Author Archives: Will Lin

[Click here to read the previous part: Current issues]

Many pharmaceutical companies have now entered the space of GLP-1 agonists and related therapies for obesity, attempting to increase effectiveness and also finding oral alternatives to the injections currently used.

Let’s dive back into the hormones involved. In part 1, we discussed how GLP-1 and GIP increase release of the pancreatic hormone insulin following a meal, which decreases blood sugar. Amylin is also produced along with insulin in beta cells, helping to delay gastric emptying and decrease food intake. Amylin and GLP-1 both suppress the production of the pancreatic hormone glucagon, whose function is to raise blood sugar and prevent it from going too low. When eating, peptide YY (PYY) is also released, which also acts to slow gastric emptying and decrease appetite.

Currently, several peptide drugs are available in the form of GLP-1 agonists (semaglutide, liraglutide) and GLP-1/GIP dual agonists (tirzepatide). However, more medications with different mechanisms are currently being investigated for weight management. There is a GLP-1/glucagon dual agonist currently under development – mazdutide. Although glucagon functions to raise blood sugar, it also has the ability to increase energy expenditure, which theoretically could increase weight loss. There is also a GLP-1/GIP/glucagon triple agonist, retatrutide, that is currently being trialled, which may have superior efficacy.

Drugs currently being developed that target other mechanisms include cagrilintide, a long-lasting analogue of amylin, which is currently being studied in conjunction with semaglutide. PYY analogues are also in the early stages of being tested along with semaglutide. Further drugs are also being developed to target different combinations of these pathways, aiming to reduce side effects and to improve efficacy.

However, all of the drugs mentioned above are peptides – they must be injected subcutaneously, as oral administration would degrade and inactivate the drug. There is an oral formulation of semaglutide available, but it must be taken in certain conditions (in the morning, with a certain amount of water, and a certain time before eating or taking other medications). To combat this, small molecule drugs are being developed – these drugs would bind to the same receptors, but they would be able to be taken orally. These include drugs such as orforglipron, lotiglipron, and danuglipron, which are all small molecule GLP-1 receptor agonists. The development of these therapies could open up this class of medications to those who prefer not to use injections, and could potentially allow for easier storage, compared to the current medications that must be kept refrigerated.

The world of obesity medicine is going through an exciting time now, with many new therapies being developed and many new mechanisms and combinations of mechanisms being explored. These medications may become more accessible to everyone, and could help reduce the risk of other chronic diseases, reducing the burden on our healthcare system in general. However, the long-term risks and benefits are still unknown, and we should still address the root causes of obesity in our society.

[Click here to read the previous part: A backgrounder]

There is currently a divide between those who are able to afford GLP-1 agonists and those who cannot. This could further contribute to the socioeconomic disparities in health we see today – those who have good insurance or who are able to spend money on treatment could have better health than those who cannot. In high-income countries, low socioeconomic status is associated with higher obesity rates. However, GLP-1 agonist therapies are mostly available to those with high SES, and not to those with low SES who stand to gain more benefit from it. For example, GLP-1 agonists are commonly used by celebrities as a method to lose a few pounds, but their use by morbidly obese individuals would convey greater health benefits to them compared to celebrities.

Obesity treatment with liraglutide or semaglutide is estimated to cost the average American over $16000 per year without insurance. Furthermore, not all insurance will cover the drug for obesity. Insurance companies and Canadian provincial health plans cite high costs, lack of long-term safety data, lack of data on other obesity-related comorbidities, lack of data about long-term benefits, and the sheer number of individuals who would qualify for the drug as reasons for not covering GLP-1 agonists for obesity.

The need for obesity treatment is still recognized by these parties – reducing obesity could be a preventative measure and could save healthcare systems and insurance companies money later on by reducing the amount spent on costly management of obesity-related chronic diseases. However, whether GLP-1 agonists are the right drug for this is still up for debate, especially given the costs and the fact that these drugs must be taken continuously to avoid weight regain.
Furthermore, the side effects of GLP-1 agonist treatment are often brushed aside – nausea and vomiting are the most common, with some patients citing them as a reason for discontinuation. There are also rarer side effects such as inflammation of the pancreas, gallbladder diseases, high heart rate, and kidney problems. The benefits should be carefully weighed against the potential risks, especially the unknown long-term side effects.

