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*Diabetes
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5469-5476
Copyright © 2004 by The Endocrine Society

ß-Cell Function and Insulin Sensitivity in Early Adolescence: Association with Body Fatness and Family History of Type 2 Diabetes Mellitus

Michael Rosenbaum, Cathy Nonas, Mary Horlick, Ilene Fennoy, Ileana Vargas, Holly Schachner, Patricia Kringas, Kristi Stanton and Richard Weil and the El Camino Diabetes Prevention Group

Department of Pediatrics, New York Presbyterian Medical Center (M.R., M.H., I.F., I.V., H.S., P.K., K.S.), and Departments of Pediatrics, Nutrition and Exercise Physiology, St. Luke’s/Roosevelt Hospital Medical Center (C.N., R.W.), New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Michael Rosenbaum, Room 620, Division of Molecular Genetics, Russ Berrie Medical Science Pavilion, 6th Floor, 1150 St. Nicholas Avenue, New York, New York 10032. E-mail: mr475{at}columbia.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The prevalence of type 2 diabetes mellitus (T2DM) among adolescents has increased 5- to 10-fold over the past decade. T2DM results from pancreatic ß-cell dysfunction and insulin resistance. Using rapid iv glucose tolerance testing, we examined ß-cell function and insulin resistance in 72 predominantly Latino eighth grade students (41 males and 31 females; mean ± SEM age, 13.6 ± 0.1 yr). Thirty-six percent of the children had body mass indexes above the 85th percentile for age and gender, and 50% had a first- or second-degree relative with T2DM. Overweight children were five times more likely to be in the highest quartile for insulin resistance. Children with a family history of T2DM were five times more likely to be in the lowest quartile for insulin secretory capacity, 4.5 times more likely to be in the lowest quartile for glucose disposal, and three times more likely to be in the lowest quartile for insulin resistance. These findings are consistent with a model for the physiology of T2DM in which a familial ß-cell dysfunction is unmasked by increasing insulin resistance secondary to overweight in this predominantly Latino population.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREVALENCE OF type 2 diabetes mellitus (T2DM) among children has increased 5- to 10-fold over the past decade. T2DM has become a pediatric disease, whose burden falls disproportionately on African- and Hispanic-Americans in whom between 25% and 50% of new-onset childhood diabetics are now type 2 (1, 2, 3).

T2DM is a complex metabolic disorder reflecting, in most instances, interactions among genes that influence an individual’s susceptibility to diabetes and an environment that favors the expression of that susceptibility by providing easy access to calorically dense foods and opportunities for a sedentary lifestyle (4, 5). Both impaired ß-cell function and insulin resistance are independently associated with an increased risk of T2DM (3, 6). In euglycemic offspring of diabetic patients at the Joslin Diabetes Center, an elevated fasting insulin level was associated with a 5-fold increased risk of developing T2DM over 25 yr (7). In studies of adults with a strong family history of T2DM, impaired pancreatic islet cell function is the first identifiable metabolic abnormality in some subjects who subsequently develop T2DM, whereas in other populations, insulin resistance is the first identifiable phenotype (8, 9, 10).

Obesity is clearly a major risk factor for T2DM in adolescents (1), and adiposity accounts for approximately 55% of the variance in insulin sensitivity in children, as measured by glucose disposal rate during a hyperinsulinemic-euglycemic clamp (11). These data along with the observation that subjects may be insulin resistant or have impaired ß-cell function yet may not go on to develop T2DM (10) suggest that T2DM is due to a combination of insulin resistance and impaired ß-cell ability to respond to that state of insulin resistance. In this sense, a state of relative insulin resistance or the expression of an underlying tendency toward conditions associated with insulin resistance (the major causes of which in adolescence would be pubertal hormonal changes and/or obesity) may act to unmask a prediabetic state of impaired insulin secretion in some individuals.

