Exploring Epigenetics To Predict Type 2 Diabetes

By Moshe Szyf, Ph.D., founder, HKG Epitherapeutics Ltd.

Type 2 diabetes is a prevalent condition that disrupts the body's glucose processing. Approximately 10.4 percent of the U.S. population, comprising around 34 million Americans, grapple with this disease.¹ Numerous factors elevate the risk of developing type 2 diabetes, including being overweight, having a family history of diabetes, high blood pressure, and smoking. Nonetheless, adopting healthy habits such as balanced nutrition, regular exercise, weight management, and cessation of smoking can mitigate some of these risk factors.

Research indicates that specific adverse early-life exposures like malnutrition or stress, alongside lifestyle choices later in life, can trigger type 2 diabetes. Additionally, the escalating diabetes rates in developing countries, linked to dietary and activity alterations prompted by economic growth, underscore how lifestyle influences the onset of this serious condition. The implications include severe chronic complications and premature mortality, significantly impacting both individual and public health.

Timely detection plays a pivotal role in implementing interventions that can prevent or delay the onset of this disease. While the risk factors aid in identifying individuals requiring significant intervention to halt the progression toward full-blown diabetes, they may not suffice for precise early detection. A comprehensive understanding of the shared mechanisms linking environmental exposures to type 2 diabetes development could lead to the discovery of biomarkers predicting future diabetes risk. Furthermore, this knowledge can facilitate the assessment of treatment effectiveness and inspire the design of innovative prevention and intervention strategies.

The Epigenetic Approach To Diabetes Prediction

DNA serves as the blueprint for proteins governing our regular bodily functions and overall health. The expression of these proteins in diverse organs and in response to various stimuli is vital for our well-being. Genetic variants inherited from our parents can lead to diabetes. Changes in gene sequences, especially in genes controlling insulin or its response, can trigger diabetes onset. Some individuals inherit a single gene that causes type 2 diabetes, including mutations in insulin genes and genes associated with early-onset diabetes (maturity-onset diabetes of the young [MODY]).² Other variations have been identified through genome-wide association studies, predicting a risk of type 2 diabetes.³ However, in most instances, the genetic differences among individuals fail to explain why some develop diabetes while others do not, despite carrying the same genetic variant.

We inherit identical DNA from our parents across all our cells. However, the proteins produced differ in various cells and throughout different life stages. This variability arises because our DNA's genes are “programmed” to express themselves at varying levels across diverse cells during development, both before and after birth. This programming, known as epigenetics, remains stable for many years after birth. It refers to alterations in gene activity and function without modifying the underlying DNA sequence.

Epigenetic programming allows two genes with identical sequences to function differently. One crucial mechanism in this process is DNA methylation, involving the addition of a methyl chemical mark to specific gene positions. These methyl marks can silence or activate genes at strategic control points, thereby altering a cell's functional program by regulating gene expression. This mechanism plays a critical role in enabling cells to express distinct programs necessary for proper tissue function, including the regulation of blood sugar levels and response to insulin.

Research underscores the impact of social and physical environments during early life on epigenetic programming and DNA methylation distribution across diverse tissues. This suggests that environmental exposures in early life could potentially modify the DNA methylation of crucial genes responsible for regulating sugar and metabolism. Furthermore, a range of factors encountered later in life, such as stress, along with nutritional and physical exposures, can significantly affect the DNA methylation of metabolic genes. These influences may contribute to the development of type 2 diabetes, potentially influenced by behavioral factors.

Another example of how our DNA can be impacted is by exposure to certain chemicals. For example, exposure to palmitate demonstrates a significant connection between type 2 diabetes and epigenetic factors, causing broad epigenetic alterations in pancreatic islets.⁴ Furthermore, DNA methylation plays a role in diabetic complications.⁵ However, despite these discoveries providing evidence of epigenetic involvement in mechanisms underlying type 2 diabetes, assessing changes in inaccessible tissues like the pancreas poses challenges for biomarker assessment.

