Does type 2 diabetes run in the family?

Type 2 diabetes mellitus (T2DM) is a complex, multifactorial disease characterized by insulin resistance and beta cell dysfunction.¹ Various population-based surveys estimate that in 2021-2022, there were 37-51 million adult Americans and 422-537 million adults worldwide with diabetes, of which 90-95% of diagnosed cases are type 2 diabetes.^2-4 By the year 2045, the number of adults worldwide with diabetes is expected to rise to 784 million.²

According to the Annals of Internal Medicine clinical practice guidelines, the following factors increase the risk of developing T2DM:⁴  

• Aged 45 years or older 
• First-degree relative with type 2 diabetes
• Certain racial and ethnic groups including African, Hispanic, Asian, Pacific Islander, or Native American 
• History of gestational diabetes 
• Delivery of an infant weighing 9 pounds or more 
• Polycystic ovary syndrome 
• Being overweight, especially abdominal obesity
• Cardiovascular disease 
• Hypertension 
• Dyslipidemia, including low HDL cholesterol, high LDL cholesterol, or high triglycerides 
• Other features of metabolic syndrome 

The American Diabetes Association (ADA) lists the following additional recommended criteria for diabetes testing in asymptomatic adults:⁵ 

• Physical inactivity 
• Other conditions associated with insulin resistance 
• Prediabetes 
• Certain medications including some HIV medications, glucocorticoids, thiazide diuretics, and atypical antipsychotics
• HIV

Genetic Component

While genetics are a risk factor for the development of T2DM, other factors are more predictive. One study examining statistical models for T2DM development found age to be a key risk factor, followed by family history of T2DM.⁶ However, for older adults (>69), blood pressure was found to be a stronger predictor than increasing age. Systolic blood pressure was found to be on average 12 mmHg higher in those with diabetes than those without diabetes (132 mmHg vs 120 mmHg). This study also reported a high correlation between physical activity and T2DM, finding the average duration of daily moderate to vigorous exercise to be 47 minutes shorter amongst participants with diabetes than those without diabetes (61 minutes per day vs 108 minutes per day).

Another study seeking to make a new assessment tool found that the following risk factors are most predictive of having undiagnosed T2DM, in order of most predictive to least predictive:⁷ 

• Aged 60 years or older 
• Extreme obesity (BMI ≥40 or waist circumference ≥50 inches for men, ≥49 inches for women) 
• Aged 50-59 years 
• Obesity (BMI ≥30 or waist circumference 40-50 inches for men, 35-49 inches for women) 
• Aged 40-49 years 
• Male 
• Family history of diabetes 
• History of hypertension 
• Overweight (BMI 25-30 or waist circumference 37-40 inches for men, 31.5-35 inches for women)

The development of T2DM is complex and involves the interaction of both genetic predisposition and environmental factors. The Discordant Twin (DISCOTWIN) study of 34,166 twin pairs from Europe and Australia estimated the heritability of T2DM to be 72% (95% CI [61-78]), meaning that 72% of the variability in risk for development of T2DM can be attributed to genetics as opposed to environmental factors.¹ However, in a study of 6,909 twins in Washington state, heritability was estimated to be only 52%.⁸ The authors noted that in the United States, where there is nearly twice the prevalence of T2DM than the eight countries in DISCOTWIN, the environmental factors may play a greater role in the development of T2DM.

Specific studies have sought to identify the exact genes that contribute to the development of T2DM. The strongest association found so far is to TCF7L2, one of the most replicated genes associated with T2DM.^9,10 Dysfunctional TCF7L2 variants are associated with impaired glucose-stimulated insulin secretion.⁹ Even with over 700 similarly implicated risk loci found in relation to T2DM, only about 20% of the heritability seen in T2DM has been explained to date.^11,12  

One research group attempted to create a predictive model for the development of T2DM by accounting for both genetic and traditional risk factors, such as age, family history of diabetes, and body-mass index.¹³ The addition of 11 genes significantly associated with T2DM to the clinical risk factors added only minimal benefit when compared to clinical risk factors alone.13 Continued work is needed to fully understand the complex relationship between role of genetics and environment involved in T2DM risk.

