Type 2 Diabetes: What's in your genes?

Every week diabetes leads to more than 169 amputations, 80 strokes and 530 heart attacks. The most recent figures now suggest that up to 4.2 million people are living with type 2 debates (T2D), a largely preventable disease (Diabetes UK, 2019). In order to combat the increasing prevalence of this disease the National Health Service is shifting its focus from management to prevention.

Although the exact mechanisms of T2D are still being investigated, there are a number of steps that can be taken to reduce the risk of developing it. These include staying active, maintaining a healthy weight and reducing alcohol consumption. Disturbed sleep has also been recognised as a significant risk factor. Just one night of poor sleep can increase insulin resistance and interfere with glucose metabolism (Holingue et al., 2018).

For a long time researchers have been interested in the role genetics might play in the development of T2D. Medical professionals were quick to note that diabetes tended run in families. Research revealed that if one parent developed this disease their child has a 15% chance of developing it too. If both parents developed it this then rose to 75% (Editor, 2019).

Twin studies have allowed researchers to elucidate the link between genetics and T2D more clearly than any other (Poulsen et al., 2009) (Lyssenko and Laakso, 2013). This is seen in the phenomenon of monozygotic twins in which both develop from the same fertilised egg, essentially sharing the same DNA. These twins have a 70% chance of developing T2D if their sibling develops the disease. In comparison dizygotic, non identical twins only carry a 20-30% risk of developing the disease. (Kaprio et al., 1992)). This observation suggests that the environment the twins are raised in only contributes partially to the likelihood of developing T2D.

Single nucleotide polymorphisms (SNPs - pronounced “snips") account for the variation in genes between people from all over the world. Variations can have minor impacts such as altering hair and eye colour or major impacts such as encoding for the susceptibility of certain diseases (National Institute of Health, 2020). To date several gene mutations have been identified that increase the risk of developing T2D, such as genes that play a role in the production of glucose, the production and regulation of insulin and how glucose levels are monitored within the body. Although each variation only poses a small increase in risk, increasing variations appear to have a cumulative impact (Sullivan, 2018).

Pandurangan et al. (2014) explain that Caplian-10 was the first diabetes gene to be identified through a genome scan and is suggestive of T2D development in certain populations. Caplain-10 is thought to be partly responsible for how glucose is oxidised in skeletal muscle. Individuals with with all 3 of the SNPs detected were observed to have a 3-fold increase in developing the disease.

The TCF7L2 gene has undergone extensive study to date. Evidence suggests a SNP variant appears to modify the sensitivity of β-cells in the pancreas to incretins. Incretins are gut peptides that are released after eating, reducing glucose-induced insulin secretion (Villareal et al., 2010). Cropano et al. (2017) found that this gene variant increases the risk of T2D in obese adolescents by impairing β-cell function and was a significant predictor of developing the disease if it was not already present.

Montesanto at al. (2018) evaluated the association of SNPs in 21 candidate genes with the development of T2D. One such gene, IGF2BP2, encodes for a type of insulin like growth factor. Carriers with a variation in this gene display an up-regulation of insulin secretion and increased insulin resistance. The authors found some evidence to suggest that changes in this gene can also negatively affect mitochondrial function further promoting disease.

The TERT gene plays an important part in telomere maintenance. Telomeres are the protective caps at the end of DNA strands that prevent damage during replication. Two SNP variants within the TERT gene have been linked to T2D development. A reduction in telomere length appears to be present in a number of diabetic complications, although it is not clear if this is causative (Qi Nan, Ling and Bing, 2015). TERT SNPs have also been observed to independently increase disease incidence by negatively affecting mitochondrial function and glucose uptake pathways (Shaheen et al., 2014).

The presence of two other SNPs have also been linked to increased T2D risk. If both alleles are present individuals were found to have a threefold increase of disease development. Montesanto et al. (2018) drew attention to the fact that several genes known to be implicated in T2D play some role in the regulation of mitochondrial-induced oxidative stress, concluding this would be a worthwhile area of further exploration.

