DESCRIPTION. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This descnption is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED.
The increased prevalence of
type 2 diabetes among children is attributed to a simultaneous increase in
childhood obesity. Most children are diagnosed during puberty. Ethnic minority
children, such as Native Americans, African Americans, and Hispanics, are disproportionately
affected. Asians represent a rapidly growing minority group in the
The overall aim of this study is to better understand in children the metabolic changes that precede the development of type 2 diabetes, and the influence of Asian ethnicity on diabetes risk. The specific aims of this project are: 1) to describe the metabolic changes and adipose factors that are associated. with the insulin resistance metabolic syndrome in prepubertal children; 2) to describe the relationship between pancreatic islet B-cell function and family history of type 2 diabetes; 3) to describe changes in these factors as children progress through puberty; 4) to describe the relationship of diet and physical activity to the metabolic and adipose factors; and 5) to describe the relationship between Japanese ancestry and metabolic, adipose, and insulin secretion factors. To accomplish these goals, a longitudinal cohort study of 450 prepubertal (8-10 year old) nondiabetic Japanese-American and Caucasian children is proposed. Measurements at baseline and 2 year follow-up will include: lipids and LDL particle size, insulin, C-peptide, proinsulin, glucose tolerance and insulin secretion determined by an intravenous glucose tolerance test, plasminogen activator inhibitor-1, fibrinogen, C-reactive protein, insulin-like growth factor-1 and insulin-like growth factor binding protein-3, body composition by DEXA, and intra-abdominal fat by MRI.
This study will improve the understanding of how pubertal changes in metabolic and adipose factors affect diabetes risk in Asian and Caucasian children.
PERFORMANCE SITE(S) (organization, city, state)
KEY PERSONNEL See instructions on Page 11. Use continuation pages as needed to provide the required information in the format shown below.
Name Organization Role on Project
The increased prevalence of type 2
diabetes among children is attributed to a simultaneous increase in childhood
obesity. Many ethnic minority groups are
known to be at increased risk for type 2 diabetes in adulthood, yet relatively
little is known about the risk factors that precede this condition among ethnic
minority youth. Asians represent a
rapidly growing minority group in the
The long-term aim of this study is to better understand in children the metabolic changes that precede the development of type 2 diabetes, and the influence of Asian ethnicity on diabetes risk. This proposal extends the Japanese American Community Diabetes Study to create a separate, longitudinal study of prepubertal children of varying proportions of Japanese ancestry (ranging from 0 to 100%) who will be followed into and through puberty.
Specific Aim 1: To describe in prepubertal (8-10 years), nondiabetic children the metabolic and adipose factors that are associated with the insulin resistance metabolic syndrome. These include fasting plasma lipids (cholesterol, triglycerides, HDL-cholesterol, and LDL-cholesterol), LDL particle size, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, C-reactive protein, glucose, insulin, C-peptide, and proinsulin; glucose tolerance assessed as glucose disappearance rate constant (KG) during an intravenous glucose tolerance test; body composition by DEXA; body fat distribution by MRI; and body mass index.
Hypothesis 1: Features of the metabolic syndrome are evident in some prepubertal children.
Specific Aim 2: To assess variation in pancreatic islet ß-cell function by measuring fasting plasma insulin, C-peptide, proinsulin, and acute insulin response to glucose (AIRg) by an intravenous glucose tolerance test.
Hypothesis 2: Glucose-stimulated insulin secretion is lower among children with a family history of type 2 diabetes.
Specific Aim 3: To describe the changes in these factors as children progress through and complete puberty. Tanner staging is used and plasma testosterone, estradiol, DHEA-S, IGF-1, and IGFBP-3 are measured.
Hypothesis 3: Puberty is associated with changes in body fat distribution and metabolic parameters in a direction consistent with higher risk of glucose intolerance and cardiovascular disease.
Specific Aim 4: To describe the relationship of lifestyle factors (diet and physical activity) to the metabolic and adipose factors, and changes therein.
Hypothesis 4: Diet and physical activity are important predictors of adiposity and metabolic changes in children.
Specific Aim 5: To describe the relationship of proportion of Japanese ancestry to the metabolic and adipose factors, and changes therein.
Hypothesis 5: A higher proportion of Japanese ancestry is associated with a greater predisposition to the metabolic syndrome and diminished insulin secretion.
B. BACKGROUND AND SIGNIFICANCE
B1. EPIDEMIOLOGY OF TYPE 2 DIABETES IN CHILDREN
· Increasing Incidence of Childhood Type 2 Diabetes.
The natural history of type 2 diabetes is characterized by both insulin resistance and islet ß-cell dysfunction, and hyperglycemia usually develops gradually. Thus, it is relatively asymptomatic in its early stages. Type 2 diabetes is often associated with obesity. In contrast, the pathophysiology of type 1 diabetes is completely different. Type 1 diabetes results from insulin deficiency due to autoimmune islet ß-cell destruction, and is thus often associated with autoantibodies to islet ß-cell components and contents. Unlike type 2 diabetes, the onset of type 1 diabetes is often precipitous with prominent diabetic symptoms, often including ketoacidosis. The majority of children with diabetes have type 1. Prior to the 1990's, there were only a few reports of childhood type 2 diabetes, which has therefore been considered a disease of adults. However, although population-based data are sparse, there is consensus that the incidence of type 2 diabetes among children and adolescents has increased in recent years [1-4]. This trend is attributed to increasing rates of childhood obesity and physical inactivity.
· Lifestyle and Childhood Obesity
The prevalence of childhood obesity in the
· Risk Factors for Childhood Type 2 Diabetes
In general, the risk factors for type 2 diabetes among children are similar to those reported for adults. Adolescents are affected more often than younger children, with an average age at diagnosis of about 13.5 years . This suggests that body composition and/or metabolic changes during puberty play an important role in the onset of diabetes. About 95% of affected children are ³ 85th age- and sex-specific percentile for body mass index (BMI), and most have a family history of type 2 diabetes [2, 5]. A strong association between acanthosis nigricans and childhood type 2 diabetes has also been reported [2, 5, 6]. As with adults, Hispanic [17, 18], African-American [5, 6], and Native-American [19, 20] children appear to be disproportionately affected. Several studies have shown a gender discrepancy, with more girls affected than boys , an observation that is consistent with the earlier onset of puberty in girls.
· Lack of Information on Asian-American Children Despite Increased Risk in Asian Adults.
There are little population-based health data available on Asian Americans, and this is especially true for Asian-American children. Yet Asians are the fastest growing ethnic minority population in the United States . Despite having a lower average BMI than Caucasians, South Asian adults living in the United Kingdom are 4 times as likely to have diabetes . The prevalence of self-reported, physician diagnosed diabetes in residents of Hawaii is lowest in Caucasians (2.7%), highest in Japanese Americans (6.4%), and intermediate in those of Chinese (3.5%), Filipino (4.6%), and Native Hawaiian (4.7%) ancestry . The increased risk of diabetes among Asians has been associated with a propensity for central or visceral adiposity [24-26]. Thus, there is reason to suspect that Asian-American children, particularly those who have adopted a western lifestyle, are at increased risk for diabetes.
