What's the Impact of Genetics on Metabolic Health and Diabetes?

When you visit a healthcare provider, they often ask about your family’s health history. There’s an important reason for this: genetics play a significant role in metabolic health, just as they do in every other system of the body. 

Your genes can affect your appetite, hormone synthesis, metabolism, nutrient absorption, and other physiological mechanisms. That’s why some genes can increase or decrease your risk of developing metabolic diseases, including diabetes.

However, we also know that environment and lifestyle are crucial factors. Otherwise, we wouldn't be able to explain why one identical twin develops diabetes while the other does not. If genetics were always 100% responsible for the disease, both twins would have diabetes, as they share the same genetic material. 

So, how do genetics contribute to diabetes, and to what extent do they increase the risk?

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How Much Does Family History Increase Your Risk of Diabetes?

If a disease runs in the family, it most likely has a genetic influence. Some risk factors for diabetes are not changeable, such as family history, race, or ethnic background. For example, some genes that increase the risk of diabetes are more commonly seen in certain ethnic groups.¹

A study looked at the relationship between family history and the risk of type 2 diabetes in people of European American and African American ancestry. Results showed that the risk of diabetes increases with the number of first-degree relatives who have diabetes:² 

• European Americans who have one first-degree relative with type 2 diabetes have a 1.8 times higher risk of developing the disease. 
• European Americans who have two first-degree relatives with type 2 diabetes have a fivefold increased risk. If they have three or more first-degree relatives, the risk increases by more than eightfold.
• The risk only increases in African Americans if they have three or more first-degree relatives with type 2 diabetes, in which case the risk increases by 2.4 times.

Therefore, if diabetes runs in the family, the risk can be higher than for someone who doesn't have a family history of diabetes. Researchers are developing methods to assess an individual’s future risk of developing diseases. This can allow healthcare providers to begin early treatment to prevent or slow disease progression and related complications.

How Do Genes Contribute to Diseases? 

Our bodies consist of trillions of cells, each containing genetic material—DNA. Cells continuously replicate to grow and replace damaged or old cells. Because each cell carries genetic material, DNA is copied when cells replicate.

Normally, DNA replication is controlled by certain mechanisms to prevent errors. Despite these controls and repair systems, errors can still occur, which are called gene variants. Our genome contains 4 to 5 million gene variants. Many variants don't have negative effects on our health; some reduce the risk of disease, while others can increase it.^{3, 4}

Changes in the genome can occur for many reasons, including but not limited to:⁵

• While DNA replicating, gene variants can occur for no reason, they can be random errors. 
• During fertilization, the genetic material from both the male and female creates genetic variants.
• Certain factors, such as high levels of radiation, chemical exposure, and viruses, can cause genetic variants. 

Gene variants can be inherited or non-inherited and develop at some point in a person’s life. While inherited variants pass down from generation to generation, non-inherited variants don't. 

The Impact of Gene Variants on Diseases

Gene variants are identified by screening the entire genome. Studies that screen the genomes of large populations are called genome-wide association studies (GWAS). These studies help find associations between gene variants and diseases. They identify gene variants and determine how common the disease is among people carrying those variants.⁶

Not all gene variants are equal; some have no impact, while others can be beneficial or cause an increased risk of diseases. DNA variants are classified as:⁷

• Pathogenic: These variants are evidently known to cause diseases.
• Likely Pathogenic: Some research supports that these variants can cause diseases, but the evidence is uncertain.
• Variant of Uncertain Significance: There is not enough research, or the results are conflicting, so it is hard to determine these variants' effects on disease development.
• Likely Benign: These variants are not likely to cause disease, but further evidence is needed.
• Benign: Strong evidence proves These variants do not cause diseases.

<div class="pro-tip"><strong>Also Read: </strong><a href=genes-weight>How Your Genes Can Influence Your Weight</a>.</div>

Gene Variants in Diabetes 

Gene variants can contribute to diabetes by causing:⁸

• Destruction of pancreatic cells that produce insulin
• Decreased insulin synthesis
• Insulin resistance (prediabetes)
• Dyslipidemia (high blood lipid levels)

Diabetes that is caused by gene variants is divided into:

• Monogenic Diabetes: It describes forms of diabetes caused by a change in a single gene. Some variants in more than 20 genes have been found to contribute to diabetes, though they are rare. Examples of monogenic diabetes include maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM).⁹ 

In every 100 people with diabetes, 1 to 5 people have monogenic diabetes. MODY is typically inherited from one or both parents. While most people with NDM do not have a family history of diabetes. This suggests that NDM is more likely to result from a gene variant that occurs during fetal development. 

