Precision Medicine in Diabetes Diagnosis and Prevention

Precision diabetes medicine is a concept and practice that seeks to evaluate an individual’s behavioral, situational, and symptomatological differences to enhance the diagnosis, prevention, and treatment of diabetes. It uses precision diagnostics and precision therapeutics to treat patients with similar characteristics. It also uses advanced technology to observe disease progression. One way it differs from the standard practice used in place today is its usage of elaborate aggregated data to accurately diagnose an individual. Such data can originate from clinical or medical records, behavioral monitors, ingestible or wearable sensors, and genomic data. Due to the variability in diabetes subgroup types and the growing burden of disease in diabetes, precision medicine is necessary for the diagnosis and prevention of diabetes in individuals.

There are many subgroups of diabetes, but two types of diabetes that are most common are Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). T1D is an autoimmune disease that results in the destruction of beta cells produced in the pancreas. It represents about 10% of all diabetes cases and is grouped into three distinct stages. Generally, T1D is not diagnosed until the patient reaches the third stage. Genetic and environmental factors both play a significant role in an individual’s susceptibility in the acquiring T1D. Since T1D is mostly genetic based, it is more prevalent in youths and children. In contrast, individuals that are likely to be diagnosed with T2D are usually older adults. Unlike individuals with T1D, individuals with T2D can produce beta cells, but their bodies have trouble responding to insulin. This leads to an increase of glucose level in the bloodstream. There is a growing global burden of T2D, as 6.28% of the global population suffer from T2D [1]. Each year, diabetes alone is responsible for over one million deaths, making it the seventh leading cause of death [2]. Thus, precision diabetes medicine must be implemented to stabilize and decrease the rising trends.

There have been initiatives set in place to address this growing epidemic of diabetes. In 2018, the American Diabetes Association partnered with the European Association for the Study of Diabetes to launch the Precision Medicine in Diabetes Initiative (PMDI). The PMDI promotes research, offers education, and embraces new recommendations to incorporate precision medicine in the diagnosis and treatment of diabetes [3]. Further, there is an active development of an international network focused on precision diabetes medicine.

To make medicine more individually directed, there must first be precision in the diagnosis of diabetes. Patients diagnosed with diabetes typically fall into two classifications: T1D or T2D. However, diagnostic complications emerge in a given case where the patient has symptomatic or situational differences that result in the patient deviating from the expected norm of a given category [5]. Additionally, the frequent misdiagnosis of T1D and T2D corroborates the dire need for precise diagnosis since the consequences of the misdiagnosis can often be fatal [5,6]. For too long, diabetes has been seen as a black and white disease and not as a spectrum: individuals must exhibit the traits necessary to fall under the subcategorization of T1D or T2D. By implementing precision diabetes diagnosis, this approach can be improved to also incorporate other subcategorization of diabetes beyond the well-known T1D and T2D.

Precision diabetes medicine also requires optimal precision prevention that is tailored to the patient. Precision prevention for T1D generally translates to heightened monitoring of the disease to promote early detection, which helps minimize the complications and additional risks associated with the disease. Early detection can also allow the commencement of possible treatment options, which can include immunotherapy or dietary changes. Despite this, actions that sought to implement such prevention have proven to be unsuccessful because the individual’s unique response to such measures were not taken into consideration [8]. For instance, there is a genetic risk associated with T1D, so dietary changes may have different effects on the individual depending on their genetic makeup [4]. Without acknowledging the individual’s distinctive genetics, such preventive measures may prove to be ineffective, supporting the need for precision prevention.

Precision prevention should also be implemented for T2D. Luckily, there are many outlets for prevention in T2D through change in lifestyle. Large prevention trials show, however, that a universal approach towards lifestyle intervention is not successful for everyone, as each individual has their own circumstances; in other words, some interventions may work well for some, while the same interventions may not work well for others. This conclusion only strengthens the need for precise prevention for individuals who do not want to acquire T2D. To decrease an individual’s chances of becoming diabetic, there has been a drive to include the stage of “pre-diabetes” so that an individual is aware of their current health status and can begin aggressive prevention methods. Precise prevention, thus, tailors to the individual’s unique characteristics to allow a specific treatment that will facilitate a much more effective method to prevent the exacerbation of diabetes.