If this model is correct, and T2DM develops when an underlying ß-cell defect becomes pathologically significant due to increased insulin resistance, then intervention to increase insulin sensitivity in an individual predisposed to develop T2DM by virtue of having impaired ß-cell function would preserve that ß-cell function. In studies of adults at high risk for T2DM by virtue of impaired glucose tolerance (12) or a history of gestational diabetes (13), institution of lifestyle (12) or pharmacological (13) therapy to decrease insulin resistance is associated with a 50–60% decrease in the likelihood of progression to T2DM over 3–4 yr.

If the full-blown diabetic phenotype is allowed to develop, the secondary effects of hyperglycemia and hyperlipidemia on ß-cells, muscle, and liver make it virtually impossible to resolve the primary contributions of ß-cell function and muscle/liver insulin resistance (14, 15). To avoid the confounding effects of gluco- and lipotoxicity on measures of ß-cell function, these prediabetic traits are most effectively examined in individuals who are not diabetic. In a group of predominantly Latino children in early adolescence, we examined isolated prediabetic phenotypes (ß-cell dysfunction and insulin resistance) using a modified version of the iv glucose tolerance test to test the hypothesis that insulin resistance reflects adiposity whereas impaired ß-cell function is more closely associated with a family history of T2DM.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

One hundred twenty-five eighth grade students in a predominantly Hispanic-American junior high school in northern Manhattan were invited to participate in a study of the effects of an exercise and health and nutrition education program on prediabetic phenotypes. Approval for these studies was obtained from the New York City school board, the New York City Board of Health, and the institutional review board of Columbia Presbyterian Medical Center and are consistent with guiding principles for research involving humans (16). Written informed consent was obtained from all parents, and written informed assent was obtained from all students. We conducted initial interviews, including family history and medical history (from students and parents), and performed height and weight measurements as well as measurement of body fat by bioimpedance Omron Body Fat Analyzer HBF-300 (Omron Health Care, Inc., Vernon Hills, IL) in all students (n = 125). Student assent and parental consent were obtained from a total of 72 subjects. As shown in Table 1Go, the distribution of somatotypes and family history of T2DM were not significantly different between subjects who participated in this study and the class as a whole. Subjects were characterized as overweight vs. not overweight if body mass index [BMI; weight (kilograms)/height (meters)2] was greater than the 85% percentile for age and sex based on data from National Health Education Survey (NHES) II and III and National Health and Nutrition Education Survey (NHANES) I, II, and III (17). Subjects were characterized as having a family history of T2DM if they reported a first- or second-degree relative with the disease who was currently undergoing treatment for T2DM and, in the case of a deceased relative, in whom the presence of T2DM could be confirmed by parental interview. Data regarding family history of diabetes were verified by direct telephone contact with the parents of each child. Based on data from NHANES III, it is estimated that approximately 20% of Hispanic-American are known type 2 diabetics, although the prevalence may be higher due to undiagnosed disease (18). It should be emphasized that it is possible that within the population reported here, there may be family members who have diabetes but are unaware of it. Direct testing was not performed on family members. Subject characteristics are presented in Table 1Go.


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  		TABLE 1. Characteristics of study population and entire class

 
Testing

Subjects underwent a rapid iv glucose tolerance test (6). Students and their parents were contacted the night before and reminded not to eat breakfast or consume any foods or beverages except for water on the morning of testing. Testing was performed between 0830 and 1000 h on school grounds either in the nurse’s office or an available room. Blood was drawn in the postabsorptive state for fasting concentrations of insulin and glucose. Students then received 0.5 mg/kg glucose, iv (50% dextrose; maximum, 25 g), over 3 min, and blood was drawn through the same indwelling butterfly needle for measurement of serum insulin concentrations at 3 and 5 min after glucose administration. After completion of testing, subjects were given breakfast by the investigators before they were escorted back to their usual classes. Insulin sensitivity was defined using the quantitative insulin sensitivity check index (QUICKI), and insulin secretory capacity was defined as the acute insulin response (AIR) (6, 19, 20, 21). QUICKI is calculated as 1/(log10[fasting glucose] + log10[fasting insulin]), is well correlated with insulin sensitivity measured by oral and iv glucose tolerance testing in adults and children, and has been shown to be a reliable means of following changes in insulin sensitivity over time (21, 22, 23). AIR (mean incremental rise in plasma insulin at 3 and 5 min after an iv glucose load) correlates well with first phase insulin release measured by iv glucose tolerance testing (24). Low AIR is predictive of development of T2DM in adults (25, 26) and of progression to impaired glucose tolerance or frank T2DM in Pima Indians (6).

