Type 2 Diabetes: Genotype, Phenotype, and Management

Disease Phenotype and Genotype Theories

Although several major risk factors — particularly obesity and overweightness — have been identified for type 2 diabetes mellitus (T2D), relatively little is known about its precise etiology. Environmental and genetic elements both play a central role, and disease risk likely reflects a multifaceted relationship between the two. Specific epidemiological features of T2D — including its broad prevalence, the heightened susceptibility seen among certain ethnic groups, and the well-established link between disease risk and low birth weight — have given rise to multiple theories. These theories attempt to explain T2D's key epidemiological characteristics while also broadening our understanding of its etiology.

A common theme in the thrifty phenotype and thrifty genotype hypotheses is the idea that T2D susceptibility may reflect prior nutritional conditions. The thrifty genotype theory holds that a patient's nutritional history favors genetic polymorphisms that increase the likelihood of disease diagnosis. The thrifty phenotype theory, by contrast, posits that early adverse nutritional circumstances may render individuals vulnerable to T2D later in life (Lindsay, 2003).

Pathophysiological Processes of Type 2 Diabetes

T2D is characterized by various intracellular deficits related to insulin activity. The most prominent of these is reduced insulin receptor activation via tyrosine phosphorylation stimulation. This accounts for endogenous insulin's diminished capacity to increase tissue glucose uptake — particularly within muscles — and to suppress hepatic glucose production, both of which contribute to the postprandial plasma glucose elevations commonly observed in diabetics.

Free fatty acids secreted by adipose cells, produced as a result of enhanced lipolysis, can further aggravate insulin resistance. They do so by inhibiting phosphorylation and glucose transport, decreasing glycogen synthesis and glucose oxidation rates, increasing apolipoprotein B secretion, and raising hepatic lipase activity. Persistently elevated free fatty acid levels also impair beta cell insulin secretion and tend to reduce insulin sensitivity in both the liver and muscles (Codario, 2011).

Genetic Predispositions and Inheritance Patterns

Both environmental and genetic determinants contribute to T2D development. Researchers have identified links between numerous gene mutations and increased diabetes susceptibility. While not every individual carrying a mutation develops the disease, at least one such mutation is present in many diabetics. Distinguishing between environmental and genetic risk can be challenging, particularly because environmental risk is often shaped by one's household. For example, a family that practices healthy eating is likely to pass those habits on to children. At the same time, genetics plays a substantial role in determining weight, and diabetes susceptibility cannot be attributed to behavior alone (Winter, 2016).

Research involving twins suggests a meaningful genetic component in T2D. Many mutations have been shown to affect T2D susceptibility, though individual genes typically exert only a modest influence. When multiple mutations accumulate in a single individual, however, risk increases considerably. In general, genetic mutations in genes that regulate body glucose — including those governing glucose synthesis, insulin secretion and regulation, and glucose sensing — may heighten vulnerability to T2D. Key T2D-associated genes include:

T2D does not follow a clearly defined inheritance pattern; however, many individuals diagnosed with the condition have a family history of diabetes. The risk of developing T2D increases as more family members are affected. While this elevated susceptibility is partly attributable to shared genetic factors, shared lifestyle influences — such as diet and exercise habits — may also contribute (US National Library of Medicine, n.d.).

Even if one considers T2D's genetic foundation to be highly complex, certain intermediate phenotypes or individual risk factors may carry somewhat less complexity. Independent of obesity, T2D can be predicted through the combined presence of impaired insulin release and increased insulin resistance (Baier & Hanson, 2004).

Diabetes may arise from missense mutations in the insulin gene, which result in the production of structurally abnormal insulin with defective receptor binding and reduced biological activity. Researchers have thus far identified three distinct mutant insulins. Their receptor binding capacity and biological activity are substantially reduced, which leads to an extension of their half-lives (Nishi & Nanjo, 2011).

Researchers have discovered a novel mechanism underlying the reduced insulin production observed in T2D patients. Findings describe how insulin-producing cells undergo a form of developmental regression, becoming functionally "immature" and ultimately failing to work effectively. This discovery opens avenues for innovative clinical interventions (University, 2017).

References

Baier, L. J., & Hanson, R. L. (2004). Genetic studies of the etiology of type 2 diabetes in Pima Indians. Diabetes, 53(5), 1181–1186.

Codario, R. A. (2011). Type 2 diabetes, pre-diabetes, and the metabolic syndrome. Humana Press.

Lindsay, R. S. (2003). Is type 2 diabetes the result of a "thrifty genotype" or a "thrifty phenotype"? International Textbook of Diabetes Mellitus.

Marathe, P. H., Gao, H. X., & Close, K. L. (2017). American Diabetes Association standards of medical care in diabetes 2017. Journal of Diabetes, 9(4), 320–324.

McGill, M., Blonde, L., Chan, J. C., Khunti, K., Lavalle, F. J., & Bailey, C. J. (2017). The interdisciplinary team in type 2 diabetes management: Challenges and best practice solutions from real-world scenarios. Journal of Clinical & Translational Endocrinology, 7, 21–27.

Nishi, M., & Nanjo, K. (2011). Insulin gene mutations and diabetes. Journal of Diabetes Investigation, 2(2), 92–100.

Orenstein, B. W. (2015, September 18). How ethnicity affects type 2 diabetes risk. Retrieved November 21, 2017, from https://www.everydayhealth.com/hs/type-2-diabetes-management/ethnicity-diabetes-risk/

The National Institute of Diabetes and Digestive and Kidney Diseases. (2016). Risk factors for type 2 diabetes. Retrieved November 21, 2017, from https://www.niddk.nih.gov/health-information/diabetes/overview/risk-factors-type-2-diabetes

University. (2017, June 6). Newly discovered disease mechanism for type 2 diabetes. ScienceDaily. Retrieved November 21, 2017, from www.sciencedaily.com/releases/2017/06/170606112756.htm

US National Library of Medicine. (n.d.). Type 2 diabetes — Genetics Home Reference. Retrieved November 21, 2017, from https://ghr.nlm.nih.gov/condition/type-2-diabetes#

Winter, S. (2016, November 21). Is type 2 diabetes caused by genetics? Retrieved November 21, 2017, from https://www.healthline.com/health/type-2-diabetes/genetics#genes3