It is time to acknowledge that an effective way to reduce the global burden of diabetes is through precision diabetes medicine. There are many variabilities in diabetes and taking into account an individual’s genetic makeup, as well as environmental and situational factors, can help them acquire precise prevention, diagnosis, and treatment of the pathogen. Implementing precision prevention T1D and T2D will allow early detection of the disease. Given that not every prevention method will prove to be efficacious for each individual, a personalized approach will allow the patient to make necessary lifestyle changes that will best suit their needs. Precision diagnosis also allows for a much more tailored diagnosis that evaluates a patient’s unique characteristics, which reduces the frequency of misdiagnosis of patients.

Edited by: Rohan Gupta

Graphic Designed by: Natalie Chou

References:

1. Khan, Moien Abdul Basith et al. “Epidemiology of Type 2 Diabetes - Global Burden of Disease and Forecasted Trends.” Journal of epidemiology and global health vol. 10,1 (2020): 107-111. doi:10.2991/jegh.k.191028.001

2. CDC. “What Is Diabetes?” Centers for Disease Control and Prevention, 11 Mar. 2020, www.cdc.gov/diabetes/basics/diabetes.html#:~:text=Diabetes%20is%20the%20seventh%20leading.

3. “Precision Medicine in Diabetes Initiative | American Diabetes Association.” Professional.diabetes.org,professional.diabetes.org/content-page/precision-medicine-diabetes-initiative-0.

4. Hakola, Leena et al. “Infant Feeding in Relation to the Risk of Advanced Islet Autoimmunity and Type 1 Diabetes in Children With Increased Genetic Susceptibility: A Cohort Study.” American journal of epidemiology vol. 187,1 (2018): 34-44. doi:10.1093/aje/kwx191

5. Thomas, Nicholas J et al. “Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank.” The lancet. Diabetes & endocrinology vol. 6,2 (2018): 122-129. doi:10.1016/S2213-8587(17)30362-5

6. Thomas, Nicholas J et al. “Type 1 diabetes defined by severe insulin deficiency occurs after 30 years of age and is commonly treated as type 2 diabetes.” Diabetologia vol. 62,7 (2019): 1167-1172. doi:10.1007/s00125-019-4863-8

7. Chung, Wendy K et al. “Precision medicine in diabetes: a Consensus Report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).” Diabetologia vol. 63,9 (2020): 1671-1693. doi:10.1007/s00125-020-05181-w

8. Knip, Mikael et al. “Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial.” JAMA vol. 319,1 (2018): 38-48. doi:10.1001/jama.2017.19826

9. Imperatore, Giuseppina, et al. “Prevalence and Incidence of Type 1 Diabetes among Children and Adults in the United States and Comparison with Non-US Countries.” 17 June 2015.

Ethics of Precision Medicine: Mass Genotyping

As healthcare becomes more individualized amid the pursuit for a “magic bullet”, there may be a day when the secrets of our genome have been elucidated and shared with healthcare providers. While our personal propensities to disease and unique responses to medication does not fully lie hidden in our A, T, C, and Gs (i.e., environmental and epigenetic factors contribute similarly), our genetic information undoubtedly influences our health outcomes. How will we uncover these predictors? One possibility is to genotype the entire population at birth, which already occurs in the United States for certain genetic, metabolic, and endocrine disorders.1 Indeed, from a purely medical standpoint, mass genotyping our population is useful, ensuring that patients receive appropriate treatment. Avoiding drugs that cause allergic reactions and matching blood types during transfusions appear routine to us yet are quintessential examples of the benefits precision medicine have in our world today.

However, it is impractical to judge the merits of one aspect in a vacuum when each aspect is wholly intertwined with one another. Medicine, so central in our lives, lies at the intersection of multitudes. For one, mass genotyping compromises patient confidentiality. Are we okay with sharing so much of ourselves with clinicians, healthcare institutions, and insurance behemoths? Would we even want to know at birth our likelihood for a long and healthy life or our risk for genetic disorders? Beyond burdening people with prognoses, a future where mass genotyping is widespread could rob individuals’ feelings of autonomy, a universal psychological need that enables wellbeing.2 Ethical implementation of mass genotyping in society necessitates that a clear line be created to divide what is public and what should remain private.