Assays

Glucose was measured by the hexokinase method (Glucose/HK, Roche Molecular Biochemicals, Werk Penzberg, Germany). Plasma insulin was measured by solid phase 125I RIA (Coat-a-Count; Diagnostic Products, Los Angeles, CA). The inter- and intraassay coefficients of variation for glucose are 1.2% and 1.1%, respectively. The inter- and intraassay coefficients of variation for insulin are 4.5% and 1.9%, respectively.

Statistics and calculations

Data are presented as the mean ± SEM. Insulin sensitivity and insulin release in response to a glucose load are significantly correlated (19, 26) (Fig. 1Go). To adjust AIR for the effects of insulin sensitivity, a glucose disposal index (GDI) was calculated as log10(AIR x fasting glucose concentration/fasting insulin concentration) in a manner similar to the correction of AIR using the insulin sensitivity index that is used in the minimal model iv glucose tolerance test to glucose utilization (19). As shown in Fig. 2Go, both the AIR and QUICKI, but not the GDI, were significantly correlated with BMI and percent body fat. It is notable that despite the fact that females had a significantly higher percent body fat than males (Table 1Go), the relationship between AIR, QUICKI, and GDI and body fat was not significantly different between sexes.



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  		FIG. 1. Relationship between AIR and QUICKI in subjects. The regression equation is: AIR = –11246(QUICKI) + 4557; r2 = 0.36, P < 0.0001.

 


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  		FIG. 2. Correlations of QUICKI, AIR, and GDI with measures of body fatness. A, Correlations of QUICKI (n = 72), AIR (n = 55), and GDI (n = 55) with BMI. QUICKI = –0.002(BMI) + 0.391 (r2= 0.14; P = 0.002). AIR = 37.7 (BMI) – 96.0 (r2= 0.20; P < 0.001). GDI = –0.005 (BMI) + 3.73 (r2= 0.007; not significant). B, Correlations of QUICKI (n = 68), AIR (n = 51), and GDI (n = 51) with percent body fat by bioimpedance. QUICKI = –0.0019 (% body fat) + 0.39 (r2= 0.23; P < 0.001). AIR = 27.0 (% body fat) + 110.0 (r2= 0.22; P < 0.001). GDI = –0.002 (% body fat) + 3.67 (r2= 0.003; not significant).

 
Between-group comparisons (males vs. females, overweight vs. not overweight, and family history of T2DM vs. no family history of T2DM) were made by ANOVA. Comparisons of the frequency of different phenotypes, i.e. impaired insulin resistance or ß-cell function, between groups, i.e. overweight vs. not overweight or family history of T2DM vs. no family history of T2DM, were made by {chi}2 analyses in which the frequency of subjects in each group vs. the frequency of subjects being lowest (or highest) quartile for AIR, QUICKI, and GDI were examined. Statistical significance was prospectively defined as P{alpha} < 0.05. To control for possible effects of body fatness on group differences, groups were also compared by analysis of covariance in which group was treated as a dichotomous variable (male vs. female, overweight vs. not overweight, and family history of T2DM vs. no family history of T2DM) and BMI z-score was treated as a continuous variable.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subjects

