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A correction has been published: N Engl J Med 2002;347(4):290.

Previous Volume 346:802-810 March 14, 2002 Number 11 Next

Abstract PDF PDA Full Text PowerPoint Slide Set Editorial by Rocchini, A. P. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article Related Article by Goran, M. I. PubMed Citation

ABSTRACT

Background Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents.

Methods All subjects underwent a two-hour oral glucose-tolerance test (1.75 mg of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose.

Results Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance.

Conclusions Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.

Although severe obesity has a prominent role in the pathogenesis of type 2 diabetes in children and adolescents,¹ it is unknown whether it is a risk factor for impaired glucose tolerance. We undertook a study to determine the prevalence of glucose intolerance in a multiethnic cohort of obese children and adolescents. Abnormal beta-cell function, as manifested by the release of large amounts of proinsulin relative to insulin levels, is clearly present in patients with overt type 2 diabetes.^8,9 Disproportionate hyperproinsulinemia is thought to represent an impending failure of insulin secretion in adults.⁸ The earlier an increase in the ratio of proinsulin to insulin occurs in the prediabetic phase, the more likely it is that abnormal processing of insulin by beta cells is fundamental to the pathogenesis of diabetes. We therefore examined the intracellular processing of proinsulin to determine whether alterations are present early in the development of glucose intolerance in obese children and adolescents.

Methods

Study Population

We recruited 55 children (4 to 10 years of age) and 112 adolescents (11 to 18 years of age) who had been referred to the Yale Pediatric Obesity Clinic between 1999 and 2001. Body weight was measured with a digital scale to the nearest 0.1 kg, and height was measured in triplicate with a wall-mounted stadiometer. The body-mass index — the weight in kilograms divided by the square of the height in meters — was calculated. All subjects had a body-mass index that was higher than the 95th percentile for age and sex and were thus classified as obese.¹⁰ Approximately 58 percent of the subjects were non-Hispanic white, 23 percent were non-Hispanic black, and 19 percent were Hispanic (Table 1). A detailed medical and family history was obtained from all subjects, and a physical examination was performed, including staging of puberty on the basis of breast development in girls and genital development in boys according to the criteria of Tanner¹¹ (stage 1 indicates preadolescent characteristics, and stage 5 indicates adult characteristics). All subjects were otherwise in good health and had normal thyroid function; none were taking any medications. A total of 23 of the adolescent girls (approximately 40 percent) had hirsutism, oligomenorrhea, acne, and increased levels of total testosterone, suggesting the presence of the polycystic ovary syndrome. The study was approved by the Institutional Review Board of the Yale University School of Medicine. Written informed consent was obtained from the parents and oral consent from the children and adolescents.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics According to Sex and Age Group.

 
Oral Glucose-Tolerance Test

All subjects followed a weight-maintenance diet consisting of at least 250 g of carbohydrates per day for seven days before the study, as confirmed by the fact that body weight remained stable (measured to the nearest 0.5 kg). Subjects were studied in the Children's Clinical Research Center at the Yale University School of Medicine at 8 a.m. after a 12-hour overnight fast. After the local application of a topical anesthetic cream containing 2.5 percent lidocaine and 2.5 percent prilocaine (Emla, Astra Zeneca, Wilmington, Del.), one antecubital intravenous catheter was inserted for blood sampling, and its patency was maintained by slow infusion of normal saline. Each child then rested while watching a videotape for 30 minutes. Two base-line samples were then obtained for measurements of plasma glucose, insulin, C peptide, proinsulin, and lipids. Thereafter, flavored glucose (Orangedex, Custom Laboratories, Baltimore) in a dose of 1.75 g per kilogram of body weight (up to a maximum of 75 g) was given orally, and blood samples were obtained every 30 minutes for 120 minutes for the measurement of plasma glucose, insulin, and C peptide. Impaired glucose tolerance was defined, according to the American Diabetes Association guidelines, as a fasting plasma glucose level of less than 126 mg per deciliter and a two-hour plasma glucose level of 140 to 200 mg per deciliter; type 2 diabetes was defined as a fasting glucose level of 126 mg per deciliter or higher or a two-hour plasma glucose level of more than 200 mg per deciliter.¹²

Although the oral glucose-tolerance test is the most sensitive method for detecting early diabetes, it can result in misclassification.¹³ To determine the reproducibility of the results, we repeated the test three months later in four obese children with normal glucose tolerance and in six obese children and adolescents with impaired glucose tolerance.