Another consideration is cost. If genotyping is neither reasonably affordable nor accessible, health disparities may worsen between higher and lower socioeconomic classes— those who can utilize it and those who cannot. Even if everyone was genotyped, different drugs may be priced differently due to supply and demand economics. This may unfairly disadvantage minority groups with rare polymorphisms if their drugs are rarer and more expensive. Additional patient information from mass genotyping may also be used by insurance companies to upcharge clients with poorer projected outcomes, which are usually those at lower socioeconomic statuses. These cost differences can all prevent social mobility and contribute to the cycle of poverty. Mass genotyping and precision medicine should be available to all, lest the chasm between classes and their health outcomes continue to widen.

When discussing genetics, race is an unavoidable topic. Despite the unscientific nature of race-based medicine (socially constructed racial groups are more genetically similar between than within subpopulations), the use of race in healthcare contributes to health disparities and reinforces institutional and individual discrimination.3 Mass genotyping may further emphasize the role genetics plays in health outcomes and add to attitudes about race-based medicine. Indeed, we have already seen the introduction of race as a biological-medical construct in the race-based pharmaceutical BiDil, which itself is mired in controversy and mixed reception.4 Nonetheless, precision medicine has the potential to transcend misconceptions about race as biologically relevant. Mass genotyping may reveal to the general public that racial groups are genetically homogenous and that human genetic variation exists most prominently from individual to individual regardless of race. Introducing precision medicine can be a powerful tool in combating racism and for promoting unity within the only race: the human race.

If precision medicine is to be used ethically and justly, society must be careful about its implementation. Stringent boundaries ought to be constructed to define what is public knowledge and what is personal information, and the remarkable benefits precision medicine can bring should be available to all. Educating the public about pharmacogenomics and social determinants of health, nebulous and complex sciences themselves, will be necessary in not only healing physical ailments, but hopefully prejudices and misconceptions as well.

Edited by: Sibani Ram

Graphic Designed by: Harris Upchurch

References:

1. Pitt J. J. (2010). Newborn screening. The Clinical biochemist. Reviews, 31(2), 57–68.

2. Yu, S., Levesque-Bristol, C. & Maeda, Y. (2018). General Need for Autonomy and Subjective Well-Being: A Meta-Analysis of Studies in the US and East Asia. J Happiness Stud 19, 1863–1882. https://doi.org/10.1007/s10902-017-9898-2

3. Ruqaiijah Yearby (2021) Race Based Medicine, Colorblind Disease: How Racism in Medicine Harms Us All, The American Journal of Bioethics, 21:2, 19-27, doi: 10.1080/15265161.2020.1851811

4. Brody, H., & Hunt, L. M. (2006). BiDil: assessing a race-based pharmaceutical. Annals of family medicine, 4(6), 556–560. https://doi.org/10.1370/afm.582

Ethical Applications of Precision Medicine: Lessons from Around the World

Since the completion of the Human Genome Project in the early 2000s, the field of genetics and genomics has rapidly expanded. As connections between genotype and phenotype were elucidated, companies arose offering to interface directly with consumers through the internet to give them information about their genomes. Because the industry and science developed rapidly, regulations around direct-to-consumer (DTC) testing developed as a reactionary mechanism. While this led to a piece-meal approach towards the regulation of a new industry, the resulting laws around the world are reflective of differing values and views of genetic information. As the world moves into the era of precision medicine, questions arise about what type of information should be released to patients, timing, and in what contexts. Laws around DTC testing have attempted to answer these questions outside of the healthcare setting and can provide perspective into the benefits and drawbacks of different approaches.

At one end of the regulatory spectrum lies France, the strictest country in Europe with regard to the regulation of DTC genetic tests (1). They have imposed an essential ban on genetic testing unless ordered directly by a physician (1). After a revision of the French Bioethics Law in 2011, a provision was put in place imposing a fine of 3,750 euros for those attempting to analyze their own genetic information through the purchase of tests (2). The French attitude maintains that genetic information is an element of the human body, but that it cannot be owned or take on monetary value (3).

Just below France in terms of stringency lies Korea. A revision to the Korean Bioethics and Safety Act in 2017 allowed for a subset of 12 phenotypes and 46 genes to be assessed by DTC tests (4). While this list is slowly expanding as individual companies receive approval for predictive tests for certain chronic diseases and cancers, progress has been slow and the government has been careful to limit what parts of their DNA citizens can access.