The only published data on the incidence of type 2 diabetes in Asian children comes from Japan . In a population-based study from Tokyo, asymptomatic schoolchildren were periodically screened for glucosuria, and an oral glucose tolerance test was performed on those who screened positive. Among primary school children, diabetes incidence increased tenfold from 0.2/100,000 in 1976-1980 to 2.0/100,000 in 1991-1995. Among junior high school children, diabetes prevalence increased from 7.3/100,000 to 13.9/100, 000 during the same years. Diabetes trends mirrored upward trends in body mass index and consumption of animal fats. Thus, it appears that vulnerability to diabetes among Asians begins in childhood. It is likely that the problem is even greater in the United States, where the prevalence of childhood obesity exceeds 20% .
The pathophysiology of hyperglycemia in type 2 diabetes includes both abnormalities in islet ß-cell function and development of insulin resistance. The latter is associated with overall obesity as well as with increased accumulation of body fat centrally.
B2a. ß-cell Dysfunction
· Abnormal Glucose-Stimulated Insulin Secretion
It is well established that even with obesity and insulin resistance, euglycemia is maintained in the presence of normal ß-cells, although at the expense of hyperinsulinemia. As is true for adults, normoglycemic obese children and adolescents are insulin resistant and hypersecrete insulin [27-30]. Japanese adults with impaired glucose tolerance demonstrate both impaired insulin sensitivity and hypersecretion of insulin, particularly if they are obese . Despite hypersecretion of insulin, however, individuals with impaired glucose tolerance exhibit reduced glucose-stimulated insulin secretion relative to the degree of insulin resistance. Furthermore, the defect is even greater in persons who have type 2 diabetes. Thus, in the setting of insulin resistance, plasma glucose levels are more likely to reach values diagnostic of diabetes among individuals with abnormal ß-cell function who are unable to maintain adequate insulin secretion to compensate for insulin resistance. Although there is evidence that insulin resistance precedes the decline in insulin secretion among some individuals at high risk for type 2 diabetes , other reports suggest that impaired insulin secretion precedes or accompanies the development of insulin resistance . In Japanese adults with impaired glucose tolerance, low insulin secretion predicts progression to diabetes [34, 35].
The causes of impaired glucose-stimulated insulin secretion are not fully understood. Among adults, aging is associated with a gradual decline in insulin secretion, and may explain the increased incidence of type 2 diabetes in the elderly [27, 36]. Insulin secretion capacity may also be genetically determined. For example, insulin secretion is 65% lower among nondiabetic individuals who have an identical twin with type 2 diabetes, compared to other nondiabetic individuals . Other studies have demonstrated reduced insulin secretion among first-degree relatives of patients with type 2 diabetes compared to individuals of similar age and BMI without a family history of diabetes . Thus, it is plausible that ethnic variation in diabetes prevalence may be partly explained by genetic determinants of insulin secretion.
· Abnormal Processing of Proinsulin to Insulin
Another measure of islet ß-cell dysfunction is incomplete processing of proinsulin to insulin. Within the secretory granules of the ß-cell, two enzymes (prohormone convertases 2 and 3) process proinsulin to intermediate proinsulin split products and then to insulin plus C-peptide . If this process is abnormal, increased amounts of proinsulin and intermediate split products are present in plasma. Depending on the assay used to measure proinsulin, this increase may be measured as the plasma concentration of either proinsulin or of proinsulin plus intermediates. Individuals with type 2 diabetes secrete excess proinsulin [40, 41]. Both the concentration of proinsulin and the proportion of immunoreactive insulin attributable to proinsulin are increased. Moreover, the magnitude of the proinsulin to insulin ratio is inversely correlated with insulin secretion in patients with type 2 diabetes . Since the orderly cleavage of proinsulin appears intact in type 2 diabetes, the excess release of incompletely processed proinsulin seems to be the result of either slower conversion or reduced storage time in the ß-cell .
This abnormality of proinsulin secretion precedes the diabetic state. Individuals with impaired glucose tolerance have an elevated proinsulin to insulin ratio compared to normoglycemic individuals , and fasting proinsulin levels predict the development of diabetes [44-46]. Among normoglycemic individuals, the proinsulin level and the proinsulin to insulin ratio are inversely correlated with insulin secretion, independent of age, gender, body mass index, waist to hip ratio, and insulin sensitivity . Although it has been reported that proinsulin levels increase following hemipancreatectomy, suggesting that this may be a response to increased ß-cell demand , insulin resistance induced by administration of nicotinic acid is not accompanied by a disproportionate increase of proinsulin [49, 50]. Thus elevated proinsulin levels found with type 2 diabetes appear not to be simply a response of the ß-cell to insulin resistance, but probably represents an intrinsic abnormality of the ß-cells.
B2b. Obesity and Insulin Resistance
Increased adiposity, as measured by BMI, triceps skinfold thickness, and dual-energy x-ray absorptiometry (DEXA), is associated with increased fasting insulin levels in prepubertal and postpubertal children [29, 51-53]. As mentioned previously, normoglycemic obese children and adolescents are insulin resistant and hypersecrete insulin [27-30]. Thus, the association between obesity and insulin resistance seems to be well established in children.
· Effect of Pubertal Stage
A recent study demonstrated transient insulin resistance (measured by euglycemic clamp) during early puberty (Tanner stages 2 to 3), returning to prepubertal levels by late puberty . Girls were more insulin resistant than boys regardless of pubertal stage in this study. These findings are consistent with prior studies demonstrating lower insulin levels in prepubertal children compared to midpubertal children [54, 55]. Both sex steroids and growth hormone (and peptides related to growth hormone action) have been implicated as causing insulin resistance during puberty since both rise during puberty [56-62]. Growth hormone effects are now more commonly assessed by measurements of insulin-like growth factor-1 (IGF-1) , the peripheral hormone that mediates many of the effects of growth hormone, and insulin-like growth factor binding protein-3 (IGFBP-3) .
· Effect of Ethnicity
The effect of ethnicity has been most extensively studied in African-American and Caucasian children. In prepubertal children, insulin sensitivity (determined by a tolbutamide-modified frequently sampled intravenous glucose tolerance test with minimal modeling) was 42% lower among African-American children compared to Caucasian children . This same group reported higher fasting insulin levels in African American prepubertal children . African-American adolescent girls have higher fasting insulin levels and decreased hepatic insulin clearance compared to Caucasians . Arslanian and colleagues also showed decreased insulin sensitivity and increased insulin secretion among African-American adolescents compared to Caucasians using a 2-hour hyperglycemic clamp . In contrast, others reported that insulin resistance (measured by euglycemic clamp) was greater in pubertal Caucasian than African-American boys, but did not differ by ethnicity in pubertal girls . It remains unclear if these discrepant findings are due to differences in methodology or pubertal stage of the subjects.
B2c. Visceral Adiposity and Features of the Insulin Resistance Syndrome.