Biochemical Analysis

The plasma glucose level was determined with a glucose analyzer (Beckman Instruments, Brea, Calif.), and the plasma lipid levels were determined by the Yale Core Lipid Laboratory with an AutoAnalyzer (model 747–200, Roche–Hitachi, Indianapolis). Plasma insulin was measured with a radioimmunoassay made by Linco (St. Charles, Mo.), which has less than 1 percent cross-reactivity with C-peptide and proinsulin. Plasma C-peptide levels were determined with an assay made by Diagnostic Product (Los Angeles), and total proinsulin with another radioimmunoassay kit (Linco), which has no cross-reactivity with insulin and a detection limit of 0.15 pmol. The intraassay variation was 11 percent for insulin, 13 percent for C peptide, and 9 percent for proinsulin, and the interassay variation was 12 percent for insulin, 12 percent for C peptide, and 11 percent for proinsulin.

Calculations

To assess beta-cell function, we used the insulinogenic index, calculated as the ratio of the increment in the plasma insulin level to that in the plasma glucose level during the first 30 minutes after the ingestion of glucose. We found that in children and adolescents, the insulinogenic index correlates well with the early insulin response obtained during a hyperglycemic-clamp study (r=0.68, P<0.001). A low insulinogenic index predicts the development of diabetes in adults.^14,15,16,17 Insulin resistance was determined by homeostatic model assessment¹⁸ and calculated as the product of the fasting plasma insulin level (in microunits per milliliter) and the fasting plasma glucose level (in millimoles per liter), divided by 22.5. Lower insulin-resistance values indicate a higher insulin sensitivity, whereas higher values indicate a lower insulin sensitivity. The estimate obtained with homeostatic model assessment (the insulin-resistance index) correlated well (r=–0.71, P<0.001) with measures of insulin resistance obtained from obese and nonobese children and adolescents with the use of the euglycemic–hyperinsulinemic clamp technique; a similar correlation has been reported in adults.^18,19

Statistical Analysis

All values are expressed as means ±SE. Variables that were not normally distributed (insulin level, insulin-resistance index, proinsulin level, and two-hour plasma insulin level) were log-transformed for analysis. However, for clarity of interpretation, results are expressed as untransformed values. Differences in the means of continuous variables were tested by two-tailed t-tests. Nonparametric statistics were applied in the analyses of data that had a skewed distribution. An analysis of covariance was used to compare the plasma levels of glucose, insulin, C peptide, and proinsulin and the insulin-resistance index of subjects with normal glucose tolerance with the values for those with impaired glucose tolerance, with age and body-mass index as covariates. Multiple logistic-regression analysis was used to evaluate the model with the use of two goodness-of-fit tests (Proc Logistic procedure, SAS software, release 6.10, SAS Institute, Cary, N.C.)²⁰ and to determine the relative risks of impaired glucose tolerance among obese children and adolescents. The dependent variable in multiple logistic-regression analyses was the plasma glucose level at 120 minutes. The independent variables entered in the several models generated were age, body-mass index, fasting insulin and proinsulin levels, two-hour plasma insulin level, the insulin-resistance index, and the insulinogenic index.

Results

Prevalence of Impaired Glucose Tolerance and Silent Type 2 Diabetes

A total of 25 percent of the children and 21 percent of the adolescents had impaired glucose tolerance (Table 2). Silent diabetes was diagnosed in four adolescents (4 percent). Among the children and adolescents with impaired glucose tolerance, 51 percent were non-Hispanic white, 30 percent were non-Hispanic black, and 19 percent were Hispanic. Four adolescents — two black and two Hispanic — had diabetes. Fourteen girls with apparent cases of the polycystic ovary syndrome had normal glucose tolerance, six had impaired glucose tolerance, and two had diabetes. A total of 30 percent of the combined group of those with impaired glucose tolerance and those with frank diabetes had a parental history of type 2 diabetes; the rate was 25 percent among those with normal glucose tolerance (P=0.54).

View this table: [in this window] [in a new window]   Table 2. Clinical and Metabolic Phenotype of Obese Children and Adolescents with Normal Glucose Tolerance, Impaired Glucose Tolerance, or Type 2 Diabetes.

 
More children with impaired glucose tolerance were girls, whereas the numbers of boys and girls were similar in the groups of adolescents with impaired glucose tolerance. The body-mass index was higher among adolescents with impaired glucose tolerance or diabetes than among those with normal glucose tolerance.

