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The Genetics of Diabetes by Dr. Omar Ali



Guest Author: Dr. Omar Ali

Dr. Ali is a pediatric endocrinologist with Valley Children's Healthcare in Central California. Before joining this position he was an associate professor of pediatric endocrinology at the Medical College of Wisconsin. He has a special interest in the genetics and epigenetics of obesity and type 2 diabetes and has published research in this area. He is also a member of Genopalate’s medical advisory board.


Is diabetes genetic? 


If you or a loved one have recently been diagnosed, this question may have crossed your mind. The short answer is that most forms of diabetes do in fact have a genetic component, but the details vary depending on the type of diabetes. Diabetes is basically a tendency to have higher blood glucose values than normal. This is referred to as hyperglycemia and once it crosses a certain threshold, the condition is labeled “diabetes”. 


There are several types of diabetes, but the most common types are type 1 diabetes and type 2 diabetes. There is also a relatively uncommon type of diabetes called MODY (monogenic diabetes of the young) that is practically entirely attributed to genotype (i.e., is it caused by a specific genetic anomaly that is passed on from parent to child and any child that inherits the “defect mutation”) will have diabetes. But in the case of the more common type 1 and type 2 diabetes, there is no single genetic mutation that causes the disease, but there is such a thing as genetic susceptibility that increases your risk of developing diabetes. 


Let’s examine the types of diabetes and what role genes play in each type so you can better understand your body and make healthy choices.


Is Type 1 Diabetes Genetic?

Over 1 million Americans have type 1 diabetes and many of those 1 million are children. Let’s take a look at type 1 diabetes and how genes play a role.


What Is Type 1 Diabetes?

To start, let’s define type 1 diabetes. Type 1 diabetes is when the body’s own immune system attacks the cells in the pancreas that make insulin—a hormone we need to help blood sugar get into our cells for energy purposes.


When our pancreas produces little or no insulin, there is nowhere for the sugar to go. This results in sugar building up in the bloodstream, which is why people who have type 1 diabetes need injections of insulin to bring their blood sugar levels down. It is crucial the balance is maintained so there is not too much or too little glucose or insulin.


We do not know what triggers the auto-immune process that causes type 1 diabetes. But we do know that some people seem to be more likely to get it than others. A good way to think about it is that something about their genetic make-up makes some people more likely to trigger this auto-immune process, but it does not mean all people with these genetic variants will develop type 1 diabetes. Something else must happen that triggers the actual process, but the susceptibility is always there. 


Type 1 Diabetes and Genetics

HLA (human leukocyte antigens) genes encode molecules that are critical to our immune systems. These molecules hold tiny chains of amino acids on the cell’s surface and immune cells analyze the chains. When the immune cells find a suspicious chain, they begin attacking it with the intent of protecting us. Without these HLA genes, our immune cells wouldn’t be able to find or fight off the appropriate chains of bacteria, viruses, or even tumor cells.


On the other hand, inheriting certain variants of HLA genes increases the chances that these immune cells will attack the body's healthy cells instead of just the harmful ones. There are several HLA variants that increase the risk of Type 1 diabetes and the more of these an individual happens to inherit, the more likely he or she is to develop diabetes. 


For instance, most Caucasian individuals with type 1 diabetes have a set of HLA genes called HLA-DR3 or HLA-DR4. Alternatively, the HLA-DR7 gene may put African Americans at a higher risk, whereas the HLA-DR9 gene may put Japanese people at a higher risk. Doctors can look at the genetic makeup of an individual and estimate their risk of developing type 1 diabetes based on what variants of the HLA system are present in this individual. 


But it is important to keep in mind that these variants are common and most of the people who inherit these variants will not develop type 1 diabetes, but they are at higher risk of doing so. But these are not the only genes involved in susceptibility to type 1 diabetes. There are also genes outside the HLA system that play a role in type 1 diabetes, such as the insulin gene itself. This is an important area of research and scientists continue to discover and refine their understanding of the genetic risk of type 1 diabetes. 


One interesting result of this genetic susceptibility is that close relatives of a person with type 1 diabetes are likely to be at somewhat higher risk than the general population, since they share many genetic variants with the individual who has already developed type 1 diabetes. For example, if one child develops type 1 diabetes, the risk of it developing in any of the siblings is about 5%, which is much higher than the risk in the general population (where the chances of developing type 1 diabetes are well below 1%), but it is important to note that while there is a 5% risk in the siblings, this also means that there is still a 95% chance that they will notdevelop diabetes. 