The terms insulin resistance syndrome, metabolic syndrome, and syndrome X refer to a constellation of metabolic findings associated with increased cardiovascular disease risk in adults [67-69]. These metabolic factors include hyperinsulinemia, insulin resistance, hypertension, dyslipidemia (elevated triglycerides, low HDL cholesterol, and increased amounts of small, dense LDL), and obesity. While not part of the original description, increases in hemostatic factors [70-72] and inflammatory markers such as C-reactive protein [73-75] are also associated with the insulin resistance syndrome. In adults, the insulin resistance syndrome is more strongly associated with central adiposity (particularly visceral or intra-abdominal fat) than total body adiposity or subcutaneous fat [76-85]. Since intra-abdominal fat deposition is influenced by gender and menopausal status [86-88], it is presumed that sex hormones are involved in body fat distribution. Thus, puberty may be an important milestone in determining body fat distribution.
· Prepubertal Children
A few research groups have studied the metabolic effects of intra-abdominal (visceral) fat in prepubertal children. Visceral adiposity is associated with elevated fasting insulin and triglycerides in prepubertal children [52, 89, 90]. Incremental 30-minute insulin measured during an oral glucose tolerance test is associated with visceral fat in Caucasian, but not African-American children . Insulin sensitivity (measured by a tolbutamide-modified, frequently sampled intravenous glucose tolerance test with minimal modeling), however, is associated with total fat mass but not visceral fat . The ratio of visceral to subcutaneous abdominal fat does not differ by gender prior to puberty, but is higher in Caucasian than African-American children . One longitudinal study showed that before puberty, visceral fat was associated with total and LDL cholesterol, but not with fasting insulin, insulin area during an oral glucose tolerance test, or HDL cholesterol . However, after puberty, visceral fat was associated with elevated insulin and low HDL cholesterol levels.
Only one study has examined hemostatic factors in relation to visceral adiposity in children. Fibrinogen and D-dimers were associated with percent body fat, subcutaneous fat mass, total fat mass, and BMI, whereas plasminogen activator inhibitor 1 (PAI-1) was associated with visceral fat and fat-free mass in children aged 7 to 11 .
· Pubertal Children
Studies of pubertal children show results similar to those seen in adults, with a correlation between increased visceral adiposity and hyperinsulinemia, insulin resistance, dyslipidemia, and elevated blood pressure [92, 94, 95].
Relatively little is known about how visceral fat depots change during puberty in normal children. In 16 obese, Italian children followed for 4 years, total fat mass increased significantly after puberty compared to prepubertal levels, whereas visceral fat was unchanged . Testosterone levels are positively correlated with visceral fat in girls at the time of menarche, independent of estrogen, LH, and total body fat .
B3. RATIONALE FOR STUDYING JAPANESE-AMERICAN CHILDREN
Asian Americans are a diverse population. Japanese Americans are the third most populous Asian subgroup in King County, Washington (see Table C1). Unlike other Asian subgroups, the vast majority of Japanese Americans living in this region are U.S. born and their families have resided here for several generations. This distinction is highly relevant to this study. Dietary habits are associated with duration of time in the United States . The rise in diabetes among Japanese children coincides with the adoption of a "westernized" lifestyle . Thus, in order to understand diabetes risk in Asian-American children, it is preferable to study children whose lifestyle is typically American. Findings in children of recent immigrants may vary with time since immigration, and may not be generalizable to subsequent generations. Furthermore, follow-up is likely to be enhanced by geographic and economic stability, and English proficiency will facilitate recruitment of participants.
Another important reason to focus on Japanese Americans is their history of participation in similar local studies. We have conducted the Japanese American Community Diabetes Study in adults
since 1983, with superb participation and cooperation by the Japanese-American community, and this will provide an excellent basis for recruitment of children for this study. Because of this history of participation in research, recruitment of Asians for the Diabetes Prevention Program Seattle clinical site was most successful in the Japanese-American community (personal communication, S. Kahn, Principal Investigator).
· Summary of Findings from the Japanese American Community Diabetes Study
Japanese Americans have experienced a higher prevalence of type 2 diabetes than in Japan, suggesting that factors associated with “westernization” play a role in bringing out underlying susceptibility to diabetes . Despite similar degrees of hyperglycemia, diabetic Seattle Japanese American men had significantly higher insulin levels than diabetic Tokyo men . This suggested that diabetic men in Seattle were more insulin resistant than in Tokyo. Since insulin resistance is related to body weight, it was not surprising that diabetic men in Seattle had significantly higher levels of body mass index (BMI) than diabetic men in Tokyo. After adjusting for BMI, however, fasting insulin levels were still significantly higher in Seattle than in Tokyo. We postulated that the higher prevalence of diabetes in Japanese Americans might be explained by the superimposition of insulin resistance upon a genetic background of reduced b-cell reserve but that BMI could not account fully for this difference. Subsequent research has shown the importance of the pattern of body fat distribution in conferring risk for diabetes . Diabetic Japanese Americans had significantly more intra-abdominal fat by CT scan than those persons with normal glucose tolerance . The importance of intra-abdominal fat as a risk factor for diabetes was further confirmed by prospective studies . Greater amounts of intra-abdominal fat were present prior to the development of diabetes. Other measures of adiposity such as BMI and skinfolds were not significant risk factors.
We have found a very close relationship between intra-abdominal fat and a number of metabolic features of the insulin resistance syndrome, including the insulin sensitivity index of Bergman (Si). The relationship of intra-abdominal fat with these variables was significantly positive for triglycerides and fatty acids and significantly negative for LDL flotation, HDL, and Si .
Intra-abdominal fat has also been associated with increased risk for coronary heart disease. Japanese American men with coronary heart disease had more intra-abdominal fat than individuals without coronary heart disease . We also found that intra-abdominal fat was an independent risk factor for incident coronary heart disease . Moreover, it is noteworthy that insulin levels were not independently related to incident coronary heart disease.
We have also reported that during a 75-g oral glucose tolerance test, insulin secretion in response to glucose was delayed as glucose tolerance deteriorated from normal to impaired to diabetic . This was demonstrated by a lower amount of insulin secreted at 30 minutes following the oral glucose load consistent with an impairment in glucose-stimulated insulin secretion. In addition, a defect in the processing of proinsulin accompanied type 2 diabetes in Japanese Americans. Importantly, abnormal glucose-stimulated insulin secretion  and elevated proinsulin levels  were present at baseline in Japanese Americans who subsequently developed diabetes. Hence both of these are risk factors for incident diabetes. Moreover, we have shown that the insulin secretory defect is present before the increase in visceral fat . These observations were made in men who were lean, had normal amounts of visceral fat, and were nondiabetic at baseline, and were followed for 5 years.
The development of diabetes involves the interaction of genetic risk for the disorder with environmental (lifestyle) factors. Two such factors are diet and physical activity. We found that a diet higher in animal fat and protein was being consumed by Japanese-American men with diabetes than those who did not have diabetes . Total energy intake was similar. Subsequently, we found that in those Japanese-American men with impaired glucose tolerance and a family history of diabetes, significantly higher 2-hr plasma glucose levels were present at 5 years in those men who were consuming higher amounts of animal fat and were less physically active at baseline . Furthermore, animal fat intake was significantly correlated with subsequent intra-abdominal fat gain.