Reproducibility of the Oral Glucose-Tolerance Test

The mean plasma glucose levels at two hours during the first oral glucose-tolerance test (108±7 mg per deciliter for subjects with normal glucose tolerance and 152±3 mg per deciliter for those with impaired glucose tolerance) were similar to those obtained during the second oral glucose-tolerance test in subjects studied to determine the reproducibility of the results (107±12 mg per deciliter for subjects with normal glucose tolerance and 146±3 mg per deciliter for those with impaired glucose tolerance). Thus, the diagnosis was confirmed during the second test in all six subjects with impaired glucose tolerance who were evaluated. Three non-Hispanic black girls were followed for two to five years, during which time the oral glucose-tolerance test was repeated several times. Subject 1 had impaired glucose tolerance at 6 years of age, which persisted until 11 years of age, when diabetes developed. Subject 2 had normal glucose tolerance at 8 years of age, which then progressed to impaired glucose tolerance at 12 years of age and remained impaired thereafter. Subject 3 had impaired glucose tolerance at six years of age, and frank diabetes developed at eight years of age.

Glucose, Insulin, and C-Peptide Responses to an Oral Glucose Challenge

Fasting plasma glucose levels were similar in the children irrespective of whether their glucose tolerance was normal or impaired (Figure 1). In contrast, the adolescents with impaired glucose tolerance had higher fasting plasma glucose levels (90±1 mg per deciliter [5.0±0.06 mmol per liter]) than those with normal glucose tolerance (82±1 mg per deciliter [4.6±0.06 mmol per liter], P=0.03), and adolescents with type 2 diabetes had the highest fasting plasma glucose levels (118±6 mg per deciliter [6.6±0.33 mmol per liter], P<0.001). After the oral glucose-tolerance test, plasma glucose levels were higher in both children and adolescents with impaired glucose tolerance than in those with normal glucose tolerance and highest in subjects with frank diabetes (P<0.001). Fasting plasma insulin and C-peptide levels (Table 2) were higher in both children and adolescents with impaired glucose tolerance or diabetes than in subjects with normal glucose tolerance, even after adjustment for differences in the body-mass index. Similarly, the plasma insulin and C-peptide responses to oral glucose-tolerance testing were dramatically elevated in children and adolescents with impaired glucose tolerance as compared with the responses in those with normal glucose tolerance. In contrast, adolescents with silent diabetes had insulin and C-peptide responses similar to the responses in those with normal glucose tolerance.

View larger version (21K): [in this window] [in a new window]   Figure 1. Mean (±SE) Plasma Glucose, Insulin, and C-Peptide Responses during the Oral Glucose-Tolerance Test in Obese Children (Panel A) and Adolescents (Panel B) with Normal Glucose Tolerance, Impaired Glucose Tolerance, or Type 2 Diabetes Mellitus. Glucose (1.75 mg per kilogram) was administered at time 0. To convert values for glucose to millimoles per liter, multiply by 0.05551; to convert values for insulin to picomoles per liter, multiply by 6; to convert values for C peptide to nanomoles per liter, multiply by 0.331.

 
Fasting Insulin and Proinsulin

Fasting proinsulin levels were nearly twice as high in children and adolescents with impaired glucose tolerance and diabetes as in those with normal glucose tolerance (P<0.002) (Figure 2). The mean plasma proinsulin level was 1.6±0.02 ng per milliliter in children with normal glucose tolerance, as compared with 2.6±0.02 ng per milliliter in those with impaired glucose tolerance (P=0.002). The mean ratio of proinsulin to insulin was 0.11±0.005 in children with normal glucose tolerance and 0.17±0.01 in those with abnormal glucose tolerance. The fasting plasma proinsulin level was 2.4±0.01 ng per milliliter in adolescents with normal glucose tolerance, 4.5±0.06 ng per milliliter in those with impaired glucose tolerance, and 6.2±0.12 in those with diabetes (P=0.002 for both comparisons with the adolescents with normal glucose tolerance). The ratio of proinsulin to insulin was 0.16±0.002 in adolescents with normal glucose tolerance, 0.17±0.02 in those with impaired glucose tolerance, and 0.23±0.06 in those with diabetes (P=0.30 for both comparisons with the adolescents with normal glucose tolerance).

View larger version (28K): [in this window] [in a new window]   Figure 2. Mean (±SE) Fasting Insulin and Proinsulin Levels and Proinsulin-to-Insulin Ratio in Obese Children (Panel A) and Adolescents (Panel B) with Normal Glucose Tolerance (NGT), Impaired Glucose Tolerance (IGT), or Type 2 Diabetes Mellitus (DM). To convert values for insulin to picomoles per liter, multiply by 6; to convert values for proinsulin to picomoles per liter, multiply by 0.00939.

