Type 2 diabetes (T2D) is a growing health concern, associated with increasing morbidity and mortality. It is projected to be one of the few rising causes of mortality, behind human immunodeficiency virus/AIDS and above motor vehicle accidents. The prevalence of T2D is projected to increase by 23 to 110%, depending on the region, with the biggest increase anticipated in Africa, South America, and South Asia. Understanding the causes of the increased risk for developing diabetes may help target our global preventive efforts more effectively. Identifying individuals at risk for developing diabetes at a younger age and at risk for developing more severe complications from diabetes may help target therapy and interventions.
Various studies have demonstrated an association of family history of T2D with higher overall risk of developing T2D and more severe disease, including earlier onset, more pronounced hyperglycemia, earlier comorbidities (microalbuminuria), more extensive metabolic associations (lipids), greater central obesity, and hypertension.[3–5] There is also an environmental/lifestyle contribution that can be associated with a positive family history, which may be reflected in a closer association of sibling history than parental history for the development of T2D; however, that may not be observed in adoptees.
Alharity et al conducted a cross-sectional study in Saudi Arabia, where the prevalence of T2D is the highest worldwide–17.6% and rising. This paper focused on the contribution of family history to the development and severity of T2D, specifically noting contribution of parental and sibling history of T2D. They observed that subjects with parental history of T2D were noted to have T2D at a younger age (diagnosed at 43.5 years old vs. 49.5 years old). They also had a more predisposing physiology with a higher body mass index (BMI) and waist circumference. Similarly, those with a sibling with T2D had a higher BMI. Importantly, the subjects with siblings with T2D were more likely to suffer a cerebrovascular accident (7.2% vs. 2.5%; P = .02). There was no difference in other risk factors for stroke, such as blood pressure; in fact, triglyceride levels were lower in the subjects with T2D siblings, and other lipids were the same.
Subjects with parents with T2D were more likely to smoke. Unlike the parental association, there was no difference in smoking rates in subjects with siblings with T2D, nor was there a statistically significant difference in passive smoke exposure.
There is a significant impact of socioeconomic factors on the risk of developing T2D. In the current study, among those who had higher education (bachelors or higher), more had family history of T2D than among those without higher education (parental 12.6% vs. 6.2%, P = .005; sibling 11.1% vs. 6.7%, P = .031), suggesting that family history is a predisposing factor despite higher education. The overall rate of higher education in this cohort with T2D was 9.4%, compared to 15.5% of the 55 to 64 year olds in the general Saudi population. More than one-half of the patients were low income (287 of 511, 56.2%), more of those without parental history of T2D were in this category (63.8% vs. 48.9%; P = .002), suggesting that people with low income may be at risk for T2D despite lack of parental history of T2D.
This study affirms the increased risk of T2D associated with family history of diabetes and highlights some of the important differences between parental versus sibling history. Sibling history of T2D may identify not only genetic predisposition but also the contribution of environmental factors, including socioeconomic status, especially early in life. Shared environment in childhood may predispose to less-healthy lifestyle habits, including poor eating habits, decreased activity, and poor sleep habits. Of this population of patients with T2D, more than half were low income, and few had attained higher education. These environmental and behavioral factors acting upon the increased risk of lower beta-cell function associated with a family history of T2D can accelerate the risk of early and more-severe T2D.
This was a small, retrospective study limited to a relatively homogeneous population with a high prevalence of T2D, 17.6%. Saudi Arabia has a national registry and fully implemented national guidelines for the care of patients with T2D. However, the screening criteria and therapeutic approaches are not described. It is therefore hard to determine if the presence of family members with T2D may have influenced the timing of diagnosis and the treatment approach in this cohort.
Where the differential contribution of mothers versus fathers was analyzed, the trends suggest a stronger contribution of maternal T2D, especially if it was earlier in the mother's life. This trend, as well as the studies that included adoptees—where presumably the postnatal environment is changed—point to a contribution of the uterine environment to the risk of early and more-severe T2D. Observations in Pima Indians, a group of native Americans who have a very high risk of T2D, demonstrated a greater incidence of T2D in offspring who were exposed to maternal diabetes in utero compared to their older siblings who were born before their mother developed T2D. There may be a similar impact of more-subtle glucose dysregulation before the diagnosis of T2D that impacts the fetus, perhaps through epigenetic mechanisms. Additional effects may include the metabolic derangements associated with maternal obesity, nutrition, activity, and sleep habits. This would explain both the stronger contribution of maternal T2D and the persistent risk on adoptees.
In summary, the current study begins to address the important questions of the genesis of T2D and perhaps points to some strategies for minimizing those risks very early in life. Genetics makes a statistically significant, but small, contribution to the risk of developing T2D, leaving hope that other risk factors can be modified. This may require an intervention even earlier than we had thought, perhaps even prenatally.
This study was small and limited to a homogeneous population that carries the burden of very high risk of T2D. Hence, the results may not be applicable universally, but the uniform populations allowed for significant environmental factors to emerge. Poverty and lack of education are risk factors that are significant despite family history. To further the understanding of the risk conferred by family history of T2D, understanding the maternal versus paternal contribution, as well as the homology between siblings, may help elucidate the relative contribution of genetics, intrauterine factors, and the postnatal environment.
Endocr Pract. 2019;25(2):197-198. © 2019 American Association of Clinical Endocrinologists