Consequently, researchers are exploring whether DNA methylation changes associated with type 2 diabetes can be detected in easily accessible blood samples. Utilizing blood for screening and early intervention purposes has garnered attention due to its accessibility.

Studies Point To A Future Of Early Detection

Researchers have conducted studies known as EWAS (epigenome-wide association studies) aiming to identify genes across the genome exhibiting methylation patterns in blood associated with type 2 diabetes, akin to GWAS (genome-wide association studies) in principle.⁶ These investigations pinpointed specific genomic positions capable of distinguishing individuals with type 2 diabetes. Moreover, they revealed methylation differences linked to type 2 diabetes, correlating with environmental exposures known to heighten diabetes risk. This supports the notion that epigenetic DNA methylation changes might mediate the environment's impact on type 2 diabetes.

These studies compared individuals with and without type 2 diabetes but were not explicitly designed to identify DNA methylation differences for early detection purposes. Consequently, some of the noted DNA methylation variances between type 2 diabetes cases and control groups might have been caused by diabetes rather than being indicative of its causation. However, researchers examined candidate genes selected from these investigations to assess their effectiveness as predictors.

A recent study, published in Nature Aging in 2023,⁷ titled, Development and Validation of DNA Methylation Scores in Two European Cohorts Augment 10-Year Risk Prediction of Type 2 Diabetes, leveraged a distinct statistical approach. The study capitalized on DNA methylation data from two well-documented European cohorts, encompassing clinical records, including DNA methylation details from individuals up to a decade before the onset of diabetes.

These extensive data allowed researchers to unearth DNA methylation variances predicting type 2 diabetes with diverse levels of accuracy. Notably, the study developed a model that predicted the development of the condition up to 10 years in advance in the Generation Scotland cohort and validated it in the German KORA study. By amalgamating these DNA methylation predictors with other high-risk factors, the authors demonstrated an enhanced capability to forecast disease onset⁷.

This research posits that integrating DNA methylation markers as predictive tools holds promise in identifying individuals at risk. Such an approach could facilitate early intervention strategies and personalized medicine within the realm of type 2 diabetes, potentially alleviating the burden of the disease. Nonetheless, the primary challenge that persists is translating these scientific breakthroughs into a robust, high-throughput clinical laboratory test. This test must be accessible to the substantial population at risk of type 2 diabetes, enabling the utilization of such tools for personalized interventions. Additionally, there is a crucial need to identify pathways for translating the discovery of causal epigenetic changes into novel strategies for preventing and treating type 2 diabetes. Moreover, harnessing DNA methylation markers to assess the efficacy of these treatments remains an essential avenue for further exploration.

References

1. https://www.cdc.gov/diabetes/basics/type2.html
2. Molven et al. 2009 https://doi.org/10.2337/db07-1467.
3. ‘Connor et al. 2022 https://diabetesjournals.org/diabetes/article/71/3/554/138938/Recessive-Genome-Wide-Meta-analysis-Illuminates
4. Ronn and Ling 2015 https://doi.org/10.2217/epi.15.7
5. Dhawan and Natarajan 2019 https://doi.org/10.1007/s11892-019-1168-8
6. Fraszczyk et al. 2022  https://link.springer.com/article/10.1007/s00125-022-05652-2.
7. Cheng et al., 2023 https://www.nature.com/articles/s43587-023-00391-4

About The Author:

Moshe Szyf, Ph.D., is the founder and CEO of HKG Epitherapeutics Ltd. He is a geneticist, a Fellow of the Royal Society of Canada and the Canadian Academy of Health Science, and previously served as a James McGill Professor Of Pharmacology And Therapeutics at McGill University, where he also held a GlaxoSmithKline-CIHR chair in pharmacology. His research in the fields of genetics and early cancer detection spans more than three decades. He received his Ph.D. from The Hebrew University and did his postdoctoral fellowship in genetics at Harvard Medical School.