In recent years, the idea of body positivity has helped decrease the stigma regarding obesity – with this, people have been able to enjoy better mental health and reduced risks of eating disorders. However, with the arrival of effective anti-obesity drugs and the deluge of people wishing to use them, the medication offers a potential solution to a group of people who have often been stigmatized or misunderstood by our society. There are concerns about how this will affect our perception of body weight – how will our perception of the ideal body image change? Will it change how we perceive people with obesity in the future?

Although the physiological effects of these drugs are being well-documented, we should also examine the effects on our society and how we perceive ourselves. And we should also not forget that obesity is also a result of societal and environmental factors, and that we should strive to address the underlying issues.

[Click here to read the next part: Future directions]

Currently, the drug semaglutide is receiving a lot of press – some celebrities openly discuss their off-label use of this drug to lose weight. As demand surges for it and similar drugs, the supply has not been able to keep up, resulting in shortages across the United States.

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. These medications were originally developed for the management of type 2 diabetes by regulating blood sugar levels. GLP-1 and GIP (gastric inhibitory peptide) are hormones known as incretins. These increase the amount of insulin released after a meal, causing decreases in blood glucose. These hormones are rapidly degraded by dipeptidyl peptidase-4 (DPP4). As targets for type 2 diabetes, one could inhibit DPP-4 (as in drugs such as sitagliptin and saxagliptin) and thus increase the actions of endogenous GLP-1, or one could target the receptor directly (as in drugs such as semaglutide, dulaglutide, and liraglutide). Furthermore, there is a GLP-1/GIP dual analogue available on the market – tirzepatide.

In obesity, GLP-1 agonists are thought to produce their anti-obesity effects by decreasing gastric emptying and decreasing gastrointestinal motility, meaning that food will spend more time in the stomach. This can make it easier to physically feel full from eating. These agonists can also affect the brain directly, causing decreased appetite, increased satiety, and decreased reward associated with food. It is also suggested that GLP-1 agonists may increase energy expenditure, which combined with decreased caloric intake, may result in weight loss.

The hormonal changes that occur during weight loss can make it very difficult to sustain weight loss (see this link for more details!). Reducing caloric intake results in decreased energy expenditure and increased appetite, and the sustained physiological changes can result in weight regain that occurs for some time afterwards. GLP-1 agonists may act as an external stimulus that helps prevent those decreases in energy expenditure and increases in appetite. However, once they are stopped, many patients regain some portion of their weight, with one study finding that participants regained two-thirds of their lost weight in a year.

Although GLP-1 agonists are a promising therapy to help manage a chronic condition that affects 40% of Americans and 30% of Canadians, we must recognize that there are other factors that lead to obesity, including a change towards a more sedentary lifestyle and lower quality diets. We must acknowledge that obesity is not simply a result of low willpower or laziness, and that complex physiological and social factors have contributed to what may be one of the greatest public health crises we face today.

[Click here to read the next part: Current issues]

With the lasting effects of the recent heat waves in the past few years in Vancouver, have you ever wondered – how does the air heat up that much? Although it sounds like a simple question, the answer is actually quite complex, as there are many factors that change air temperature.

While the sun does transfer some energy directly to the air and warms it up, much of it is absorbed by the ground and the oceans. The ground and oceans then transfer heat to the air, which warms up the air. Summers are generally hotter than winters as during the summer, the earth tilts in a way that allows more that hemisphere to receive more direct radiation from the sun; combined with the longer daylight hours, more solar energy is absorbed, and thus the air temperature is warmer in the summer than in the winter.

However, the geography of the area can also change the air temperature. In Vancouver, we experience a strong moderating effect from the ocean – water has a high heat capacity, and thus greater heat transfer is needed in order for the temperature to change. Because of this, the ocean is able to cool down coastal locations in the summer by absorbing more of the energy, and keep them warmer in the winter as the ocean releases heat back into the atmosphere.