The regulatory environment in the United States sits somewhere in the middle. Many of the most well known DTC companies, such as 23andMe, were founded in the US and were essentially unregulated until 2010. Conflicts between testing companies and the FDA began when letters were sent to the largest companies stating that their tests fell into the category of “medical devices” that needed to be submitted to the FDA for approval (5). Currently, the FDA regulates tests for “moderate to high-risk medical purposes” (6). However, 23andMe and others will also return raw data to consumers, which can then be analyzed by software accessible via the internet, effectively circumventing FDA regulation (7). Also, the FDA does not currently regulate tests for what they consider “low risk medical” and “non-medical purposes”. Attitudes in the US center around themes of autonomy and property rights, with genetic information being something that can be bought and sold (3).

On the far end of the spectrum lie countries with very loose oversight of DTC genetic testing. In China, no specific legislation has been created to oversee DTC companies; only existing laws focused around genetic resource security apply (8). This has lead to criticism about the existence of holes in consumer protection, especially with respect to the treatment of health information and privacy (8). The situation is similar in South Africa, as well as across the African continent as a whole, where there is a lack of guidance and regulation surrounding the tests (9). Although this approach emphasizes the individual’s autonomy in exploring their genetics, it doesn’t hold companies accountable in areas such as data privacy and test accuracy.

Because the rise of the DTC genetic testing landscape has preceded the widespread application of precision medicine in healthcare, the different regulatory approaches that have been taken can be used as a blueprint. Each provides its own set of benefits and drawbacks with respect to the extent individuals should be allowed access to information about their genome and their future. While widespread integration of genetic data into the healthcare sphere will come with its own set of challenges, there is much to be learned from the initial philosophies that have emerged.

Edited by: Danika Dai

Graphic Designed by: Simone Nabors

References:

1. Kalokairinou L, Howard HC, Slokenberga S, et al. Legislation of direct-to-consumer genetic testing in Europe: a fragmented regulatory landscape. J Community Genet. 2018;9(2):117-132. doi:10.1007/s12687-017-0344-2.

2. LOI n° 2021-1017 du 2 août 2021 relative à la bioéthique . Legifrance.gouv.fr. https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000024323102/.

3. Stoeklé HC, Forster N, Turrini M, et al. La propriété des données génétiques - De la donnée à l’information [The ownership of genetic data: from data to information]. Med Sci (Paris). 2018;34(12):1100-1104. doi:10.1051/medsci/2018291.

4. Kim J. W. (2019). Direct-to-consumer genetic testing. Genomics & informatics, 17(3), e34. https://doi.org/10.5808/GI.2019.17.3.e34.

5. Allyse MA, Robinson DH, Ferber MJ, Sharp RR. Direct-to-Consumer Testing 2.0: Emerging Models of Direct-to-Consumer Genetic Testing. Mayo Clin Proc. 2018;93(1):113-120. doi:10.1016/j.mayocp.2017.11.00.

6. Center for Drug Evaluation and Research. Direct-to-consumer tests. U.S. Food and Drug Administration. https://www.fda.gov/medical-devices/in-vitro-diagnostics/direct- consumer-tests.

7. Jautrou H. Les tests génétiques en libre accès - Régulation par le marché, ou régulation médicale ? [Direct-to-consumer genetic testing: a regulation by the market, or a medical regulation?]. Med Sci (Paris). 2020;36(2):153-159. doi:10.1051/medsci/2019264.

8. Du, L., & Wang, M. (2020). Genetic Privacy and Data Protection: A Review of Chinese Direct-to-Consumer Genetic Test Services. Frontiers in genetics, 11, 416. https://doi.org/10.3389/fgene.2020.00416.

9. Dandara, C., Greenberg, J., Lambie, L., Lombard, Z., Naicker, T., Ramesar, R., Ramsay, M., Roberts, L., Theron, M., Venter, P., & Bardien-Kruger, S. (2013). Direct-to-consumer genetic testing: To test or not to test, that is the question. South African Medical Journal, 103(8), 510-512. doi:10.7196/SAMJ.7049.