Thus lifestyle factors interacting with an underlying genetic risk appear to underlie the high prevalence of diabetes in Japanese Americans. Preceding the appearance of diabetes appears to be the development of central (visceral) adiposity, insulin resistance, and other features associated with this insulin resistance metabolic syndrome, such as dyslipidemia (high triglycerides, low HDL-cholesterol, and small and dense LDL particles), hypertension, and coronary heart disease. We have postulated that the superimposition of these metabolic changes upon a genetic background of reduced b-cell reserve results in hyperglycemia and diabetes in Japanese Americans. It is highly likely that these changes have their beginnings during childhood.
The risks of diabetic complications, such as renal failure, lower extremity amputation, blindness, and cardiovascular disease, increase with duration of diabetes. Thus, the increased prevalence of type 2 diabetes in children is especially concerning. Based upon observation from studies among adults, Asian-American children are probably at increased risk for type 2 diabetes, yet they are an under-studied group. The proposed study will provide important information on the metabolic features of the insulin resistance syndrome in Japanese-American children as they progress through puberty, and will also provide an opportunity to better understand the effect of Japanese ancestry on metabolic risk. These studies will probably be relevant to other Asian populations in the United States.
E. HUMAN SUBJECTS
E1. DESCRIPTION OF STUDY SUBJECTS
A total of 450 children, aged 8-10, will be studied. This age range was chosen so that children will be prepubertal at baseline and approximately half will enter or pass through puberty by the 2-year follow-up (see section D5c). Since this study focuses on Japanese Americans, we will initially recruit 300 children with any proportion of Japanese ancestry. We anticipate many of these children will be of mixed Japanese/Caucasion ancestry (see section C2). To allow study of the influence of Japanese ethnicity while minimizing the confounding effects of ethnic heterogeneity, 150 Caucasian children will also be studied.
E2. SOURCES OF RESEARCH MATERIAL
Information about medical and family history, diet and exercise habits will be obtained by questionnaire from children and a parent. Anthropometric measurements and sexual maturity will be ascertained by physical examination. Blood specimens will be obtained. Magnetic resonance imaging and dual-energy x-ray absorptiometry (DEXA) will be performed.
E3. RECRUITMENT OF SUBJECTS
This is a critically important aspect of this research and we will depend heavily upon the experience we have gained and the extensive networking we have established over the past two decades in performing the Japanese American Community Diabetes Study. We will recruit children of Japanese ancestry through a variety of techniques that have proven to be successful in the past. Letters will be sent to the approximately 600 living adult participants in our Japanese American Community Diabetes Study, residing in King County, Washington, informing them about the expansion of our study to include children and asking them to contact us if they know of eligible children who may be interested. Our website (http://depts.washington.edu/jacds/) will include recruitment information. We will also carry out community-wide publicity through community events and activities as arranged through our Community Advisory Board (such as writing articles for the Tayori newsletter and participating in church bazaars). A draft of an article that will appear in the next issue of the Tayori is included in the Appendix. We will send information and recruitment letters to Japanese households in King County using a comprehensive mailing list. In addition, we will target private Japanese language schools and other activities in which Japanese-American children are likely to participate. We will also ask parents whose participant children are of Japanese/Caucasian ancestry for permission to recruit Caucasian cousins. Initial publicity has already begun about the growing epidemic of type 2 diabetes in youth, and our intention to study this in Japanese-American children. This includes discussions with our Community Advisory Board (see Appendix for letter of support).
Participants will be offered compensation for time and discomfort in the form of gift certificates. Twenty-five dollar gift certificates will be provided for each evaluation. Children will be allowed to select from a wide range of gift certificates, such as movie theaters, video rental, sporting events, activities (such as miniature golf or bowling), and toy stores. Parking vouchers will be provided to parents.
E4. RISKS AND DISCOMFORT
Serious potential risks from this study are extremely unlikely. Possible minor risks include discomfort, ecchymoses, or inflammation from venipunctures. Blood will be drawn through an intravenous catheter to minimize these risks. Entertainment (such as electronic games, television, and videos) will be available to distract children during venipunctures. There is also risk of pain and inflammation if glucose is injected extravascularly. While examination for sexual maturity is essential to interpretation of the study results, efforts will be made to minimize embarrassment. Children may choose to be examined in the presence of their parents, and all exams will be performed by an experienced clinician with a chaperone present. Moreover, since assessment of sexual maturation is a standard component of a routine pediatric examination, most children will already be familiar with this procedure. The radiation exposure associated with DEXA is less than 0.1 microGy (10 mrem) , which is at the lower end of the exposure range for diagnostic radiographs. This represents about 3% of the average annual exposure from natural background radiation in the United States. Magnetic resonance imaging does not involve radiation exposure. No investigational drugs will be used.
E5. CONFIDENTIALITY AND MINIMIZING RISK
Although it is considered unlikely that a menarcheal girl might be pregnant at the time of her scheduled follow-up visit, urine sample will be obtained from all menarcheal girls for pregnancy tests, and any girl found to have a positive test will not undergo tests scheduled for the follow-up visit and will instead be referred back to their primary care physician for further follow-up. Hematocrits will be done on all participants, and any child with a hematocrit <35 will not be studied.
Results which may be relevant to the participant's medical care (e.g. height, weight, blood pressure, hematocrit, glucose, cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) will be sent by mail to the child and consenting parent. If the parent provides written consent, these results will also be provided to the child's physician. All other study information, including genetic information, will be completely confidential and will be used for research purposes only.
Each study participant will be assigned a study code number. All data collected and stored on each participant will be identified by this code. A master sheet linking participant identification and their study code will be stored in a secured location. All information will remain strictly confidential and will be stored in a locked file cabinet and on a password-protected computer file. No data containing participant identifiers will be accessible to individuals who are not investigators or staff. Any information used for research presentations or publications will be reported in statistical format only.
· Institutional Review Board.
The protocol for this study is currently under review by the University of Washington Institutional Review Board (Human Subjects Review Committee). Approval will be obtained and submitted within 60 days. Written, informed consent to participate will be obtained from each child and a parent by a member of the investigating team.
Potential risks are very unlikely, and are far outweighed by potential benefits to society. Clinically relevant information about each child will be reported to the child and their parents, and to the child's physician with written permission from the child's parents. While most children are expected to be healthy, a beneficial effect on the medical care of some children (e.g. those with hyperlipidemia) is possible. All participants may derive future benefit from the increased knowledge about type 2 diabetes and associated conditions expected to be gained from this study.
F. VERTEBRATE ANIMALS
G. LITERATURE CITED
1. Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes in youth. Diabetes Care. 1999;22(2):345-54.
2. Dabelea D, Pettitt DJ, Jones KL, Arslanian SA. Type 2 diabetes mellitus in minority children and adolescents. An emerging problem. Endocrinol Metab Clin North Am. 1999;28(4):709-29, viii.
3. Dean H. Diagnostic criteria for non-insulin dependent diabetes in youth (NIDDM- Y). Clin Pediatr (Phila). 1998;37(2):67-71.
4. American Diabetes Association. Consensus statement: Type 2 diabetes in children and adolescents. Diabetes Care. 2000;23:381-389.
5. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr. 1996;128(5 Pt 1):608-15.
6. Scott CR, Smith JM, Cradock MM, Pihoker C. Characteristics of youth-onset noninsulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus at diagnosis. Pediatrics. 1997;100(1):84-91.
