A Boost to the Study of Insulin Secretion in Children and Adolescents
Article Outline
Abbreviations: IV, Intravenous, IVGTT, Intravenous glucose tolerance test
Obesity, insulin resistance, and a cluster of associated disorders—often referred to collectively as the metabolic syndrome—are increasing in prevalence in the pediatric population. The appearance of these historically adult phenomena in the pediatric population has raised concerns about risk for early onset of diabetes, as well as cardiovascular disease, in an increasing population of young adults. In turn, it has increased recognition of the need to develop research tools appropriate for this population.
See related article, p 618
When obesity or inactivity leads to insulin resistance, the pancreas is pressed to compensate by increasing insulin secretion to maintain normal glucose tolerance. In certain circumstances, compensation eventually fails, and glucose intolerance or frank type 2 diabetes mellitus develops. Little is known about this process or about specific determinants of pancreatic failure in obese adolescents. Similarly, during the development of autoimmune-associated diabetes (type 1), pancreatic function declines until normoglycemia no longer can be maintained. In either case, the ability to identify the decline in pancreatic insulin secretion (β-cell function) before glucose abnormalities occur is desirable, so that interventions can be targeted to populations at high risk of progressing to diabetes. In addition, the ability to track β-cell function over time would be an important tool for gaining insight into the natural history of β-cell function during growth, development, and progression to disease, as well for monitoring the effect of proposed interventions.
The article by Bacha et al1 in this issue of The Journal focuses on noninvasive ways to estimate pancreatic β-cell function. Although technical in nature, the article addresses an important topic for both pediatric clinicians and researchers as we struggle to become better acquainted with issues new to our patient population.
The gold standard method for measuring β-cell function is the hyperglycemic clamp.2 In this technique, first-phase and steady-state insulin secretion is determined in response to a hyperglycemia-inducing intravenous (IV) bolus of dextrose, followed by dextrose infusion to maintain hyperglycemia. Alternatively, in the intravenous glucose tolerance test (IVGTT), the response of serum insulin to an IV bolus of glucose is determined through frequent blood sampling. The results of the IVGTT correlate well with those from the hyperglycemic clamp technique. However, both of these techniques are labor-intensive, time-consuming, and relatively invasive, requiring placement of an IV catheter, infusion of IV solutions, and frequent blood sampling. Thus, a less invasive method that could be applied to the clinical setting or to a large research population is desirable.
Indices based on fasting measures of serum glucose and insulin have been shown to provide reasonable estimates of insulin sensitivity. Similarly, fasting insulin and the insulinogenic index have correlated well with first- and steady-phase insulin secretion determined by the hyperglycemic clamp in at least 1 pediatric study of normal youth (r = 0.79 to 0.86; P < .05).3 However, fasting indices of β-cell function likely will not perform well once pancreatic function has begun to decline. Consequently, methods based on measurement of insulin after oral glucose challenge have been explored.
Oral challenge methods likely will never correlate perfectly with IV gold standard methods, because oral glucose is absorbed more slowly than IV glucose and because oral ingestion of glucose stimulates both insulin and incretins, whereas IV administration stimulates only insulin. Previous attempts to develop indices that estimate insulin secretion have focused on the time point 30 minutes after consumption of glucose during an oral glucose tolerance test. This would seem to be is a logical time point, because insulin secretion peaks 30 minutes after glucose ingestion; however, in reality, correlations with gold standard measures at this time point are less robust than desired.
Bacha et al report that the ratio of C-peptide to glucose at the 15-minute time point correlates more strongly with insulin secretion as measured by the hyperglycemic clamp. The authors speculate that the 15-minute time point correlates better because it measures early insulin secretion independent of incretin effects, whereas the 30-minute time point is affected by incretin-stimulated insulin secretion. Other studies have used multiple time points, but none correlates as well as Bacha et al's 15-minute time point, and they require more blood draws.4
This elegant study demonstrates good correlation with the hyperglycemic clamp using a simple, easy-to-perform approach that can be done practically in pediatric clinics and in large research studies. There are several caveats regarding the ability to generalize these research findings, however. The first is that this study included only prepubertal youth (mean age, 9.9 years) with normal glucose tolerance. Further research is needed to determine whether these findings apply to younger children and to pubertal children and adolescents. Puberty itself, with its associated decline in insulin sensitivity, could affect the response to such a test. Even more importantly, determining such a test can function properly in the setting of pancreatic dysfunction will require the inclusion of subjects with impaired glucose tolerance and diabetes, both type 1 and type 2. In addition, longitudinal studies are needed to determine whether the index can in fact predict the development of glucose intolerance or diabetes.
The fact that C-peptide correlated better than insulin is not surprising. As the authors mention, serum insulin concentrations are affected by changes in insulin clearance. In addition, C-peptide is more reliable when extended to multicenter trials and clinical care, because insulin assays are notoriously variable and multiple insulin assay methods exist, contributing to the high degree of variability between centers. Furthermore, insulin assays may not be accurate in a subject who has received previous insulin injections or infusions, due to anti-insulin antibodies that can interfere with the assay. Insulin assays also cross-react with insulinomimetic compounds and proinsulin, the secretion of which varies as pancreatic function declines.5
It is convenient that results were equivalent whether the challenge was glucola or Boost shakes. Boost may increase the availability and tolerability of such a test in the clinical pediatric setting. Boost does not require refrigeration, is more palatable, and is less expensive. In addition, because Boost is not composed solely of glucose, it may be a challenge to the pancreas that is more representative of an actual meal and may cause less nausea. However, because the American Diabetes Association guidelines for the diagnosis of diabetes are based on the glucose response to glucola, not Boost, a clinician wishing to diagnose impaired glucose tolerance or diabetes will still need to use glucola.
Although Bacha et al's results are quite promising, the 15-minute C-peptide–to-insulin ratio as a measure of pancreatic β-cell function currently remains applicable only to the research setting. There is still no evidence that this technique is applicable to patients with abnormal pancreatic function, or that the ratio is predictive of declining β-cell function over time. In addition, the 15-minute time point provides no information about the existence of diabetes or prediabetes, which still requires measurement of glucose at the fasting and 2-hour time points after ingestion of a standard dose of glucola. Therefore, it is not yet time to add the proposed 15-minute index to a standard clinical glucose tolerance test. The intriguing possibility remains, however, that the inclusion of an additional time point at 15 minutes will one day provide important information regarding β-cell function and the future risk of diabetes.
References
- . Measures of β-cell function during glucose tolerance test and liquid mixed-meal and the hyperglycemic clamp. J Pediatr. 2007;152:618–621
- . Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214–E223
- . Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. Diabetes Care. 2002;25:2081–2087
- The BIGTT test: a novel test for simultaneous measurement of pancreatic β-cell function, insulin sensitivity, and glucose tolerance. Diabetes Care. 2007;30:257–262
- Simultaneous assessment of insulin secretion and insulin sensitivity using a hyperglycemia clamp. J Clin Endocrinol Metab. 1992;75:379–382
PII: S0022-3476(08)00008-5
doi:10.1016/j.jpeds.2008.01.005
© 2008 Mosby, Inc. All rights reserved.
Refers to article:
- Measures of β-Cell Function during the Oral Glucose Tolerance Test, Liquid Mixed-Meal Test, and Hyperglycemic Clamp Test , 13 February 2008