Subject characteristics are presented in Table 1Go. Fifty percent of subjects had a first or second degree relative with T2DM, and 22% of subjects had a first degree relative with T2DM. Thirty-six percent of subjects were overweight (BMI for age and sex >85th percentile). Males had a significantly lower percentage body fat than females. The demographics of subjects who participated in rapid iv glucose tolerance testing were similar to those of the class as whole. There were no significant differences in gender or body fatness between subjects who had a positive family history of T2DM and those who did not. There were no significant differences in gender or the prevalence of relatives with T2DM between subjects who were overweight and those who were not (Table 2Go), although there was a trend for those with a family history of T2DM to have a higher BMI than those without a family history of T2DM (P = 0.08), and individuals who had a first degree relative with T2DM had a significantly higher BMI than those with only second degree diabetic relatives.


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  		TABLE 2. Study population subgroups

 
Testing

QUICKI data, calculated from fasting glucose and insulin values, were obtained from 72 subjects. The AIR, calculated as the mean rise in circulating insulin concentrations above baseline at 3 and 5 min after the administration of iv glucose, was determined for 55 of 72 subjects. Incomplete datasets were due to poor venous access and/or possible infiltrates during glucose administration (n = 11) or requests by students to stop the test because they felt nauseated (n = 6, note that all of these subjects complained of nausea at the sight of their own blood, and none received iv glucose). Standards related to gender, age, and ethnic group for QUICKI and AIR are not available for children, although QUICKI and AIR are closely correlated to insulin resistance and insulin secretory capacity, respectively, as measured by iv and oral glucose tolerance testing (19, 21, 27, 28). The population was divided into quartiles for QUICKI, AIR, and GDI values (Table 4Go and Figs. 3–5GoGoGo).


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  		TABLE 4. Mean (SEM) and range for quartiles for QUICKI (n = 72), AIR (n = 55), and GDI (n = 55) and distribution of subjects by gender, overweight vs. not overweight, family history of T2DM vs. no family history of T2DM, and fraction in the lowest quartile for other assessments of insulin sensitivity (QUICKI), insulin secretory capacity (AIR), and glucose disposal (GDI)

 


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  		FIG. 3. Effects of gender on distribution of QUICKI, AIR, and GDI data. Data were divided into quartiles, and the percentages of total males ({diamondsuit}) and females ({circ}) falling within each quartile were graphed. QUICKI data reflect 40 males and 32 females. AIR and GDI data reflect 32 males and 23 females. No significant effects of gender on data distribution were noted. See Table 4Go for quartile values.

 


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  		FIG. 4. Effects of overweight ({diamondsuit}) vs. not overweight ({circ}) on distribution of QUICKI, AIR, and GDI data. Data were divided into quartiles, and the percentages of total overweight and nonoverweight subjects falling within each quartile were graphed. QUICKI data reflect 23 overweight and 39 nonoverweight subjects. AIR and GDI data reflect 20 overweight and 35 nonoverweight subjects. Overweight subjects were five times more likely to have high AIR and low QUICK (both P < 0.05). See Table 4Go for quartile values.

 


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  		FIG. 5. Effects of family history of T2DM ({diamondsuit}) vs. no family history of T2DM or overweight (•) on distribution of QUICKI, AIR, and GDI data. Data were divided into quartiles, and the percentages of total subjects with and without a family history of T2DM falling within each quartile were graphed. QUICKI data reflect 36 subjects with a family history of T2DM and 36 subjects with no family history of T2DM. AIR and GDI data reflect 29 subjects with a family history of T2DM and 26 subjects with no family history of T2DM. Subjects with a family history of T2DM were 4.5 times more likely to have low AIR, four times more likely to have low GDI (both P < 0.05), and three times more likely to have low QUICKI (P = 0.08). See Table 4Go for quartile values.

