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We prospectively examined the relationship between leptin and markers of insulin resistance and secretion and future visceral adipose tissue accumulation. In this study, 518 nondiabetic Japanese-American men and women underwent the following measurements at baseline and at 5- and 10-year follow-ups: plasma glucose and insulin measured after an overnight fast and during a 75-g oral glucose tolerance test, insulin secretion ratio (ISR) [(30-min insulin - fasting insulin)/30-min glucose], fasting C-peptide levels, plasma leptin (baseline only), and fat areas (intra-abdominal and subcutaneous) measured by computed tomography. Predictors of future intra-abdominal fat (IAF) were determined using multiple linear regression. Fasting insulin and C-peptide levels at baseline were significantly associated with IAF area at 5 years (coefficient = 0.041, P = 0.001 and coefficient = 1.283, P < 0.001, respectively) and 10 years (coefficient = 0.031, P = 0.020 and coefficient = 0.221, P = 0.035, respectively). ISR was not significantly associated with IAF at 5 or 10 years. Leptin level at baseline was positively associated with IAF at 5 years (coefficient = 0.055, P = 0.002) and 10 years (coefficient = 0.059, P = 0.003). In conclusion, higher levels of fasting insulin, C-peptide, and circulating leptin level predicted visceral fat accumulation independent from subcutaneous fat accumulation in nondiabetic Japanese-American men and women in both short-term (5 years) and long-term (10 years) follow-up.

The prevalence of glucose intolerance and type 2 diabetes increases with age. To determine whether the hyperbolic relationship between insulin sensitivity and the insulin response is affected by age and whether the decline in beta-cell function with age is related to increases in intra-abdominal fat or age per se, we studied 220 healthy subjects with fasting glucose <6.1 mmol/l (89 men and 131 women, aged 26-75 years, BMI 18.7-40.4 kg/m(2)). The insulin sensitivity index (S(i)) and the acute insulin response to glucose (AIRg) were determined, and from these beta-cell function was estimated as the disposition index (S(i) x AIRg). Intra-abdominal fat and subcutaneous fat areas were quantified by computed tomography. S(i) (5.40 +/- 0.5 vs. 7.86 +/- 0.7 x10(-5) min(-1)/[pmol/l]), P < 0.01) was decreased and intra-abdominal fat (117 +/- 10 vs. 81 +/- 9 cm(2), P < 0.05) was increased in the oldest (age 60-75 years) versus the youngest (age 26-44 years) quartile. The hyperbolic relationship between S(i) and AIRg was present independent of age; thus, beta-cell function measured as the disposition index (1,412 +/- 120 vs. 2,125 +/- 150 x10(-5) min(-1), P < 0.01) was lower in the oldest versus the youngest quartile. In multiple regression, intra-abdominal fat (r = -0.470, P < 0.001) but not age was associated with S(i), but both intra-abdominal fat (r = -0.198, P = 0.003) and age (r = -0.131, P = 0.05) were correlated with the disposition index. These data suggest that although intra-abdominal fat is a strong determinant of insulin sensitivity and beta-cell function, age has an independent effect on beta-cell function that may contribute to the increased prevalence of type 2 diabetes in older populations.

The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n = 89) and women (n = 129) with a broad range of age (26-75 years) and BMI (18.4-46.8 kg/m2), underwent quantification of the insulin sensitivity index (Si) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower Si [median: 3.13 vs. 6.09 x 10(-5) min(-1)/(pmol/l)] and higher IAF (166.3 vs. 79.1 cm2) and SCF (285.1 vs. 179.8 cm2) areas compared with subjects without the syndrome (P < 0.001). Multivariate models including Si, IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with Si and IAF and SCF areas (P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose <6.4 mmol/l.