7. Libman IM, LaPorte RE, Becker D, Dorman JS, Drash AL, Kuller L. Was there an epidemic of diabetes in nonwhite adolescents in Allegheny County, Pennsylvania? Diabetes Care. 1998;21(8):1278-81.
8. Libman IM, Pietropaolo M, Trucco M, Dorman JS, LaPorte RE, Becker D. Islet cell autoimmunity in white and black children and adolescents with IDDM. Diabetes Care. 1998;21(11):1824-7.
9. Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL. Overweight prevalence and trends for children and adolescents. The National Health and Nutrition Examination Surveys, 1963 to 1991. Arch Pediatr Adolesc Med. 1995;149(10):1085-91.
10. Maffeis C, Pinelli L, Schutz Y. Fat intake and adiposity in 8 to 11-year-old obese children. Int J Obes Relat Metab Disord. 1996;20(2):170-4.
11. Kitagawa T, Owada M, Urakami T, Yamauchi K. Increased incidence of non-insulin dependent diabetes mellitus among Japanese schoolchildren correlates with an increased intake of animal protein and fat. Clin Pediatr (Phila). 1998;37(2):111-5.
12. Pinhas-Hamiel O, Standiford D, Hamiel D, Dolan LM, Cohen R, Zeitler PS. The type 2 family: a setting for development and treatment of adolescent type 2 diabetes mellitus. Arch Pediatr Adolesc Med. 1999;153(10):1063-7.
13. Gortmaker SL, Must A, Sobol AM, Peterson K, Colditz GA, Dietz WH. Television viewing as a cause of increasing obesity among children in the United States, 1986-1990. Arch Pediatr Adolesc Med. 1996;150(4):356-62.
14. Robinson TN. Reducing children's television viewing to prevent obesity: a randomized controlled trial. JAMA. 1999;282(16):1561-7.
15. Raitakari OT, Taimela S, Porkka KV, et al. Associations between physical activity and risk factors for coronary heart disease: the Cardiovascular Risk in Young Finns Study. Med Sci Sports Exerc. 1997;29(8):1055-61.
16. Owens S, Gutin B, Allison J, et al. Effect of physical training on total and visceral fat in obese children. Med Sci Sports Exerc. 1999;31(1):143-8.
17. Neufeld ND, Raffel LJ, Landon C, Chen YD, Vadheim CM. Early presentation of type 2 diabetes in Mexican-American youth. Diabetes Care. 1998;21(1):80-6.
18. Glaser NS, Jones KL. Non-insulin dependent diabetes mellitus in Mexican-American children. West J Med. 1998;168(1):11-6.
19. Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ. Increasing prevalence of Type II diabetes in American Indian children. Diabetologia. 1998;41(8):904-10.
20. Dean HJ, Mundy RL, Moffatt M. Non-insulin-dependent diabetes mellitus in Indian children in Manitoba. CMAJ. 1992;147(1):52-7.
21. Fujimoto WY. Diabetes in Asian and Pacific Islander Americans. In: Harris MI, ed. Diabetes in America. 2nd ed: NIH, NIDDK, NIH Publ No 95-1468; 1995:661-681.
22. Whitty CJ, Brunner EJ, Shipley MJ, Hemingway H, Marmot MG. Differences in biological risk factors for cardiovascular disease between three ethnic groups in the Whitehall II study. Atherosclerosis. 1999;142(2):279-86.
23. Office of Health Status Monitoring Hawai'i Department of Health. HHS 1998, 12 Nov 1999, Web Page. Available at: http://www.hawaii.gov/doh/stats/surveys/table4_6.html. Accessed 20 March, 2000.
24. Unwin N, Harland J, White M, et al. Body mass index, waist circumference, waist-hip ratio, and glucose intolerance in Chinese and Europid adults in Newcastle, UK. J Epidemiol Community Health. 1997;51(2):160-6.
25. Potts J, Simmons D. Sex and ethnic group differences in fat distribution in young United Kingdom South Asians and Europids. J Clin Epidemiol. 1994;47(8):837-41.
26. Fujimoto WY, Bergstrom RW, Boyko EJ, et al. Diabetes and diabetes risk factors in second- and third-generation Japanese Americans in Seattle, Washington. Diabetes Research and Clinical Practice. 1994;24 Suppl:S43-52.
27. Cerutti F, Sacchetti C, Bessone A, Rabbone I, Cavallo-Perin P, Pacini G. Insulin secretion and hepatic insulin clearance as determinants of hyperinsulinaemia in normotolerant grossly obese adolescents. Acta Paediatr. 1998;87(10):1045-50.
28. Sarioglu B, Ozerkan E, Can S, Yaprak I, Topcuoglu R. Insulin secretion and insulin resistance determined by euglycemic clamp. J Pediatr Endocrinol Metab. 1998;11(1):27-33.
29. Caprio S, Bronson M, Sherwin RS, Rife F, Tamborlane WV. Co-existence of severe insulin resistance and hyperinsulinaemia in pre- adolescent obese children. Diabetologia. 1996;39(12):1489-97.
30. Hoffman RP, Armstrong PT. Glucose effectiveness, peripheral and hepatic insulin sensitivity, in obese and lean prepubertal children. Int J Obes Relat Metab Disord. 1996;20(6):521-5.
31. Wasada T, Arii H, Kuroki H, et al. The relationship between insulin resistance and insulin secretion in Japanese subjects with borderline glucose intolerance. Diabetes Res Clin Pract. 1995;30(1):53-7.
32. Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340(8825):925-9.
33. Chen KW, Boyko EJ, Bergstrom RW, et al. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-Year follow-up of initially nondiabetic Japanese-American men. Diabetes Care. 1995;18(6):747-53.
34. Kosaka K, Hagura R, Kuzuya T. Insulin responses in equivocal and definite diabetes, with special reference to subjects who had mild glucose intolerance but later developed definite diabetes. Diabetes. 1977;26(10):944-52.
35. Kadowaki T, Miyake Y, Hagura R, et al. Risk factors for worsening to diabetes in subjects with impaired glucose tolerance. Diabetologia. 1984;26(1):44-9.
36. Iozzo P, Beck-Nielsen H, Laakso M, Smith U, Yki-Jarvinen H, Ferrannini E. Independent influence of age on basal insulin secretion in nondiabetic humans. European Group for the Study of Insulin Resistance. J Clin Endocrinol Metab. 1999;84(3):863-8.
37. Alford FP, Henriksen JE, Rantzau C, et al. Impact of family history of diabetes on the assessment of beta-cell function. Metabolism. 1998;47(5):522-8.
38. Fernandez-Castaner M, Biarnes J, Camps I, Ripolles J, Gomez N, Soler J. Beta-cell dysfunction in first-degree relatives of patients with non- insulin-dependent diabetes mellitus. Diabet Med. 1996;13(11):953-9.
39. Steiner DF, Rouille Y, Gong Q, Martin S, Carroll R, Chan SJ. The role of prohormone convertases in insulin biosynthesis: evidence for inherited defects in their action in man and experimental animals. Diabetes Metab. 1996;22(2):94-104.
