces hunger and leads to eating less. Slowing food movement also slows sugar absorption, preventing sharp blood sugar spikes and giving the body more time to process sugar so less is turned into fat.
Cagrilintide also affects the brain directly. Studies in mice show that it binds to amylin receptors in a part of the brain called the arcuate nucleus. This binding influences the brain stem and pituitary gland, creating a sense of fullness and reducing the urge to eat.
Lastly, cagrilintide works in the pancreas, similar to natural amylin, by reducing the release of glucagon through a feedback loop. This helps limit the conversion of glucose into fat.
Cagrilintide Clinical Trials
Two major studies have explored the effects of cagrilintide, providing insight into how this peptide works. In the first study, cagrilintide was given once a week and led to a weight loss of 6-11% of total body weight in just six weeks compared to a placebo. This weight loss was greater than that seen with liraglutide, another drug used for comparison in the trial. The side effects of cagrilintide were about the same as those of liraglutide.
In the second study, cagrilintide was combined with semaglutide, resulting in even greater weight loss than either drug alone. The combined effect was stronger than expected, suggesting that the two drugs work together synergistically. This combination led to a weight loss of up to 17.1% over 20 weeks. For example, a person weighing 200 pounds could lose 34 pounds in just five months.
Cagrilintide and Blood Sugar Control
Cagrilintide and similar drugs, like pramlintide, can significantly reduce insulin resistance and lower hemoglobin A1C levels by blocking glucagon secretion. Studies have shown that these peptide treatments can lower A1C levels by 2.2% in a short amount of time.
Cagrilintide only needs to be taken once a week, which makes it easier to use and more effective. Its long-lasting effect helps maintain better blood sugar control over time and, for weight loss, helps keep appetite in check for longer periods.
Blood Sugar, Amylin, and Cognitive Dysfunction
The connection between blood sugar control and brain function has been known for a long time. For example, diabetes is linked to problems with memory, attention, and thinking speed, even in younger people. High blood sugar, or hyperglycemia, can harm brain cells by activating a protein called protein kinase C. It can also increase inflammation and oxidative stress, which contribute to cognitive decline and other diabetes-related issues like heart and kidney disease.
Studies consistently show that blood sugar levels affect brain function. Both very high and very low blood sugar levels can harm the brain, but high blood sugar is especially concerning. For instance, a four-year study of older women found that consistently high blood sugar was linked to a higher risk of mild cognitive impairment and dementia. Interestingly, high blood sugar in the body may lead to lower glucose levels in the brain, which is a problem because the brain relies almost entirely on glucose for energy. Another study suggests that insulin resistance in the brain is a major cause of cognitive problems in people with diabetes. Overall, these findings show that when the brain can’t use glucose properly—especially when there’s too much in the blood—it may contribute to dementia.
Amylin, a protein produced by the pancreas, may also play a role in brain function. Like blood sugar, having too much or too little amylin in the blood can harm the brain. Data from a large heart study showed that both very high and very low amylin levels are linked to worse cognitive function and a higher risk of Alzheimer’s disease.
The connection between blood sugar, diabetes, and Alzheimer’s disease isn’t new. In fact, Alzheimer’s was once called “type 3 diabetes,” and this term is being used again as researchers explore the link between blood sugar and brain function. Amylin is also getting more attention for its role in cognitive health.
Amylin can easily cross into the brain and has similarities to beta amyloid, the main component of the amyloid plaques strongly linked to Alzheimer’s disease. Both amylin and beta amyloid have similar structures, bind to the same brain receptors, and are broken down by the same enzyme. Although a direct connection between amylin and beta amyloid hasn’t been proven, researchers strongly suspect one exists. For example, a study found a strong link between amylin levels in the blood and the buildup of amyloid plaque precursors in the brain. This connection held true even after accounting for factors like age, gender, ethnicity, body mass index, diabetes severity, stroke, kidney function, cholesterol levels, and a genetic marker for Alzheimer’s disease. Remarkably, when synthetic amylin was given to mice with Alzheimer’s, it reduced amyloid plaques in their brains and increased amylin levels in their blood. One possible explanation is that too much amylin in the blood may clump together, preventing it from entering the brain and allowing beta amyloid to build up into plaques.
These findings suggest a strong link between amylin and cognitive problems. While much more research is needed, there’s hope that drugs like cagrilintide, a synthetic version of amylin, could one day help treat or prevent Alzheimer’s disease. This area of research is active and open for further exploration, but no studies have yet looked at whether cagrilintide can clear beta amyloid from the brain or help with cognitive problems.
Cagrilintide Summary
Cagrilintide is a man-made version of amylin, a protein that the pancreas naturally produces. It belongs to a group of drugs first created to treat diabetes but now used to help with weight loss. Similar to other drugs like semaglutide, cagrilintide slows down how quickly food moves through the stomach and signals the brain to make you feel full. Although it’s still being studied, early results suggest cagrilintide may lead to even more significant weight loss than drugs like semaglutide. When combined with these drugs, cagrilintide seems to work even better, helping people lose more weight.
Beyond weight loss, cagrilintide might also help with heart disease and possibly even Alzheimer’s disease or other forms of dementia, but these benefits are still just possibilities and need more research.
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