• Polygenic Diabetes: It describes forms of diabetes caused by multiple gene variants. In polygenic diabetes, multiple gene variants together increase diabetes risks. Type 1 and type 2 diabetes are examples of polygenic forms of diabetes.¹⁰

The occurrence of a disease can be influenced by hundreds or even thousands of gene variants. Polygenic risk score (PRS) estimates a person’s risk for a disease based on their gene variants, showing the accumulated effects of multiple variants. PRS show relative risks because they are derived by comparing people with and without the disease.⁴

A 2024 GWAS study analyzed 650 genetic variants that are associated with type 2 diabetes; there are even more to be discovered. A study involving more than 5,000 individuals showed that participants with high PRS have twice the risk for type 2 diabetes compared to those with low PRS.^{11, 12}

Having certain HLA gene variants can increase the risk of type 1 diabetes by 40 to 50 %. Variants in the HLA-DQA1, HLA-DQB1, and HLA-DRB1 genes are associated with a higher risk. However, only 5% of people carrying these gene variants develop type 1 diabetes. There are also protective variants of the HLA gene too.^{13, 14}

These are just examples from a few studies. Many gene variants are identified, and much more remains to be explored in different populations. Some gene variants have no effects; some are protective, while others increase disease risk. Your risk can be low, medium, or high, depending on the gene variants you carry and their combination. 

Genetic Variations Can Affect the Efficacy of Diabetes Drugs

Genes can also affect how an individual responds to a drug. For example, enzymes are crucial in metabolizing drugs. If the gene encoding that enzyme has a variant, it can affect how well the enzyme metabolizes the drug, thus impacting its efficacy for an individual.¹⁵ 

A study looked at how certain gene variants affect the response to metformin. The results revealed that people with the rs543159 and rs1317652 variants in the SLC22A3 gene respond better to metformin treatment. Having these variants can improve drug response by 2.4 times.¹⁶

The Interaction Between Lifestyle and Genes

Gene-diet and gene-exercise interactions can influence type 2 diabetes risk by affecting the impact of these interventions on disease development. A systematic review investigated 66 studies, and 28 of them reported significant interactions between lifestyle and genes.¹⁷

For example, some of these studies found that TCF7L2 variants influence the effects of fiber intake on type 2 diabetes. While people with some TCF7L2 variants can benefit from increased dietary fiber intake, others benefit less or not at all. This means that fiber consumption can influence the incidence of diabetes to different extents, depending on which variant a person carries.^{17, 18}

The review also reports that while some people with certain gene variants benefit from physical activity, others did not respond as well in terms of lowering their type 2 diabetes risk.¹⁷

However, lifestyle can influence how much genes contribute to diseases. A study followed 440 people with type 2 diabetes over 14 years. Researchers found that participants with a high PRS had twice the risk of developing diabetes compared to those with a low PRS. 

When researchers followed up with these participants, they observed that people with a high PRS who followed an "ideal lifestyle" had a significantly reduced risk of developing diabetes. Participants who followed general guidelines for diabetes management, such as maintaining a healthy diet, body weight, exercising regularly, and not smoking, had a reduced incidence of diabetes, which decreased from 6.77% to 3.28% over 10 years.¹²

Can Genetic Screening Help With Diabetes Prevention and Management?

Genomic analysis can help in screening for diabetes risk and in choosing the proper medications and interventions to prevent and manage diabetes. 

However, clinical applications of GWAS have some limitations for now. One limitation is that the calculation of PRS lacks a standard. Additionally, it only presents probability, not certainty. Second, most studies (78%) are carried out in populations of European ancestry, which is not optimal for detecting diabetes risk in populations of non-European ancestries.^{4, 19}

What You Can Do

Although some variants increase risk more than others, many people who carry these variants do not develop diabetes. You can always consult your healthcare provider if you're worried that you may be at high risk for diabetes. Even though genetic analysis is not common in clinics, regular visits can help with early diagnosis.

In conclusion, there are both modifiable and non-modifiable risk factors for diabetes. You cannot change the genes you carry, your race or ethnic background, age, or a history of gestational diabetes. But you can change lifestyle factors such as nutrition, exercise, sleep, stress management, and more.

Although we don't know how to prevent some types of diabetes, such as type 1 diabetes, following a healthy and balanced diet, exercising regularly, and managing your weight can help prevent type 2 diabetes.^{20, 21}

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