Risk Reduction

Both the Annals of Internal Medicine and ADA clinical practice guidelines recommend the following to prevent or delay the development of type 2 diabetes:^4,14 

• Adults with overweight or obesity should lose and maintain a loss of at least 7% of their initial body weight 
• At least 150 minutes per week of moderate-intensity physical activity, like brisk walking 
• Eat a healthy diet with the goal of weight loss and reduction of total caloric intake

These lifestyle modifications have been found to prevent or delay T2DM in even genetically high-risk populations. The Diabetes Prevention Program Outcomes Study (DPPOS) found that maintenance of at least 7% weight loss and 150 minutes of physical activity each week significantly reduced T2DM incidence (Hazard Ratio [HR] 0.73, 95% Confidence Interval [CI] [0.65-0.83]).^15,16 Over a mean follow-up of 15 years, there was a 7% difference in cumulative incidences of diabetes between the group receiving lifestyle intervention compared to placebo (55% vs 62%, Relative Risk [RR] reduction 27%). Although diet and exercise were the most effective ways to prevent diabetes, the DPPOS did find that medication such as metformin was also effective, with a cumulative incidence of 56% in the group receiving medication intervention, only 1% higher than the lifestyle intervention group and 6% lower than placebo (RR reduction 18%, HR 0.82, 95% CI [0.72-0.93]).

Screening 

Most people with T2DM don’t have any symptoms at first and are identified with screening tests.^4,5 Screening for T2DM is recommended every 3 years for people over age 45 with normal test results. People at risk for T2DM, including younger adults and children 10 or older, may be tested sooner or more often.¹⁷

References 

1. Willemsen G, Ward KJ, Bell CG, et al. The Concordance and Heritability of Type 2 Diabetes in 34,166 Twin Pairs From International Twin Registers: The Discordant Twin (DISCOTWIN) Consortium. Twin Research and Human Genetics. 2015;18(6):762-771. doi:10.1017/thg.2015.83
2. IDF Diabetes Atlas, 10th ed. International Diabetes Federation. Accessed June 15, 2023. https://www.diabetesatlas.org
3. National Diabetes Statistics Report. Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services. Accessed June 22, 2023. https://www.cdc.gov/diabetes/data/statistics-report/index.html
4. Vijan S. Type 2 diabetes. Annals of internal medicine. Nov 5 2019;171(9):Itc65-itc80. doi:10.7326/aitc201911050
5. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. Jan 1 2022;45(Suppl 1):S17-s38. doi:10.2337/dc22-S002
6. Turi KN, Buchner DM, Grigsby-Toussaint DS. Predicting Risk of Type 2 Diabetes by Using Data on Easy-to-Measure Risk Factors. Prev Chronic Dis. Mar 9 2017;14:E23. doi:10.5888/pcd14.160244
7. Bang H, Edwards AM, Bomback AS, et al. Development and validation of a patient self-assessment score for diabetes risk. Annals of internal medicine. Dec 1 2009;151(11):775-83. doi:10.7326/0003-4819-151-11-200912010-00005
8. Avery AR, Duncan GE. Heritability of Type 2 Diabetes in the Washington State Twin Registry. Twin Research and Human Genetics. 2019;22(2):95-98. doi:10.1017/thg.2019.11
9. da Silva Xavier G, Loder MK, McDonald A, et al. TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes. Apr 2009;58(4):894-905. doi:10.2337/db08-1187
10. Saxena R, Gianniny L, Burtt NlP, et al. Common Single Nucleotide Polymorphisms in TCF7L2 Are Reproducibly Associated With Type 2 Diabetes and Reduce the Insulin Response to Glucose in Nondiabetic Individuals. Diabetes. 2006;55(10):2890-2895. doi:10.2337/db06-0381
11. DeForest N, Majithia AR. Genetics of Type 2 Diabetes: Implications from Large-Scale Studies. Curr Diab Rep. May 2022;22(5):227-235. doi:10.1007/s11892-022-01462-3
12. Vujkovic M, Keaton JM, Lynch JA, et al. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat Genet. Jul 2020;52(7):680-691. doi:10.1038/s41588-020-0637-y
13. Lyssenko V, Jonsson A, Almgren P, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med. Nov 20 2008;359(21):2220-32. doi:10.1056/NEJMoa0801869
14. 3. Prevention or Delay of Type 2 Diabetes and Associated Comorbidities: Standards of Medical Care in Diabetes-2022. Diabetes Care. Jan 1 2022;45(Suppl 1):S39-s45. doi:10.2337/dc22-S003
15. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care. Dec 2002;25(12):2165-71. doi:10.2337/diacare.25.12.2165
16. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. Nov 2015;3(11):866-75. doi:10.1016/s2213-8587(15)00291-0
17. Mangione CM, Barry MJ, Nicholson WK, et al. Screening for Prediabetes and Type 2 Diabetes in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. Jama. Sep 13 2022;328(10):963-967. doi:10.1001/jama.2022.14543