Diabetes Week 2021: human-based research in the FAL

One of the main areas of research the FRAME Alternatives Laboratory (FAL) is currently focused on is the effects of obesity and exercise on skeletal muscle tissue to help understand the causes, and therefore possible treatments and prevention strategies for Type II diabetes.

Whilst studies on animals did help in the discovery of the hormone insulin and its role in treating diabetes, using laboratory animals to study Type II Diabetes today may not offer as much relevant insight into the condition as human-based research methods.

On Diabetes Week 2021, Andrew Wilhelmsen, PhD student in the FAL explains his research to investigate possible links between obesity and Type II diabetes using human muscle cells.

The issue

Type II Diabetes (T2D) is a complex disease where your body is no longer able to sufficiently produce, and/or respond to, the hormone insulin, in order to keep your blood sugar (glucose) level stable. Currently, there are around 4 million people living with diabetes in the UK and 90% of those people have T2D. It was estimated in 2012 that the cost of diabetes to the NHS was over £1.5 million an hour.

Our risk of developing T2D depends on many different lifestyle and genetic factors. One key factor, however, is obesity. As we gain excessive fat on our bodies, our cells can become less sensitive to the effects of insulin. Insulin is vital because it enables glucose to enter our cells and fuel our bodies. After we eat, the food is broken down into smaller substances and our blood glucose level rises. Our pancreas notices that our blood glucose is rising and pumps insulin into our blood stream to tell the cells in our bodies, particularly our muscle, liver and fat cells, to take up more glucose until we get back to our normal level. If our muscle cells stop responding well to insulin, they are no longer able to take up as much glucose from the blood. We call this ‘muscle insulin resistance’ and it is one of the first signs that we might develop T2D. In T2D, this system no longer works well enough to keep out blood glucose levels stable. This can lead to excessively high glucose in our system, which can be toxic and cause serious health problems, which require medication and lifestyle changes to control. The exact processes that cause muscle insulin resistance are still not well understood. Understanding the causes of T2D and associated risk factors may help lead to more efficient treatments, management and prevention strategies in the future.

The project

My research as a PhD student is focused on the development of insulin resistance in muscle. My work covers a range of approaches to try and paint a comprehensive picture of how and why insulin resistance occurs and the potential role of a protein called myostatin, which is known to limit muscle growth. The risk of developing T2D increases with age, so I started this project looking at the effects of age as well as obesity. We found that older adults with obesity have higher levels of the myostatin gene than those without obesity. Importantly, we also found that older adults without obesity have similar levels of the myostatin gene as younger adults. This suggests that obesity, but not ageing, may increase myostatin, which supports the idea that it could be linked to the development of T2D.

In my project, we study live human skeletal muscle cells in the lab. We take small muscle samples from human volunteers and use this sample to extract and grow new muscle cells, which maintain many of the features of real human muscle. We can treat these cells with nutrient mixtures that mimic the blood stream in obese or diabetic individuals; stimulate them with electricity to mimic exercise; or treat them with different substances in order to study the processes involved in insulin resistance.

Using these muscle cells, we have mimicked high-fat diets and caused changes typically seen in the development of T2D, but did not find any changes in myostatin levels. This has led us to our current work investigating whether high levels of body fat, which directly affects healthy muscle cells causing insulin resistance, is also accompanied by higher levels of myostatin. We know from other research that muscle and fat tissue in our bodies communicate with each other, and we suspect that excessive body fat found in obesity is causing the muscle to produce higher levels of myostatin, and that this may be involved in the process of developing insulin resistance. In order to do this, we take small pieces of fat tissue from adults with and without obesity and put them in liquid overnight to collect all of the communication factors that they pump out. When we grow muscle cells in this liquid, with added nutrients to help them develop normally, the cells receive the communication factors from fat tissue that they would be receiving in the body. We can alter the concentration of communication factors to reflect the amount of fat present in adults with or without obesity. The findings of these experiments might help us to better understand why adults with obesity often have more myostatin and this information will help inform our understanding of T2D.

Replacing animal research

Studying muscle in people is an excellent tool for understanding T2D, however we all have different genes, health and lifestyles. For instance, one person with obesity might do lots of regular exercise and another might not do any, so even though they are both considered to have obesity, they might have very different muscle health and function. In order to carry out effective experiments, we need to do as much as possible to control the variation seen between individuals so that we can focus just on the factors we are interested in. The control element is one reason why, historically, animals and animal-derived cells have often been used for scientific investigation. Selective breeding, genetic modification and controlled living conditions help to limit variation between the animals being studied.

Animal research was vital to our early understanding of the role of the pancreas and insulin and led to the first insulin therapies to treat diabetes. Indeed, the original research into the role of myostatin in obesity was undertaken in mice and revealed many fascinating observations. Today, however, with greater knowledge and technologies, we are able to move away from using animals and animal cells and focus on models of the body that use human cells in our experiments. This is important because while there are many animal models of diabetes, they are just that – models of human disease in a different species. We know that human and animal muscle tissue is not exactly the same. Using human muscle cells in my project improves the relevance of our findings and the potential impact it may have on human health, which is why we are always grateful to the volunteers who donate their tissue for projects such as mine.

For more information about the work of the FAL, click here.