How Does Type 1 Diabetes Develop?

Some individuals happen to have certain genes that make them more likely to develop type 1 diabetes in their lifetime. Luckily, many of these predisposed individuals won’t end up actually getting diabetes. To actually develop the disease, a second factor is needed: something in the environment that triggers the immune system to attack its own insulin making cells and knock them out. The exact nature of this trigger is yet to be discovered, but viral infections and other environmental exposures are the most likely suspects. 


It’s important to note that diet and lifestyle habits do not cause type 1 diabetes. The risk factors for type 1 diabetes are not quite as clear to experts as they are when it comes to prediabetes or type 2 diabetes—but the undeniable relationship between diabetes and genetics remains.


In the U.S., white people are more likely to develop this type of diabetes than Latinos and African Americans. This is likely to be due to differences in the genetic variants found in these populations, though some lifestyle factors may also play a role. For example, we know that the disease is less common in South Asia, but South Asians who move to the West seem to increase their risk, probably because of changes in their lifestyle and exposures to various (as yet unknown) triggers. 


Is Type 2 Diabetes Genetic?

More than 100 million Americanscurrently have type 2 diabetes or prediabetes. Genes play a larger role in this type of diabetes than they do in type 1 diabetes.

 

What Is Type 2 Diabetes?

With type 2 diabetes, your body has become resistant to insulin, i.e. insulin does not work well in these patients even when it is present. Obesity and lack of exercise are major factors in producing this resistance to insulin and if these are not reversed, the insulin resistance will get worse over time. Early in the course of insulin resistance, your body can overcome this resistance by producing more insulin. This naturally puts more strain on the beta cells that produce insulin. 


At some point, these cells can no longer produce the amount of insulin that is needed to overcome insulin resistance and move glucose into the cells where it is needed. At this point, the person will develop higher than normal glucose levels and we label the condition prediabetes (because the patient’s blood sugar is higher than normal, but not yet high enough to reach the threshold for calling it diabetes). If the patient does not change his or her lifestyle and insulin resistance continues to get worse (and insulin secretion fails to keep up), the rising blood sugar will reach the threshold for calling it diabetes. 

 

Type 2 Diabetes and Genetics

Type 2 diabetes has a stronger genetic component than type 1 diabetes. There are a large number of genetic variants that seem to increase an individual’s risk of obesity, of insulin resistance, or beta cell failure. The more a given individual inherits these high-risk variants, the more likely they are to develop type 2 diabetes. As noted, the most common condition leading to type 2 diabetes is obesity and there are a lot of genetic variants that can increase your risk of developing obesity, but obesity alone is not enough. One factor seems to be just the way fat is distributed in the body. 


Thus, people who accumulate a lot of fat around their middle (“apple shaped”) seem to be at increased risk of diabetes, while those who store fat more in their lower body (“pear shaped”) tend to tolerate their obesity better and have lower risk of developing diabetes. Beyond this, there are differences in how much insulin resistance a person develops at a given weight and these too are partly genetic. 


Finally, the ability to make more insulin is also affected by your genes, thus there are some people who have insulin resistance but have very healthy beta cells and can make a lot more insulin and thus overcome their insulin resistance. On the other hand, some people have genetic variants that make them more prone to beta cell failure and therefore to developing diabetes. 


Because genetic risk plays a bigger role in type 2 diabetes than in type 1 diabetes, it means type 2 diabetes is much more likely to run in families than type 1 diabetes. A large number of genes, such as TCF7L2, are known to be involved in the risk of type 2 diabetes. Research suggests that this gene is important in beta cell function and genetic variants within the TCF7L2 gene impair the production of insulin in some fashion, thus increasing the risk of type 2 diabetes. Interestingly the gene that seems to be involved in the effect of fatty acids on beta cells and a high fat diet may increase the risk of beta cell dysfunction. 

 

Other Genes Associated with Diabetes Risk

Large clinical studies have identified even more genes and gene variants associated with a person's risk of developing type 2 diabetes—some of these including KCNJ11, CDKAL1, WFS1, PPARG, FTO, and T2DM. These genes are involved in a wide array of physiological processes and how they increase the risk of diabetes is a very active area of research today. 