40. Kahn SE, Halban PA. Release of incompletely processed proinsulin is the cause of the disproportionate proinsulinemia of NIDDM. Diabetes. 1997;46(11):1725-32.
41. Saad MF, Kahn SE, Nelson RG, et al. Disproportionately elevated proinsulin in Pima Indians with noninsulin- dependent diabetes mellitus. J Clin Endocrinol Metab. 1990;70(5):1247-53.
42. Roder ME, Porte D, Jr., Schwartz RS, Kahn SE. Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin- dependent diabetes mellitus. J Clin Endocrinol Metab. 1998;83(2):604-8.
43. Larsson H, Ahren B. Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose tolerance. J Clin Endocrinol Metab. 1999;84(6):2068-74.
44. Wareham NJ, Byrne CD, Williams R, Day NE, Hales CN. Fasting proinsulin concentrations predict the development of type 2 diabetes. Diabetes Care. 1999;22(2):262-70.
45. Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstrom RW, Fujimoto WY. Proinsulin as a marker for the development of NIDDM in Japanese- American men. Diabetes. 1995;44(2):173-9.
46. Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstom RW, Fujimoto WY. Proinsulin levels predict the development of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese-American men. Diabet Med. 1996;13(9 Suppl 6):S63-6.
47. Mykkanen L, Haffner SM, Hales CN, Ronnemaa T, Laakso M. The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects. Diabetes. 1997;46(12):1990-5.
48. Seaquist ER, Kahn SE, Clark PM, Hales CN, Porte D, Jr., Robertson RP. Hyperproinsulinemia is associated with increased beta cell demand after hemipancreatectomy in humans. J Clin Invest. 1996;97(2):455-60.
49. Kahn SE, Beard JC, Schwartz MW, et al. Increased beta-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance. Diabetes. 1989;38(5):562-8.
50. Kahn SE, McCulloch DK, Schwartz MW, Palmer JP, Porte D, Jr. Effect of insulin resistance and hyperglycemia on proinsulin release in a primate model of diabetes mellitus. J Clin Endocrinol Metab. 1992;74(1):192-7.
51. Moran A, Jacobs DR, Jr., Steinberger J, et al. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes. 1999;48(10):2039-44.
52. Gower BA, Nagy TR, Goran MI. Visceral fat, insulin sensitivity, and lipids in prepubertal children. Diabetes. 1999;48(8):1515-21.
53. Gower BA, Nagy TR, Trowbridge CA, Dezenberg C, Goran MI. Fat distribution and insulin response in prepubertal African American and white children. Am J Clin Nutr. 1998;67(5):821-7.
54. Potau N, Ibanez L, Rique S, Carrascosa A. Pubertal changes in insulin secretion and peripheral insulin sensitivity. Horm Res. 1997;48(5):219-26.
55. Smith CP, Archibald HR, Thomas JM, et al. Basal and stimulated insulin levels rise with advancing puberty. Clin Endocrinol (Oxf). 1988;28(1):7-14.
56. Arslanian SA, Kalhan SC. Correlations between fatty acid and glucose metabolism. Potential explanation of insulin resistance of puberty. Diabetes. 1994;43(7):908-14.
57. Attia N, Tamborlane WV, Heptulla R, et al. The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity. J Clin Endocrinol Metab. 1998;83(5):1467-71.
58. Caprio S. Insulin: the other anabolic hormone of puberty. Acta Paediatr Suppl. 1999;88(433):84-7.
59. Hesse V, Jahreis G, Schambach H, et al. Insulin-like growth factor I correlations to changes of the hormonal status in puberty and age. Exp Clin Endocrinol. 1994;102(4):289-98.
60. Juul A, Dalgaard P, Blum WF, et al. Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab. 1995;80(8):2534-42.
61. Saitoh H, Kamoda T, Nakahara S, Hirano T, Matsui A. Insulin-like growth factor binding protein-1 as a predictor of glucose- stimulated hyperinsulinemia in prepubertal obese children. Eur J Endocrinol. 1999;140(3):231-4.
62. Travers SH, Labarta JI, Gargosky SE, Rosenfeld RG, Jeffers BW, Eckel RH. Insulin-like growth factor binding protein-I levels are strongly associated with insulin sensitivity and obesity in early pubertal children. J Clin Endocrinol Metab. 1998;83(6):1935-9.
63. Rosenfeld RG, Wilson DM, Lee PD, Hintz RL. Insulin-like growth factors I and II in evaluation of growth retardation. J Pediatr. 1986;109(3):428-33.
64. Blum WF, Ranke MB. Use of insulin-like growth factor-binding protein 3 for the evaluation of growth disorders. Horm Res. 1990;33(Suppl 4):31-7.
65. Jiang X, Srinivasan SR, Radhakrishnamurthy B, Dalferes ER, Berenson GS. Racial (black-white) differences in insulin secretion and clearance in adolescents: the Bogalusa heart study. Pediatrics. 1996;97(3):357-60.
66. Arslanian S, Suprasongsin C. Differences in the in vivo insulin secretion and sensitivity of healthy black versus white adolescents. J Pediatr. 1996;129(3):440-3.
67. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595-607.
68. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14(3):173-94.
69. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes. 1992;41(6):715-22.
70. Meigs JB, Mittleman MA, Nathan DM, et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA. 2000;283(2):221-8.
71. Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb. 1993;13(12):1865-73.
72. Sakkinen PA, Cushman M, Psaty BM, et al. Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. Arterioscler Thromb Vasc Biol. 1999;19(3):499-504.
73. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol. 1999;19(4):972-8.
74. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia. 1997;40(11):1286-92.
75. Hak AE, Stehouwer CD, Bots ML, et al. Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol. 1999;19(8):1986-91.
76. Wei M, Gaskill SP, Haffner SM, Stern MP. Waist circumference as the best predictor of noninsulin dependent diabetes mellitus (NIDDM) compared to body mass index, waist/hip ratio and other anthropometric measurements in Mexican Americans--a 7-year prospective study. Obes Res. 1997;5(1):16-23.
77. Dowse GK, Zimmet PZ, Gareeboo H, et al. Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians. Diabetes Care. 1991;14(4):271-82.
78. Cassano PA, Rosner B, Vokonas PS, Weiss ST. Obesity and body fat distribution in relation to the incidence of non- insulin-dependent diabetes mellitus. A prospective cohort study of men in the normative aging study. Am J Epidemiol. 1992;136(12):1474-86.
79. Carey VJ, Walters EE, Colditz GA, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The Nurses' Health Study. Am J Epidemiol. 1997;145(7):614-9.
80. Bjorntorp P. Metabolic implications of body fat distribution. Diabetes Care. 1991;14(12):1132-43.
81. Bjorntorp P. Regional obesity and NIDDM. Adv Exp Med Biol. 1993;334:279-85.
82. Despres JP. Abdominal obesity as important component of insulin-resistance syndrome. Nutrition. 1993;9(5):452-9.
83. Kissebah AH. Intra-abdominal fat: is it a major factor in developing diabetes and coronary artery disease? Diabetes Res Clin Pract. 1996;30 Suppl:25-30.