 
Early-Phase Insulin Secretion and Insulin Resistance

Impaired glucose tolerance in children was not associated with significant differences in the early changes in the glucose level, the insulin level, or the insulinogenic index (Figure 3). In contrast, among adolescents with impaired glucose tolerance, there were changes in the plasma glucose level at 30 minutes that were significantly greater than those that occurred in adolescents with normal glucose tolerance, although these changes were not associated with a significant increase in plasma insulin levels. Consequently, the calculated insulinogenic index was slightly but not significantly lower than that among adolescents with normal glucose tolerance (P=0.09). On the other hand, a significant reduction in the insulinogenic index was clearly observed among the adolescents with type 2 diabetes. After adjustment for differences in age and body-mass index, the subjects with glucose intolerance or diabetes had a significantly higher insulin-resistance index than did those with normal glucose tolerance (P<0.001) (Table 2).

View larger version (26K): [in this window] [in a new window]   Figure 3. Mean (±SE) Changes from Base Line to 30 Minutes in Plasma Glucose and Insulin Levels and the Ratio of the Change in Insulin to the Change in Glucose (the Insulinogenic Index) in Obese Children and Adolescents with Normal Glucose Tolerance (NGT), Impaired Glucose Tolerance (IGT), or Type 2 Diabetes Mellitus (DM). To convert values for glucose to millimoles per liter, multiply by 0.05551; to convert values for insulin to picomoles per liter, multiply by 6.

 
Cardiovascular Risk Factors

Fasting lipid and lipoprotein profiles were similar in all groups, except that the fasting triglyceride levels were higher among the adolescents with impaired glucose tolerance than among those with normal glucose tolerance (150±20 vs. 115±7 mg per deciliter [1.7±0.2 vs. 1.3±0.08 mmol per liter], P=0.05). No differences in systolic and diastolic blood pressure were observed between children or adolescents with normal glucose tolerance and those with impaired glucose tolerance.

Risk Factors Associated with Impaired Glucose Tolerance

Risk factors associated with the presence of impaired glucose tolerance included in the logistic-regression analysis were the body-mass index, age, the insulinogenic index (as a categorical variable), the fasting plasma insulin and proinsulin levels, the two-hour insulin levels, and the insulin-resistance index. Body-mass index, age, and the insulinogenic index did not significantly predict impaired glucose tolerance. However, the insulin-resistance index strongly predicted the two-hour glucose level, with an odds ratio for impaired glucose tolerance of 1.27 (95 percent confidence interval, 1.15 to 1.40) per increment of 0.24 in the insulin-resistance index (P<0.001); other predictors, in order of predictive power, were the fasting proinsulin level, the two-hour insulin level, and the fasting insulin level. A positive, continuous relation was found in the entire cohort between the insulin-resistance index and the two-hour glucose level (r=0.42, P<0.001).

Discussion

In a multiethnic cohort of obese children and adolescents, we found a high prevalence of impaired glucose tolerance. Previously undiagnosed type 2 diabetes was detected only among the adolescents (4 percent), and all four subjects with diabetes were members of minorities. Children and adolescents with impaired glucose tolerance included both white and minority children. The risk factors associated with impaired glucose tolerance included insulin resistance, marked hyperinsulinemia both after fasting and after a glucose challenge, and hyperproinsulinemia after fasting. Like Arslanian et al.,²¹ we also found impaired glucose tolerance in some obese adolescents with the polycystic ovary syndrome. On the other hand, our study did not confirm that a family history of type 2 diabetes is a risk factor for impaired glucose tolerance, perhaps because we studied a group of high-risk obese children and adolescents. Although children and adolescents with mildly impaired glucose tolerance provide a unique model that can help us identify the early events that lead to diabetes without the confounding effects of aging and hyperglycemia, there is little information available about risk factors associated with impaired glucose tolerance in young persons. Our data indicate that insulin resistance is a strong predictor of the two-hour plasma glucose levels in obese children and adolescents. Thus, it may play an important part in the transition from normal to impaired glucose tolerance.

The degree of obesity was not found to be a significant risk factor, possibly because the majority of our subjects were severely obese. The effects of obesity on the deterioration of glucose tolerance are most likely mediated by its metabolic complications — particularly insulin resistance and hyperinsulinemia. Similar findings have been reported among adult Pima Indians²² and Mexican-American adults.²³ Although longitudinal studies are required to determine the sequence of events involved in the transitions from normal to impaired glucose tolerance and from glucose intolerance to diabetes, our study suggests that the onset of impaired glucose tolerance in obese children and adolescents is clearly associated with the development of severe insulin resistance while normal beta-cell function is still relatively preserved. In the presence of overt diabetes, insulin secretion declines, as demonstrated by the lower insulin levels during the oral glucose-tolerance test in the adolescents with type 2 diabetes.

