These observations explore the natural history of impaired glucose regulation and diabetes status in a community-based population of children free from a selection bias monitored longitudinally over a period of 21 years. Data linked the conditions of pre-diabetes and type 2 diabetes in young adults with concurrent longitudinal changes in some metabolic syndrome risk variables from childhood to young adulthood. The present population study shows that among the metabolic syndrome risk variables, in a comparison with normoglycemic subjects, glucose was consistently higher from childhood through adulthood in both pre-diabetic and diabetic subjects; LDL cholesterol, insulin, and HOMA-IR were higher in pre-diabetic subjects since adolescence; and obesity, triglycerides, insulin, and HOMA-IR were higher and HDL cholesterol was lower in diabetic subjects beginning in childhood. In terms of adverse longitudinal changes from childhood to adulthood, LDL cholesterol and glucose were independently related with pre-diabetic status, whereas obesity, HDL cholesterol, and glucose were related to diabetic status.
In the current study, the prevalence of both pre-diabetes, which may represent an impaired fasting glucose state, and diabetes was lower than that found previously (1
). This difference can be explained by the lower average age of our cohort. The observed differences of sex (male > female) in the pre-diabetic group (1
) and race (black > white) in the diabetic group (1
) in the study cohort are in agreement with the earlier reports. Further, compared with other race-sex groups, pre-diabetes (10
) and diabetes (1
) were less prevalent among white females.
It is of interest that levels of obesity were higher beginning in childhood, changed adversely through adulthood, and related independently with diabetes in adulthood. This observation is consistent with the known tracking of risk factor variables over time and especially of childhood obesity in predicting adulthood obesity (17
). The persistent elevation of obesity has influenced the onset of type 2 diabetes occurring at a younger age (17
). With respect to the longitudinal changes in this present study cohort, obesity was the most consistent predictor of adverse changes leading to diabetes, regardless of age, race, or sex. A number of studies have shown baseline obesity as an independent and modifiable risk factor for type 2 diabetes (18
). Although of different populations, studies showed obesity in young children and adolescents as a strong predictor of subsequent diabetes (17
). Such observations suggest the molecular mechanisms by which obesity plays a part in glucose intolerance are complex and include a combination of genetic factors and mechanisms in which skeletal myocytes and central adipocytes play a role (19
This study demonstrates that both pre-diabetic and diabetic groups displayed excess basal glucose, insulin, and HOMA-IR index values at least by adolescence. Of note, the diabetic group displayed a persistent elevation of glucose from childhood through adulthood. Further, glucose, but not insulin, along with lipid and obesity (in the diabetic group) variables were the independent predictors of adverse longitudinal changes of impaired glucose regulation. Of interest, blood pressure was not independently associated in the models, which is consistent with an earlier study in childhood and adolescence (18
). Although blood pressure and insulin were individually predictors of diabetes, they were not independently correlated once obesity, glucose, and lipid variables were introduced in the multivariate analyses (18
The deterioration in glucose levels to pre-diabetes or diabetes that, after a relatively stable period, occurs as a rapid, incremental increase accompanied by a decline in insulin sensitivity has been noted (20
). In the current cohort study, both showed progressively increased glucose levels beginning in early life, before the onset of impaired glucose regulation status, suggesting that even small changes in glucose levels may be a marker of altered carbohydrate-insulin imbalance.
In the present study, adverse changes in LDL cholesterol and HDL cholesterol were independently correlated among the pre-diabetic and diabetic groups. Of relevance to this present finding, HDL cholesterol was demonstrated as an independent modifiable predictor of diabetes in childhood and adolescence in Pima Indians (18
). Individuals with diabetes usually have increased triglycerides and decreased HDL cholesterol resulting from the release of fatty acids from adipose tissue, the elevation of delivery of free fatty acids to the liver, and the hepatic synthesis of VLDLs (21
). This abnormal lipid profile is characterized by modestly elevated LDL cholesterol and high triglycerides levels with a markedly increased cardiovascular risk among diabetic patients (22
Perhaps most important is the observation that young adults with pre-diabetes and diabetes showed an increased prevalence of metabolic syndrome and its multiple risk factors. The observed overall prevalence of metabolic syndrome is in agreement with an earlier report (23
). Also, metabolic syndrome status was more prevalent in the pre-diabetic and diabetic groups, as might be expected and is consistent with previous findings (11
). A pre-diabetic status reflects an atherogenic profile of metabolic syndrome risk variables long before an overt clinical macrovascular event (24
). Further, these multiple risk factors related to autopsy findings of coronary atherosclerosis that we studied in our young individuals, evidence of “silent,” subclinical disease that evolves from childhood.
As limitations, this study lacks postchallenge glucose and in vivo insulin action and secretion. Instead, an established simple surrogate measure HOMA-IR index applicable to population studies was used. Also, because of the lack of dietary intake data, this study did not address the role of diet in the regulation of glucose homeostasis and related risk of obesity, cardiovascular disease, and type 2 diabetes (25
). The fasting status was based on self-report.
In summary, these findings indicate that adverse levels of risk variables of metabolic syndrome, adiposity, and measures of glucose homeostasis in particular, and their accelerated rates of change since childhood, characterizes the early natural history of carbohydrate-insulin imbalance. The current findings reinforce a primary role for early prevention of and intervention for these risk factors, especially obesity, beginning in childhood.