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
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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)
Children's
Hospital and
Veteran's
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.
In
· 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 [2]. 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 [2], 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 [21]. Despite having a lower average BMI than
Caucasians, South Asian adults living in the United Kingdom are 4 times as
likely to have diabetes [22]. 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 [23]. 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 [11]. 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% [9].
B2. PATHOPHYSIOLOGY OF TYPE 2 DIABETES
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 [31]. 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 [32], other reports suggest that impaired insulin secretion precedes or
accompanies the development of insulin resistance [33]. 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 [37]. 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 [38]. 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 [39]. 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 [42]. 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 [40].
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 [43], 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 [47]. Although it has been reported
that proinsulin levels increase following hemipancreatectomy, suggesting that
this may be a response to increased ß-cell demand [48], 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 [51]. 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) [63], the peripheral hormone
that mediates many of the effects of growth hormone, and insulin-like growth
factor binding protein-3 (IGFBP-3) [64].
· 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 [52]. This same group reported higher fasting
insulin levels in African American prepubertal children [53]. African-American adolescent girls have higher
fasting insulin levels and decreased hepatic insulin clearance compared to
Caucasians [65]. 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 [66]. 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 [51]. 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.
· Adults
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 [53]. 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 [52]. 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 [91]. 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 [92]. 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 [93].
· 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 [92]. Testosterone levels are positively correlated
with visceral fat in girls at the time of menarche, independent of estrogen,
LH, and total body fat [96].
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 [97]. The rise in diabetes among Japanese children
coincides with the adoption of a "westernized" lifestyle [11]. 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 [26]. Despite similar degrees of hyperglycemia,
diabetic Seattle Japanese American men had significantly higher insulin levels
than diabetic Tokyo men [98]. 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 [99]. Diabetic Japanese Americans had significantly
more intra-abdominal fat by CT scan than those persons with normal glucose
tolerance [100]. The importance of intra-abdominal fat as a
risk factor for diabetes was further confirmed by prospective studies [101]. 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 [102].
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 [103]. We also found that intra-abdominal fat was an
independent risk factor for incident coronary heart disease [104]. 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 [105]. 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 [106] and elevated proinsulin
levels [45] 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 [33]. 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 [107]. 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 [108]. 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.
B4. SIGNIFICANCE
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) [138], 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.
E6. BENEFITS
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
Not
Applicable
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.
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