While some genes have a direct association with the development of diabetes, some contribute to a person’s risk indirectly by influencing other physiological processes in our bodies. Take the fat mass and obesity-associated (FTO) gene, for instance. Common variations in the FTO gene have been linked to obesity, the regulation of eating patterns and expenditure of energy. Research tells us that certain variations in the FTO gene are associated with an increased risk of type 2 diabetes. However, this effect most likely depends on differences in BMI (i.e., the increased diabetes risk is mostly due to an increase in the risk of obesity). 

 

Genetic Risk for Diabetes

Type 2 diabetes has a stronger connection to family history than type 1 does. Studies of twins, in fact, have shown that if one member of an identical twin pair develops diabetes, the other will almost always develop it too, though it may take years before it appears. But as with type 1 diabetes, genetics is not destiny. Individuals with a higher genetic risk are more likely to develop diabetes, but only if they also have the lifestyle factors that work on the genetic background to cause full blown diabetes. If an individual avoids unhealthy foods, remains active and controls his or her weight, they can still prevent this diabetes. 


Diabetes is thus the result of a combination of factors. Genetic variants alone don’t determine whether you will develop diabetes, but they do play a role and this role is greater in type 2 diabetes than it is in type 1 diabetes.


A Few Words about MODY

There is another kind of diabetes that is not so common, but that is almost entirely genetic in origin; this is MODY (monogenic diabetes of the young). In this form of diabetes, the patient has a single specific genetic defect (a genetic mutation) that so damages their ability to produce insulin that they practically always develop diabetes, no matter what their lifestyle. As you may expect, this type of diabetes runs in families and usually someone from every generation is affected. There are many different genetic defects that can lead to MODY, but luckily they are all relatively rare. 


We mention this here to show how type 1 and type 2 diabetes are not genetic disorders in this sense; genes play a role in these disorders (especially in type 2 diabetes), but they do not determine the course of the illness by themselves; lifestyle factors play a large role and not everyone with the same set of genetic variants will develop diabetes. 


What Does This Mean for You?

While we now know that there is a correlation between diabetes and genetics, studies show that certain lifestyle changes can lead to delaying or preventing the disease. Diabetes is a serious health condition, but knowing what your DNA says about your risk can help you make informed health decisions.


We are here to tell you that, even with an increased risk, you can still make lifestyle changes that can improve health outcomes. If making healthy modifications seems overwhelming, not to fear—we can help guide you in how to do that.


If you’re ready to take control of your health, read our article “Can a DNA Test Really Tell You How to Eat?” to learn more about how your DNA can help you navigate making smarter eating choices.This guide can help you understand the connection between diabetes and genetics as well as how DNA ties into many other aspects of health so you can ultimately be guided toward the healthiest path.


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References


1. Centers for Disease Control and Prevention. (2020). National diabetes statistics report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services.


2. Noble, J. A., Johnson, J., Lane, J. A., & Valdes, A. M. (2011). Race‐specific type 1 diabetes risk of HLA‐DR7 haplotypes. Tissue antigens, 78(5), 348-351.


3. Center for Disease Control. (March 24, 2020). Diabetes Risk Factors. Retrieved from: https://www.cdc.gov/diabetes/basics/risk-factors.html. 


4. Centers for Disease Control and Prevention. (2017). New CDC report: More than 100 million Americans have diabetes or prediabetes. Retrieved from Centers for Disease Control and Prevention: https://www. cdc. gov/media/releases/2017/p0718-diabetesreport. html.


5. Chauhan, G., Spurgeon, C. J., Tabassum, R., Bhaskar, S., Kulkarni, S. R., Mahajan, A., ... & Ghosh, S. (2010). Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians. Diabetes, 59(8), 2068-2074.


6. Freathy, R. M., Timpson, N. J., Lawlor, D. A., Pouta, A., Ben-Shlomo, Y., Ruokonen, A., ... & Lindgren, C. M. (2008). Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. Diabetes, 57(5), 1419-1426.


7. Chatterjee, S., Khunti, K., & Davies, M. J. (2017). Type 2 diabetes. The Lancet, 389(10085), 2239-2251.


8. Shubrook, J. H., Chen, W., & Lim, A. (2018). Evidence for the prevention of type 2 diabetes mellitus. J Am Osteopath Assoc, 118(11), 730-737.




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