The EarlyBird study investigated how to predict future pre-diabetes and type 2 diabetes in children.
Years of research have shown us that there are many factors that predispose patients to type 2 diabetes. However, researchers at the University of Plymouth, in collaboration with Nestlé Institute of Health Sciences, monitored children to gain more insight into the factors that predispose them to type 2 diabetes in adulthood. The EarlyBird study, which is a prospective cohort study, investigated the genetic risk markers of type 2 diabetes in healthy children, as well as the influence trajectory of insulin and glucose independently of BMI.
EarlyBird followed 300 children from the ages of 5 to 16 years old to determine who would become at-risk for developing type 2 diabetes, and why. Annual clinical anthropometric and physiological measurements were taken from the children. Researchers were among the first to report an early occurrence of β-cell dysfunction in children who later developed pre-diabetes. This study also showed impaired fasting glycemia in subjects by the age of 15 years; these children had previously exhibited high blood glucose levels at the age of 5. The genetic variants, puberty, and weight gain were also analyzed by EarlyBird to see how these factors could influence insulin action and blood glucose levels at an early age.
Results from this study proved to be signiﬁcant because they reveal the changes in insulin secretion, insulin action, and glycemia over time. Genetic linkage of the SNPs associated with adult diabetes was mirrored in the children in their association with insulin and glycemic traits. SNP’s susceptibility also showed age-speciﬁc interactions in the child subjects, with some of these traits including: rs780094(GCKR), rs4457053(ZBED3), rs11257655(CDC123), rs12779790 (CDC123 and CAMK1D), rs1111875 (HHEX), rs7178572 (HMG20A), rs9787485 (NRG3), and rs1535500 (KCNK16). Many of the common genetic variants were associated with a variety of high levels of fasting blood glucose.
GCKR and ZBED3 were two intronic genetic variants that were associated with different trajectories of fasting blood glucose from an early age throughout childhood. An increased risk of developing type 2 diabetes showed some correlation from the SNP ZEBD3 through elevated WNT activity. This pathway is controlled by short-chain fatty acids produced during the digestion of dietary fiber. ZEBD3 is known to affect fiber intake, which has led to the belief that this SNP is a relevant genetic maker for children who would benefit from increased consumption of dietary intake. GCKR is believed to be associated with lower fasting blood glucose levels in adults. In this study, it was found that the GCKR genotype was negatively associated with an age-dependent course of glucose; however, children at the age of 5 years old showed a positive association with blood glucose.
One of the most pivotal discoveries in this study is that relative defects in β-cell function were a determining factor for who developed pre-diabetes. HOMA-B (β-cell function) carried the most genetic associations of diabetes susceptibility. SNPs in the CDC123, HHEX–IDE, and KCNK16 loci, showed a negative association with HOMA-B. SNPs in the CDC123 loci may represent that there is β-cell mass and can influence function throughout growth. Evidence from the EarlyBird study showed that that the interactions of the SNP in HHEX–IDE loci with the trajectories of SHBG, IGF-1, and 17-OHP may inﬂuence endocrine traits and therefore the maturation of other biological processes in childhood. Through these findings, it is believed that insulin action is also inﬂuenced by genetic variations in the growth hormone–IGF-1 axis and adrenal and sex steroid activity, with a negative association in both HOMA-B and SHBG (sex hormone-binding globulins). Since the HHEX– IDE SNP relates to insulin secretion capacity in early life, it is believed that there are effects beyond fetal development into pubertal growth and development.
The EarlyBird study was successful in demonstrating that SNPs previously associated with diabetes in adults also can be influential in children with the course of glycemic and insulin traits, independent of BMI.
- The earliest event leading to pre-diabetes is an early dysfunction of the beta-cell in children.
- Beta-cell dysfunction was associated with the presence of genetic factors previously associated with type 2 diabetes in adults.
- Discovery of such factors could lead to the early identification of children that are at risk of future type 2 diabetes.
Carayol, J. et al. (2020) Genetic Susceptibility Determines β-Cell Function and Fasting Glycemia Trajectories Throughout Childhood: A 12-Year Cohort Study (EarlyBird 76). Diabetes Care. doi.org/10.2337/dc19-0806.
Chardae Whitner, 2020 PharmD. Candidate, Lake Erie College of Osteopathic Medicine