Vancouver also experiences the urban heat island effect. The way cities are built causes the temperature in them to be higher than their surroundings. Dark concrete and asphalt is able to absorb more heat in the day, and release it in the night. Additionally, many urban environments tend to have fewer plants. Trees can provide shade and cool down surroundings through evapotranspiration – plants take up water from the ground with their roots, and the water then evaporates from the leaves or stems. cooling down the surroundings, as a lot of energy is needed to for the water to turn from a liquid into a gas. Other factors contributing to the urban heat island effect include heat from cars, air conditioning, and factories, as well as the greenhouse effect from greater levels of greenhouse gases such as carbon dioxide, methane, and nitrous oxide in cities.

It is also possible for air temperature to increase without any transfer of heat (no energy being transferred due to a difference in temperature)- this is called adiabatic heating. The famous chinook winds in Alberta are an example of this – as air goes down the mountains, the pressure on the air increases, compressing it. With this compression, work is being done on the air, increasing its internal energy and increasing the air temperature.

Weather systems also significantly affect how hot a given area becomes. In Vancouver, warm high-pressure systems arriving from the subtropics during the summer are often associated with hot and dry conditions. Descending air causes higher air pressure in at the surface, warming up the air and preventing cloud formation as the air pushes outwards and can hold more moisture without condensing. The lack of cloud cover allows for more sunlight to reach the ground, which further contributes to warming in the summer.

Lately, the term “heat dome” has entered the public consciousness as some particularly strong heat waves have hit coastal BC. In a heat dome, a high pressure system is sandwiched by two other low pressure systems, forming a pattern known as an omega block. Although hot air rises, the high pressure system traps the hot ocean air in one area and forces it down. As the air sinks, it compresses and warms up even more, resulting in the record-breaking heat seen here on the west coast.

In previous posts, we discussed the chemistry of sugars as important parts of the structure of antibiotics, and the importance of sugars in toxic molecules in foods. Today, we will discuss one other function of sugars in the human body: cell recognition.

Many of you are probably familiar with the ABO system of blood types. This is based on the presence of A and B antigens on the surface of red blood cells, which is especially important for blood transfusions to avoid unwanted immune reactions. The A blood type is characterized by the presence of the A antigen, the B blood type has B antigen present, AB has both, and O has neither. But what are these antigens?

Polysaccharides present on red blood cells in the ABO system. Source: https://www.researchgate.net/figure/Biochemical-basis-of-ABO-groups_fig1_233799814

This system actually refers to different polysaccharides present on the surface of red blood cells, attached to lipids and proteins. The base of the A and B antigens is the H antigen, present in people with type O blood [1]. The H antigen is then subsequently modified by enzymes by the addition of other sugars to form the A or B antigens. The sugars involved include fucose, galactose, N-acetylglucosamine, and N-acetylgalactosamine. These last two compounds are derived from glucose and galactose from the addition of an amine and an acetyl group [2] [3].

Another important carbohydrate is Sialyl-Lewis X (sLeX) which is important for white blood cells to travel to the affected site when an inflammatory response occurs. Cells in the inner layer of blood vessels in express proteins called selectins, which bind to sLeX on white blood cells and cause the cells to slow down, allowing them to move through out of the blood vessel and into the site of inflammation [4].

Structure of Sialyl-Lewis X. Source: https://link.springer.com/article/10.1007/s10719-020-09912-4/figures/1

As you can see, sugars have many other roles in the body other than just being energy sources! There are also other roles we haven’t discussed. Stay tuned and we may cover them in future posts!

Sources:
1. Dean L. The Hh Blood Group. National Center for Biotechnology Information (US); 2005. Accessed July 20, 2021. https://www.ncbi.nlm.nih.gov/books/NBK2268/
2. Dean L. ABO Blood Group. In: Pratt VM, Scott SA, Pirmohamed M, et al., eds. Medical Genetics Summaries. National Center for Biotechnology Information (US); 2012. Accessed July 20, 2021. http://www.ncbi.nlm.nih.gov/books/NBK100894/
3. Wood E, Shortt J, Polizzotto M. Controversies and innovations in the management of critical bleeding and massive transfusion in trauma. Defence Medical Debate. 2008;1:15-23.
4. Jin F, Wang F. The physiological and pathological roles and applications of sialyl Lewis x, a common carbohydrate ligand of the three selectins. Glycoconj J. 2020;37(2):277-291. doi:10.1007/s10719-020-09912-4