84. Boyko EJ, Leonetti DL, Bergstrom RW, Newell-Morris L, Fujimoto WY. Visceral adiposity, fasting plasma insulin, and blood pressure in Japanese-Americans. Diabetes Care. 1995;18(2):174-81.
85. Boyko EJ, Leonetti DL, Bergstrom RW, Newell-Morris L, Fujimoto WY. Visceral adiposity, fasting plasma insulin, and lipid and lipoprotein levels in Japanese Americans. Int J Obes Relat Metab Disord. 1996;20(9):801-8.
86. Gower BA, Nagy TR, Goran MI, Toth MJ, Poehlman ET. Fat distribution and plasma lipid-lipoprotein concentrations in pre- and postmenopausal women. Int J Obes Relat Metab Disord. 1998;22(7):605-11.
87. Kotani K, Tokunaga K, Fujioka S, et al. Sexual dimorphism of age-related changes in whole-body fat distribution in the obese. Int J Obes Relat Metab Disord. 1994;18(4):207-2.
88. Lemieux S, Despres JP, Moorjani S, et al. Are gender differences in cardiovascular disease risk factors explained by the level of visceral adipose tissue? Diabetologia. 1994;37(8):757-64.
89. Treuth MS, Hunter GR, Figueroa-Colon R, Goran MI. Effects of strength training on intra-abdominal adipose tissue in obese prepubertal girls. Med Sci Sports Exerc. 1998;30(12):1738-43.
90. Ku CY, Gower BA, Nagy TR, Goran MI. Relationships between dietary fat, body fat, and serum lipid profile in prepubertal children. Obes Res. 1998;6(6):400-7.
91. Goran MI, Nagy TR, Treuth MS, et al. Visceral fat in white and African American prepubertal children. Am J Clin Nutr. 1997;65(6):1703-8.
92. Brambilla P, Manzoni P, Agostini G, et al. Persisting obesity starting before puberty is associated with stable intraabdominal fat during adolescence. Int J Obes Relat Metab Disord. 1999;23(3):299-303.
93. Ferguson MA, Gutin B, Owens S, Litaker M, Tracy RP, Allison J. Fat distribution and hemostatic measures in obese children. Am J Clin Nutr. 1998;67(6):1136-40.
94. Caprio S, Hyman LD, McCarthy S, Lange R, Bronson M, Tamborlane WV. Fat distribution and cardiovascular risk factors in obese adolescent girls: importance of the intraabdominal fat depot. Am J Clin Nutr. 1996;64(1):12-7.
95. Caprio S, Hyman LD, Limb C, et al. Central adiposity and its metabolic correlates in obese adolescent girls. Am J Physiol. 1995;269(1 Pt 1):E118-26.
96. Bandini LG, A. M, Spadano JL, et al. Relationship between visceral fat, sex hormone levels and activity in girls at menarche. Obes Res. 1999;7(Supplement 1):57S.
97. Story M, Harris LJ. Food preferences, beliefs, and practices of Southeast Asian refugee adolescents. J Sch Health. 1988;58(7):273-6.
98. Fujimoto WY, Akanuma Y, Kanazawa Y, Mashiko S, Leonetti D, Wahl P. Plasma insulin levels in Japanese and Japanese-American men with type 2 diabetes may be related to the occurrence of cardiovascular disease. Diabetes Res Clin Pract. 1989;6(2):121-7.
99. Kissebah AH, Vydelingum N, Murray R, et al. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab. 1982;54(2):254-60.
100. Shuman WP, Morris LL, Leonetti DL, et al. Abnormal body fat distribution detected by computed tomography in diabetic men. Invest Radiol. 1986;21(6):483-7.
101. Bergstrom RW, Newell-Morris LL, Leonetti DL, Shuman WP, Wahl PW, Fujimoto WY. Association of elevated fasting C-peptide level and increased intra-abdominal fat distribution with development of NIDDM in Japanese-American men. Diabetes. 1990;39(1):104-11.
102. Fujimoto WY, Abbate SL, Kahn SE, al. e. The visceral adiposity syndrome in Japanese-American men. Obesity Res. 1994;2:364-371.
103. Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW, Fujimoto WY. Association of plasma triglyceride and C-peptide with coronary heart disease in Japanese-American men with a high prevalence of glucose intolerance. Diabetologia. 1990;33(8):489-96.
104. Fujimoto WY, Bergstrom RW, Boyko EJ, et al. Visceral adiposity and incident coronary heart disease in Japanese-American men. The 10-year follow-up results of the Seattle Japanese-American Community Diabetes Study. Diabetes Care. 1999;22(11):1808-12.
105. Bergstrom RW, Wahl PW, Leonetti DL, Fujimoto WY. Association of fasting glucose levels with a delayed secretion of insulin after oral glucose in subjects with glucose intolerance. J Clin Endocrinol Metab. 1990;71(6):1447-53.
106. Boyko EJ, Leonetti DL, Bergstrom RW, Fujimoto WY. Fasting insulin level underestimates risk of non-insulin-dependent diabetes mellitus due to confounding by insulin secretion. Am J Epidemiol. 1997;145(1):18-23.
107. Tsunehara CH, Leonetti DL, Fujimoto WY. Diet of second-generation Japanese-American men with and without non- insulin-dependent diabetes. Am J Clin Nutr. 1990;52(4):731-8.
108. Leonetti DL, Tsunehara CH, Wahl PW, Fujimoto WJ. Baseline dietary intake and physical activity of Japanese-American men in relation to glucose tolerance at 5-year follow-up. Am J Hum Biol. 1996;8:55-67.
109. USA Counties 1996 on CD-ROM (machine-readable data files). Prepared
by the Bureau of the Census. Washington, DC, 1996. Available at: : http://govinfo.library.orst.edu/cgi-bin/usaco-list?24-033.wac (1990 data) and http://govinfo.library.orst.edu/cgi-bin/usaco-list98?01-033.wac (1996 data). Accessed: March 13, 2000. .
110. Leonetti DL, Newell-Morris L. Exogamy and change in the biosocial structure of a modern urban population. American Anthropologist. 1982;84:19-36.
111. Baker KK, Onaka AT, Reyes-Salvail F, et al. Multi-Race Health Statistics: A State Perspective. Hawaii Health Survey (HHS) 1998. . National Conference for Health Statistics. Honolulu, Hawaii: Office of Health Status Monitoring, State of Hawaii Department of Health; 1999.
112. NHANES III anthropometric procedures (videotape stock No. 017-022-01335-5) National Center for Health Statistics. Washington DC: US Government Printing Office; 1996.
113. WHO Expert Committee. Physical status: the use and interpretation of anthropometry. World Health Organ Tech Rep Ser. 1995;854:1-452.
114. Fujieda K. Pubertal development in boys. Clin Pediatr Endocrinol. 1993;2(Suppl 3):7-14.
115. Matsuo N. Skeletal and sexual maturation in Japanese children. Clin Pediatr Endocrinol. 1993;2(Suppl 1):1-4.
116. Sperling M, ed. Pediatric Endocrinology. Philadelphia, Pennsylvania: W.B. Saunders; 1996.
117. Bandini LG, Cyr H, Must A, Dietz WH. Validity of reported energy intake in preadolescent girls. Am J Clin Nutr. 1997;65(4 Suppl):1138S-1141S.