 
No significant effects of gender on QUICKI, AIR, or GDI were noted (Table 3Go and Fig. 3Go). As shown in Fig. 1Go and as reported by others (19), the ß-cell insulin secretory capacity (AIR) was significantly correlated with insulin sensitivity (QUICKI). QUICKI was lower, and AIR was higher, in subjects who were overweight (see Table 3Go and Fig. 4Go). When adjusted for insulin sensitivity (QUICKI), there was no significant difference in glucose disposal, as measured by GDI, between overweight and nonoverweight children.


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  		TABLE 3. Results of testing for fasting glucose, fasting insulin, QUICKI, insulin secretory capacity (AIR), and GDI

 
QUICKI, GDI, and AIR were significantly lower in subjects with a first- or second-degree relative with T2DM (Table 3Go and Fig. 5Go). Effects on QUICKI, GDI, and AIR of family history of T2DM were analyzed by analysis of covariance to correct for BMI z-score. There was no significant group effect (family history T2DM vs. no family history T2DM) on QUICKI (P = 0.10), but AIR (P = 0.03) and GDI (P = 0.025) were still significantly lower in subjects with a family history of T2DM.

Overweight children were five times more likely to be in the lowest quartile for QUICKI (P = 0.009) and in the highest quartile for AIR (P = 0.016). Children with a family history of T2DM were five times more likely to be in the lowest quartile for AIR (P = 0.016), 4.5 times more likely to be in the lowest quartile for glucose disposal (P = 0.035), and three times more likely to be in the lowest quartile for insulin resistance (P = 0.08; Figs. 4Go and 5Go). Overall, even when data from all quartiles are shown, overweight subjects tended to be in the lower quartiles for QUICKI and higher quartiles for AIR, whereas subjects with a family history of T2DM tended to be in the lower quartiles for AIR and GDI and, to a lesser extent, QUICKI (Table 4Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The following conclusions were drawn from these data. 1) In this particular population (Latino with a high frequency of obesity and of family history of T2DM), impaired ß-cell function is closely associated with a family history of T2DM, independent of body fatness, whereas insulin resistance is not. The association of impaired ß-cell function with a family history of T2DM suggests that early ß-cell dysfunction probably reflects a predisposing genetic diathesis. Insulin resistance, resulting primarily from increased body fat, potentiates and unmasks impaired ß-cell function in those children with low AIR and GDI. 2) In this particular population, insulin resistance is apparently due to overweight (increased fatness), whereas impaired ß-cell function is not.

Genetic susceptibility to T2DM is probably conveyed by alleles of genes that directly or indirectly mediate tissue responses to insulin and the function, production, and survival of pancreatic ß-cells (10). Insulin resistance and ß-cell function have been reported to be impaired in 40–50% of first-degree, euglycemic, adult relatives of patients with T2DM (8, 29). Although none of the children in this study was frankly diabetic, insulin release by ß-cells after iv glucose administration (AIR) was significantly lower in children with a family history of T2DM even when corrected for insulin resistance and BMI using the derived glucose disposal index.

Obesity exerts a powerful effect on insulin sensitivity, and body fatness is therefore a part of the environment within which the pancreatic ß-cells must function. Obesity is the major risk factor for T2DM in adolescents, and, as in adults, 50–90% of children with T2DM have a BMI above the 85th percentile for age and gender (1, 30, 31). Using the glucose disposal rate during a 2-min hyperinsulinemic-euglycemic clamp, Arslanian et al. (11) found that adiposity accounted for 55% of the variance in insulin sensitivity in children. We found that 30% of overweight children, defined as a BMI greater than the 85th percentile for age and sex (17), were insulin resistant using a QUICKI value of less than 0.30 as an indicator of insulin resistance, as reported by others (21, 22, 27, 32). Similarly, Sinha et al. (2) reported that 25% of obese children, defined as a BMI above the 95th percentile for age and sex, had silent T2DM or impaired glucose tolerance (defined using the homeostasis model assessment).