Research is now starting to explore if genetic testing will prove to be an effective measure for motivating those with the highest risk of developing T2D to modify their behaviours, and thus reduce their chance of developing the disease (Vassy et al., 2018).

However at present other factors are a far better predictors of disease such as:

• BMI

• Family history

• Hypertension

• Hyperlipidaemia

• Hypercholestolaemia

• Certain ancersty e.g. hispanic, African-American or Asian-American

(Diabetes UK, no date)

It is important to note that genetic variations do not guarantee development of T2D. This disease appears to rely on both a genetic predisposition in combination with a number of lifestyle factors. (Barnett and Kumar, 2009) (Rana et al., 2007).

If you would like to learn more about your risk of developing T2D, and what you can do to reduce it, Diabetes UK have created an online tool you can find here:

https://riskscore.diabetes.org.uk/start.

References

Barnett, A.H. and Kumar, S. (2009). Obesity and diabetes. 2nd edn. Chichester: Wiley-Blackwell.

Cropano, C. et al. (2017) ‘The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity’. Diabetes Care, 40(8), pp. 1082–1089.

Diabetes UK (2019) Us, diabetes and a lot of facts and stats. Available at: https://www.diabetes.org.uk/resources-s3/2019-02/1362B_Facts%20and%20stats%20Update%20Jan%202019_LOW%20RES_EXTERNAL.pdf (Accessed: 6 May 2020).

Diabetes UK (no date) Diabetes Risk Factors. Available at: https://www.diabetes.org.uk/preventing-type-2-diabetes/diabetes-risk-factors (Accessed: 6 May 2020).

Editor (2019) Diabetes and Genetics. Available at: https://www.diabetes.co.uk/diabetes-and-genetics.html (Accessed: 2 May 2020).

Holingue, C. et al. (2018) ‘Disturbed sleep and diabetes: A potential nexus of dementia risk’. Metabolism, 84, pp. 85–93.

Kaprio et al. (1992) ‘Concordance for Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland’. Diabetologia, 35(11), pp.1060–1067.

Lyssenko, V. and Laakso, M. (2013) ‘Genetic screening for the risk of type 2 diabetes: worthless or valuable?’. Diabetes care, 36 Supplement 2, pp. S120–S126.

Montesanto, A. et al. (2018) ‘Genes associated with Type 2 Diabetes and vascular complications’. Aging, 10(2), pp.178–196.

National Institute of Health (2020) What are single nucleotide polymorphisms (SNPs)?. Available at: https://ghr.nlm.nih.gov/primer/genomicresearch/snp (Accessed: 6 May 2020).

Pandurangan, M. et al. (2014) ‘The calpain system and diabetes’. Pathophysiology, 21(2), pp. 161–167.

Poulsen, P. et al. (2009) ‘Increased risk of type 2 diabetes in elderly twins’. Diabetes, 58(6), pp. 1350-1355.

Qi Nan, W., Ling, Z. and Bing, C. (2015) ‘The influence of the telomere-telomerase system on diabetes mellitus and its vascular complications’. Expert Opinion on Therapeutic Targets,19, pp. 849–864. DOI: 10.1517/14728222.2015.1016500.

Rana, J.S. et al. (2007) ‘Adiposity compared with physical inactivity and risk of type 2 diabetes in women’. Diabetes care, 30(1), pp. 53–58.

Shaheen, F. et al. (2014) ‘Extra-nuclear telomerase reverse transcriptase (TERT) regulates glucose transport in skeletal muscle cells’. BBA - Molecular Basis of Disease, 1842(9), pp.1762–1769.

Sullivan, D. (2018) Is Type 2 Diabetes Caused by Genetics?. Available at: https://www.healthline.com/health/type-2-diabetes/genetics (Accessed: 5 May 2020).

Vassy, J.L. et al. (2018) ‘Six-Year Diabetes Incidence After Genetic Risk Testing and Counseling: A Randomized Clinical Trial’. Diabetes care, 41(3), pp. e25–e26.

Villareal, D.T. et al. (2010) ‘TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action’. Diabetes, 59(2), pp. 479–85.