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EDITORIAL |
Children’s Hospital/University of Colorado, Division of Endocrinology, Denver, Colorado 80218
Address all correspondence and requests for reprints to: Dr. Philip S. Zeitler, Children’s Hospital/University of Colorado, Division of Endocrinology, 1056 19th Avenue, Denver, Colorado 80218. E-mail: zeitler.philip{at}tchden.org.
The prevalence of type 2 diabetes is increasing among youth and adults throughout the world, with striking rates of increase in rapidly developing countries (1, 2, 3). In adults, type 2 diabetes may remain undiagnosed for several years because hyperglycemia develops gradually and may not cause symptoms (2, 4). Therefore, it has been estimated that nearly 50% of prevalent cases of diabetes among adults remain undiagnosed (2, 5) Yet, it is also known that the risk for cardiovascular morbidity and mortality is increased well before the diagnosis of diabetes is made, including in subjects with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (6). Therefore, the challenge of developing cost-effective approaches to the identification of undiagnosed diabetes among adults and the value of identifying IFG and IGT remain areas of substantial controversy.
The challenge is even greater among youth. Although the obesity prevalence among children in the United States ranges from 10–30% (7), studies suggest that the prevalence of undiagnosed diabetes is surprisingly low (8), even among youth with multiple risk factors. Thus, there is little evidence to support wide-scale screening for diabetes among asymptomatic youth, because this would be a labor-intensive and expensive task with uncertain benefit, even when multiple risk factors are present.
On the other hand, 40% of a cohort of eighth-graders had IFG, and rates of IFG and IGT are even higher among youth referred for evaluation in obesity clinics (9). Yet, the prognostic and therapeutic value of identifying IFG and IGT in youth is controversial, and the potential harm and long-term effects of labeling a population as abnormal are unknown. Furthermore, although there is evidence that the combination of IFG and IGT in youth is a strong predictor of progression to overt diabetes in the short term (10), no trial has yet established either that systematic screening for early glucose abnormalities in obese children or that early treatment improves health outcome.
Nevertheless, there are clearly circumstances in which testing for undiagnosed diabetes, along with the identification of IFG and IGT may be desirable. For example, the identification of dysglycemia is important for establishing cohorts for research into the pathophysiology of these states in adolescents as well as for the exploration of potential approaches to intervention. Similarly, limited availability may require that clinical resources for the treatment of obese adolescents be focused on those most at risk for disease progression and comorbidities. However, a number of important questions remain. Who should be screened? Which test should be used? How often should the screening be repeated?
Determination of hemoglobin A1c is not sufficiently sensitive to detect early or subtle abnormalities in glucose excursion and has no clear utility in identification of IFG and IGT. Furthermore, the utility of this simple measure of average glucose has been limited in the past by poor reproducibility and lack of standardization (11, 12). Measurement of fasting glucose allows the identification of both IFG and diabetes. However, ensuring adherence to fasting guidelines can be challenging in an obese adolescent population. Furthermore, the 2-h postload plasma glucose has been shown to have increased sensitivity for the diagnosis of both diabetes and IGT in adults (5) and children (9). In addition, it has been proposed that the oral glucose tolerance test (OGTT) is preferable to measurement of fasting glucose because IGT, which can only be identified through glucose challenge, has also been associated with an increased risk for development of cardiovascular disease (13, 14). However, the reproducibility of the test has been questioned.
In this issue of the Journal, Ingrid Libman and her colleagues at the University of Pittsburgh (15) report a prospective study of the reproducibility of the OGTT in overweight children and confirm what has previously been reported in adults, namely that the reproducibility of the test is poor, particularly among those adolescents with the greatest degree of apparent abnormality. Clinically, these results mean that an isolated abnormal postload plasma glucose is not sufficient for the diagnosis of diabetes or impaired glucose metabolism in the pediatric population, further complicating the argument between the use of fasting glucose and OGTT for screening of at-risk children. Nevertheless, the authors support the utility of the test, arguing that those children with inconsistent results have a more insulin-resistant phenotype and may be at greater risk for the development of diabetes. However, they do not discuss how the inconsistency of the results of repeated tests could be developed into a clinical test given the patient burden and expense of such an approach. Furthermore, there are other, simpler clinical approaches to identifying the insulin-resistant phenotype, such as fasting triglycerides, the presence of metabolic syndrome components, and fasting C-peptide (16, 17). Therefore, although the inconsistency of OGTT results in insulin-resistant individuals is interesting from a physiological perspective, the only compelling reason to perform an OGTT is for the identification of abnormalities of glucose homeostasis. The casting of doubt on the reproducibility of OGTT identification of such abnormalities must, therefore, raise serious questions about the value of routine performance of the OGTT in at-risk obese adolescents.
At the same time, Libman et al. (15) report that fasting blood glucose values exhibited a higher correlation on repeated measurement than postload values. These findings have also been reported in adults and are not surprising. The primary pathophysiology in diabetes is the imbalance between decreased insulin sensitivity and the ability of the increasingly impaired β-cell to compensate by secreting more insulin. In the fasting state, the serum glucose concentration is a relatively straightforward function of the ability of insulin to regulate peripheral glucose uptake and hepatic glucose output, whereas the postload glucose concentration is determined by these two factors as well as many other variables that are less well understood, such as the intestinal nutrient absorption rate and the secretion and actions of gut peptides with central, peripheral, and pancreatic actions. Therefore, it is not surprising that the results of a postload test would be less predictable from one time to the next, given the potential variability in diet, activity, and hormonal state. Libman and her colleagues, in an effort to replicate the clinical setting, did not attempt to standardize any of these factors, and this likely contributes to the lack of reproducibility.
The findings in this article reflect an important dilemma facing clinicians and researchers interested in identifying the optimal approach to screening and diagnosis of glucose abnormalities in at-risk adolescents. On the one hand, a higher prevalence of abnormalities is noted on the postload sample than on the fasting sample, confirming previous studies and suggesting that reliance on a fasting sample alone will miss adolescents with type 2 diabetes, as well as more subtle abnormalities in glucose homeostasis. Findings such as these have been used to support arguments for more widespread use of the OGTT. On the other hand, the postload glucose values are less reproducible than the fasting samples, raising questions about the validity and implications of the abnormalities identified. This leaves us with the following question: if we identify more abnormalities, but we can’t be sure if they are real, have we accomplished something valuable?
As we attempt to answer this question, it is useful to remember that the original definitions of diabetes, IFG, and IGT in adults were rooted in an understanding of the long-term implications of these glucose abnormalities for cardiovascular and microvascular health. Ideally, then, the criteria we use for diagnosis in adolescents should also have implications beyond representing glucose values that are outside of a range determined in adults. Ultimately, proof of the validity of screening approaches in at-risk adolescents is going to require more than documentation of reproducibility. Rather, we need to have insight into the relationship of the findings to relevant aspects of medium- and long-term health. Clearly, we are a long way from such an understanding in the pediatric population.
The OGTT will continue to have its place as a research tool as we grapple with the implications of varying degrees of dysglycemia in obese children and adolescents, but the report of Libman et al. (15) reminds us to be humble in our interpretation of the results. Furthermore, given the low prevalence of undiagnosed diabetes and the uncertain implications of IGT in obese children and adolescents, there is little evidence to support widespread use of the OGTT for screening. Rather, the OGTT should be reserved for use in the focused evaluation of individual patients. Who? When? How Often? More questions than answers.
Footnotes
Abbreviations: IFG, Impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test.
Received September 9, 2008.
Accepted September 12, 2008.
References
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