118. Livingstone MB, Prentice AM, Coward WA, et al. Validation of estimates of energy intake by weighed dietary record and diet history in children and adolescents. Am J Clin Nutr. 1992;56(1):29-35.
119. Lindquist CH, Cummings T, Goran MI. Use of tape-recorded food records in assessing children's dietary intake. Obes Res. 2000;8(1):2-11.
120. Sallis JF, Strikmiller PK, Harsha DW, et al. Validation of interviewer- and self-administered physical activity checklists for fifth grade students. Med Sci Sports Exerc. 1996;28(7):840-51.
121. Ainsworth BE, Haskell WL, Leon AS, et al. Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc. 1993;25(1):71-80.
122. Anderson DR, Field DE, Collins PA, Lorch EP, Nathan JG. Estimates of young children's time with television: a methodological comparison of parent reports with time-lapse video home observation. Child Dev. 1985;56(5):1345-57.
123. Robinson TN, Killen JD. Ethnic and gender differences in the relationships between television viewing and obesity, physical activity and dietary fat intake. J Health Educ. 1995;26:S91-S98.
124. Austin MA, Mykkanen L, Kuusisto J, et al. Prospective study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women. Circulation. 1995;92(7):1770-8.
125. McCulloch DK, Bingley PJ, Colman PG, Jackson RA, Gale EA. Comparison of bolus and infusion protocols for determining acute insulin response to intravenous glucose in normal humans. The ICARUS Group. Islet Cell Antibody Register User's Study. Diabetes Care. 1993;16(6):911-5.
126. Bingley PJ. Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+ relatives: the ICARUS data set. Islet Cell Antibody Register Users Study. Diabetes. 1996;45(12):1720-8.
127. Bergman RN. Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes. 1989;38(12):1512-27.
128. Davis SN, Piatti PM, Monti L, et al. A comparison of four methods for assessing in vivo beta-cell function in normal, obese and non-insulin-dependent diabetic man. Diabetes Res. 1992;19(3):107-17.
129. Toffolo G, Cefalu WT, Cobelli C. Beta-cell function during insulin-modified intravenous glucose tolerance test successfully assessed by the C-peptide minimal model. Metabolism. 1999;48(9):1162-6.
130. Toffolo G, Bergman RN, Finegood DT, Bowden CR, Cobelli C. Quantitative estimation of beta cell sensitivity to glucose in the intact organism: a minimal model of insulin kinetics in the dog. Diabetes. 1980;29(12):979-90.
131. Best JD, Alford FP, Martin IK, Pestell RG, Ward GM. Practical application of methods for in vivo assessment of insulin secretion and action. Horm Metab Res Suppl. 1990;24:60-6.
132. Bardet S, Pasqual C, Maugendre D, Remy JP, Charbonnel B, Sai P. Inter and intra individual variability of acute insulin response during intravenous glucose tolerance tests. Diabete Metab. 1989;15(5):224-32.
133. Matthews DR, Hosker JP, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
134. Howard G, Bergman R, Wagenknecht LE, et al. Ability of alternative indices of insulin sensitivity to predict cardiovascular risk: comparison with the "minimal model". Ann Epidemiol. 1998;8:358-369.
135. Bavdekar A, Yajnik CS, Fall CH, et al. Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both? Diabetes. 1999;48(12):2422-9.
136. Dabelea D, Pettitt DJ, Hanson RL, Imperatore G, Bennett PH, Knowler WC. Birth weight, type 2 diabetes, and insulin resistance in Pima Indian children and young adults. Diabetes Care. 1999;22(6):944-50.
137. Crowther NJ, Cameron N, Trusler J, Gray IP. Association between poor glucose tolerance and rapid post natal weight gain in seven-year-old children. Diabetologia. 1998;41(10):1163-7.
138. Mazess RB, Barden HS, Bisek JP, Hanson J. Dual-energy x-ray absorptiometry for total-body and regional bone- mineral and soft-tissue composition. Am J Clin Nutr. 1990;51(6):1106-12.
139. Yanovski JA, Yanovski SZ, Filmer KM, et al. Differences in body composition of black and white girls. Am J Clin Nutr. 1996;64(6):833-9.
140. Dezenberg CV, Nagy TR, Gower BA, Johnson R, Goran MI. Predicting body composition from anthropometry in pre-adolescent children. Int J Obes Relat Metab Disord. 1999;23(3):253-9.
141. Goran MI, Gower BA, Treuth M, Nagy TR. Prediction of intra-abdominal and subcutaneous abdominal adipose tissue in healthy pre-pubertal children. Int J Obes Relat Metab Disord. 1998;22(6):549-58.
142. Figueroa-Colon R, Mayo MS, Treuth MS, Aldridge RA, Weinsier RL. Reproducibility of dual-energy X-ray absorptiometry measurements in prepubertal girls. Obes Res. 1998;6(4):262-7.
143. Norgan NG. The assessment of the body composition of populations. In: Davies PSW, Cole TJ, eds. Body Composition Techniques in Health and Disease. Vol. 36. Cambridge, U.K.: Cambridge University Press; 1995:195-221.
144. Owens S, Litaker M, Allison J, Riggs S, Ferguson M, Gutin B. Prediction of visceral adipose tissue from simple anthropometric measurements in youths with obesity. Obes Res. 1999;7(1):16-22.
145. Brambilla P, Manzoni P, Sironi S, et al. Peripheral and abdominal adiposity in childhood obesity. Int J Obes Relat Metab Disord. 1994;18(12):795-800.
146. Elbers JM, Haumann G, Asscheman H, Seidell JC, Gooren LJ. Reproducibility of fat area measurements in young, non-obese subjects by computerized analysis of magnetic resonance images. Int J Obes Relat Metab Disord. 1997;21(12):1121-9.
147. Stata Corporation. Stata User's Guide College Station, TX: Stata Press; 1997.
148. Edwards KL, Austin MA, Newman B, Mayer E, Krauss RM, Selby JV. Multivariate analysis of the insulin resistance syndrome in women. Arterioscler Thromb. 1994;14(12):1940-5.
149. Edwards KL, Burchfiel CM, Sharp DS, et al. Factors of the insulin resistance syndrome in nondiabetic and diabetic elderly Japanese-American men. Am J Epidemiol. 1998;147(5):441-7.
150. Chen W, Srinivasan SR, Elkasabany A, Berenson GS. Cardiovascular risk factors clustering features of insulin resistance syndrome (Syndrome X) in a biracial (Black-White) population of children, adolescents, and young adults: the Bogalusa Heart Study. Am J Epidemiol. 1999;150(7):667-74.
151. Kleinbaum DG, Kupper LL, Muller KE. Applied Regression Analysis and Other Multivariable Methods. 2nd edition ed Boston, MA: PWS-KENT Publishing Co.; 1988.
152. Stevens J. Applied Multivariate Statistics for the Social Sciences. Hillsdale, NJ: Lawrence Erlbaum Associates.; 1986.
153. Kaiser H. The application of electronic computers to factor analyis. Educational and Psychological Measurement. 1985;20:141-151.
154. Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr. 1985;107(3):317-29.