The relative genetic contributions to states of impaired ß-cell function and insulin sensitivity probably vary among ethnic groups. The molecular mapping of diabetes phenotypes is consistent with this hypothesis, because the location of linkage signals varies by ethnicity (33, 34, 35, 36, 37, 38). First degree relatives of T2DM patients of northern European ancestry show decreased maximal, phase 1, and/or phase 2 insulin release even in the setting of normal insulin sensitivity (8, 29, 39, 40). In contrast, among African-Americans, insulin resistance, without impaired ß-cell function, has been reported to be the first identifiable phenotype in subjects who go on to become diabetic (9, 41, 42). In the Pima Indians of Arizona, insulin resistance and impaired ß-cell function are independent risk factors for subsequent T2DM (6, 43, 44).

In 21 pairs of prepubertal children who were matched for ethnicity, age, gender, and fat mass and grouped by positive vs. negative family history of T2DM, Goran et al. (45) recently reported no effect of family history of T2DM on insulin sensitivity, AIR, or glucose deposition index measured by iv glucose tolerance. However, Goran et al. (45) studied a population that was younger (mean age, 9.6 yr) and more ethnically diverse (38% non-Hispanic white, 24% African-American, 29% Latino, and 9% other) than the population studied here. The association of decreased pancreatic ß-cell function with a family history of diabetes in this study, but not Goran’s, may be due to ethnic and/or age differences in the populations studied. Ethnicity, as reflected in genetic admixture, and socioeconomic status have both been shown to be significantly related to AIR (46). We specifically targeted an ethnically and socioeconomically homogenous population of children at high risk of T2DM by virtue of ethnicity (Latino) and age (the metabolic stress of early to midpuberty), whereas Goran et al. (45) examined a more ethnically and socioeconomically diverse prepubertal population.

In summary, we used a rapid iv glucose tolerance test to screen a population of 12- to 15-yr-old students for insulin resistance and impaired ß-cell function. Evidence of impaired ß-cell function was closely associated with a family history of T2DM. The degree of insulin resistance was closely related to the degree of adiposity. In the children studied here, the major familial influence on T2DM susceptibility appeared to be conveyed by effects on ß-cell function and not insulin resistance. These findings are consistent with a model for the physiology of T2DM in which a familial ß-cell dysfunction is unmasked by insulin resistance secondary to overweight in this predominantly Latino population. These results also suggest that efforts to enhance insulin sensitivity by weight loss and/or exercise would reduce the incidence of T2DM in these children.


   Acknowledgments
 
The El Camino Diabetes Prevention Group also included Ms. Ellen Murphy, Mr. Andrew Siris, Dr. Sanobar Parkar, Dr. Daisy Chin, Dr. Robin Goland, Dr. Sharon Oberfield, and Dr. Rudolph L. Leibel at New York Presbyterian Medical Center, and Mr. Lawrence Lynch, Ms. Maria Guillermo, Ms. Bianca Tirrito, Ms. Marisol Rosario, Mr. David Getz, and Mr. Joshua Raskin within the New York City public school system. We acknowledge Dr. John O’Connor, Director of the Core laboratory of Columbia Presbyterian Medical Center General Clinical Research Center, and his staff for performing laboratory analyses, and Dr. Beverly Diamond for her assistance with statistical analyses. We also thank the New York City Board of Education, especially Dr. Henry Solomon, and Ms. Ronnie Watman for their support of this study. We particularly acknowledge the parents of all of the students who participated in this study for their recognition of the incredible social, medical, and economic costs of T2DM in the United States.


   Footnotes
 
This work was supported in part by NIH Grants RR-00645 and DK-63068 and funds provided by the Barry Foundation and Guardian Mutual Research.

Abbreviations: AIR, Acute insulin response; BMI, body mass index; GDI, glucose disposal index; QUICKI, quantitative insulin sensitivity check index; T2DM, type 2 diabetes mellitus.

Received May 21, 2004.

Accepted August 17, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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