The loss of the first phase of insulin secretion has important pathogenic consequences, since it plays a key part in priming insulin action in target tissues that are responsible for normal glucose homeostasis.^24,25 As a marker of early beta-cell response, we used the insulinogenic index, which was partially preserved in the adolescents with impaired glucose tolerance, whereas it was significantly reduced in the presence of frank diabetes. To further evaluate beta-cell function early in the prediabetic stage in obese children, we measured proinsulin levels and calculated the ratios of proinsulin to insulin. Disproportionate hyperproinsulinemia is a clear marker of beta-cell dysfunction in overt type 2 diabetes.^8,9,26 In Japanese-American men,²⁷ Mexicans,²⁸ and elderly white persons,²⁹ increased proinsulin levels have been found to predict the development of type 2 diabetes. In this study, fasting proinsulin levels were increased in children with impaired glucose tolerance, but their proinsulin-to-insulin ratios did not differ significantly from the ratios among those with normal glucose tolerance. Thus, in the very early stages of glucose intolerance in children and adolescents, despite the increased demand for beta-cell secretion, the hyperproinsulinemia is proportional to the hyperinsulinemia. The vigorous hyperinsulinemic response to glucose found in the prediabetic stage in obese children and adolescents may reflect an up-regulation of beta-cell function caused by chronic severe insulin resistance. Such a degree of hyperinsulinemia is not present in adults with impaired glucose tolerance.³⁰ It is conceivable that advanced age, together with changes in the size and mass of beta cells, the accumulation of amyloid in the islets, or both may contribute to the phenotypic expression of impaired insulin secretion that is found in some adults with impaired glucose tolerance.^8,24

The oral glucose-tolerance test is a labor-intensive method for studying carbohydrate metabolism. Unquestionably, the fasting plasma glucose level is easier and faster to measure, and its measurement is more acceptable to patients than an oral glucose-tolerance test. In our cohort of obese children and adolescents with impaired glucose tolerance, the prevalence of impaired fasting glucose levels (more than 110 mg per deciliter or 6 mmol per liter) was extremely low (less than 0.08 percent), whereas all four adolescents with diabetes had impaired fasting glucose levels. This suggests that fasting hyperglycemia is indicative of a more advanced stage of clinical diabetes, and the determination of its presence represents a very insensitive method for detecting impaired glucose tolerance. Similar findings on the low prevalence of impaired fasting glucose levels in adolescents have recently been reported by Fagot-Compagna et al.³¹ Our study suggests that the oral glucose-tolerance test can reliably establish a diagnosis of impaired glucose tolerance, since the intraperson variation was low in obese children and adolescents. This test may be required for the early detection of impaired glucose tolerance as well as of silent type 2 diabetes in patients with severe childhood obesity.

In summary, this cross-sectional study suggests that insulin resistance, initially associated with hyperinsulinemia and hyperproinsulinemia, is the most important risk factor linked to the development of impaired glucose tolerance in severe childhood obesity. In the presence of established diabetes, beta-cell failure becomes fully manifest.

Supported by grants (RO1 HD-28016 [to Dr. Caprio], RO1 HD 40787 [to Dr. Caprio], K24HD01464 [to Dr. Caprio], MO1 RR 00125, and MO1 RR 06022) from the National Institutes of Health.

We are indebted to all the children and adolescents who participated in the study; to Aida Grozman and Andrea Belous for technical assistance in measuring all hormones; and to Nancy Canetti for assistance in the preparation of the manuscript.

Source Information

From the Departments of Pediatrics (R.S., W.V.T., V.R., S.T., G.B., S.C.) and Internal Medicine (R.S.S.), the Children's General Clinical Research Center (G.F., B.T., B.B., K.A., M.S.), and the Division of Biostatistics, Department of Epidemiology and Public Health (G.F.), Yale University School of Medicine, New Haven, Conn.

Address reprint requests to Dr. Caprio at the Department of Pediatrics, Yale University School of Medicine, 333 Cedar St., P.O. Box 208064, New Haven, CT 06520, or at sonia.caprio{at}yale.edu.

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Abstract PDF PDA Full Text PowerPoint Slide Set Editorial by Rocchini, A. P. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article Related Article by Goran, M. I. PubMed Citation

Related Letters:

Impaired Glucose Tolerance in Obese Children and Adolescents
Goran M. I., Uwaifo G. I., Elberg J., Yanovski J. A., Invitti C., Gilardini L., Viberti G., Speiser P. W., Gaenzer H., Caprio S., Rocchini A. P.
Extract | Full Text | PDF  
N Engl J Med 2002; 347:290-292, Jul 25, 2002. Correspondence

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