This community-based study demonstrates that elevated levels of glucose, insulin, and insulin resistance index (HOMA-IR) in childhood track and persist in ranking over a 17-year period. Childhood levels relate independently to corresponding adulthood levels and predict pre-diabetes (except childhood glucose) and diabetes conditions in adulthood, independent of age, race, sex, change in BMI Z score over time, childhood BMI Z score, MAP, and total-to-HDL cholesterol ratio. In addition, childhood high- versus low-risk status (top quintile versus the rest) with respect to glucose homeostasis variables was associated with increased prevalences of the metabolic syndrome and its component cardiometabolic risk factors. Of particular interest, childhood glucose levels clinically considered within the normal range persist into adulthood and can predict diabetes.
The concept of tracking of cardiometabolic risk factors over time is well recognized. The current findings showing the persistence of adverse levels of glucose homeostasis variables since childhood (7
), and related predictability of adult pre-diabetes and diabetes conditions, are in agreement with previous reports (6
). Bao et al. (8
) have demonstrated that the individuals with relatively high/low insulin levels trended to retain such levels over an 8-year follow-up. Of those who had insulin levels ranked in the top quartile at baseline, 40% remained so after 8 years (8
). Elevations in fasting plasma glucose within the normoglycemic range indeed may track from childhood to adulthood and reflect the progression from normal glucose tolerance before the onset of impaired glucose regulation as a continuous process in the development of diabetes (10
Of note, gain in adiposity (BMI), a modifiable risk factor, from childhood to adulthood along with childhood adiposity were the best predictors of the adult glucose homeostasis variables in this study. Because obesity is pathologically linked to insulin resistance/hyperinsulinemia, it plays a crucial role as an initiating factor in the development of dysglycemia. This is consistent with earlier observations showing temporal associations between the degree of baseline adiposity and the incidence of hyperinsulinemia (20
) or metabolic syndrome (21
), independently of baseline insulin levels. Studies (6
) have also shown baseline obesity to be an independent risk factor for type 2 diabetes.
The observational nature of the current study can not address the issue of causality but only suggests putative mechanisms for the observed relationships. Intra-abdominal and intramyocellular lipid accumulation along with adipocyte-derived cytokines have been involved in the development of insulin resistance and the attendant type 2 diabetes (22
). It is also apparent from the present study that children with top quintile (high risk) of glucose, insulin, and HOMA-IR levels displayed increased prevalence of metabolic syndrome and are associated with type 2 diabetes. As mentioned earlier, excess adiposity, especially visceral fat, may be the initiating factor in the observed adverse relationships (21
). Excess fat and related insulin resistance/hyperinsulinemia increase triglyceride (VLDLs) levels as a result of abnormal fatty acid metabolism and excess hepatic triglyceride synthesis and/or low clearance of triglycerides from the circulation (23
). In turn, increases in LDL cholesterol and decreases in HDL cholesterol levels ensue (24
With respect to blood pressure, hyperinsulinemia could relate to raises in levels by 1
) increasing renal sodium retention, 2
) stimulating the sympathetic nervous system, 3
) disturbing cell membrane calcium transport, and 4
) increasing the smooth muscle cell proliferation (5
). Alternatively, excess adiposity, per se, increases blood pressure by adversely altering, among others, intravascular volume, cardiac output, renal pressure natriuresis, and the adipose renin-angiotensin-aldosterone system (25
). Taken together, it appears that excess levels of glucose homeostasis variables within the normoglycemic range even in childhood is a biomarker of risk for developing adverse cardiometabolic conditions including diabetes and subtle abnormalities of the cardiovascular system.
The present study has certain limitations in that it lacks direct assessments of postchallenge glucose, in vivo insulin action and secretion, glycosylated hemoglobin, and body fat mass and distribution. Instead, we used well-established simple surrogate measures of glucose homeostasis that are applicable to population studies. The fasting status for metabolic variables including glucose was based on self-report. However, it should be mentioned that nonsystematic misclassification of self-reports would actually tend to underestimate the outcome. Further, the current findings should be viewed with caution in view of the modest number of events, especially diabetes.
In summary, the present findings indicate the importance of even moderately elevated levels of childhood glucose homeostasis variables (glucose, insulin, and HOMA-IR) considered within the normoglycemic range in terms of predicting pre-diabetes, diabetes, and metabolic syndrome and its cardiometabolic risk factors in apparently healthy young adults, with obesity and the change of obesity levels over time being the major contributors. Additional longitudinal population-based studies are obviously needed to validate the current findings and to develop the common glucose homeostasis variable cutoff values for type 2 diabetes and other cardiometabolic risk assessment and intervention in pediatric population.