Our aim was to develop a statistical method to correct for non-parallelism in an estrone-3-glucuronide (E1G) enzyme immunoassay (EIA). Non-parallelism of serially diluted urine specimens with a calibration curve was demonstrated in an EIA for E1G. A linear mixed-effects analysis of 40 urine specimens was used to model the relationship of E1G concentration with urine volume and derive a statistical correction. The model was validated on an independent sample and applied to 30 menstrual cycles from American women. Specificity, detection limit, parallelism, recovery, correlation with serum estradiol, and imprecision of the assay were determined. Intra-and inter-assay CVs were less than 14% for high- and low-urine controls. Urinary E1G across the menstrual cycle was highly correlated with serum estradiol (r= 0.94). Non-parallelism produced decreasing E1G concentration with increase in urine volume (slope = -0.210, p < 0.0001). At 50% inhibition, the assay had 100% cross-reactivity with E1G and 83% with 17beta-estradiol 3-glucuronide. The dose-response curve of the latter did not parallel that of E1G and is a possible cause of the non-parallelism. The statistical correction adjusting E1G concentration to a standardized urine volume produced parallelism in 24 independent specimens (slope = -0.043+/-0.010), and improved the average CV of E1G concentration across dilutions from 19.5%+/-5.6% before correction to 10.3%+/-5.3% after correction. A statistical method based on linear mixed effects modeling is an expedient approach for correction of non-parallelism, particularly for hormone data that will be analyzed in aggregate.

The purpose of this study was to quantify differences in joint range of motion, foot deformity, and foot morphology among pes cavus, neutrally aligned, pes planus rigid, and pes planus flexible feet. A cohort of 1047 veterans with diabetes (contributing 2047 feet) was enrolled in a prospective study of diabetic ulcer risk factors (the Seattle Diabetic Foot Study). Significant differences between foot types were found. Pes cavus feet had an increased percentage of prominent metatarsal heads, bony prominences, and hammer/claw toes (p < .0001), as well as significantly increased amounts of hallux dorsiflexion and decreased amounts of hallux plantarflexion (p < .0001) with a total range of motion equal to the other foot types (p = .3). Neutrally aligned feet had a lower percentage of intrinsic muscle atrophy, bony prominences, and hammer/claw toes (p < .0001). Pes planus feet had an increased lateral talometatarsal angle (p < .0001) and an increased second metatarsal length. These data demonstrate structural differences between foot types in a population with diabetes.

Background: Monitoring of reproductive steroid hormones at the population level requires frequent measurements, hormones or metabolites that remain stable under less than ideal collection and storage conditions, a long-term supply of antibodies, and assays useful for a range of populations. We developed enzyme immunoassays for urinary pregnanediol 3-glucuronide (PDG) and estrone conjugates (E1Cs) that meet these criteria., Methods: Enzyme immunoassays based on monoclonal antibodies were evaluated for specificity, detection limit, parallelism, recovery, and imprecision. Paired urine and serum specimens were analyzed throughout menstrual cycles of 30 US women. Assay application in different populations was examined with 23 US and 42 Bangladeshi specimens. Metabolite stability in urine was evaluated for 0-8 days at room temperature and for 0-10 freeze-thaw cycles., Results: Recoveries were 108% for the PDG assay and 105% for the E1C assay. Serially diluted specimens exhibited parallelism with calibration curves in both assays. Inter- and intraassay CVs were <11%. Urinary and serum concentrations were highly correlated: r = 0.93 for E1C-estradiol; r = 0.98 for PDG-progesterone. All Bangladeshi and US specimens were above detection limits (PDG, 21 nmol/L; E1C, 0.27 nmol/L). Bangladeshi women had lower follicular phase PDG and lower luteal phase PDG and E1Cs than US women. Stability experiments showed a maximum decrease in concentration for each metabolite of <4% per day at room temperature and no significant decrease associated with number of freeze-thaw cycles., Conclusions: These enzyme immunoassays can be used for the field conditions and population variation in hormone metabolite concentrations encountered in cross-cultural research.

Objective: To determine whether diet and endurance exercise improved adiposity-related measurements in Japanese Americans with impaired glucose tolerance (IGT)., Research Design and Methods: This study compared the effects of an American Heart Association (AHA) step 2 diet (<30% of total calories as fat, <7% saturated fat, 55% carbohydrate, and < 200 mg cholesterol daily) plus endurance exercise for 1 h three times a week (treatment group) with an AHA step 1 diet (30% of total calories as fat, 10% saturated fat, 50% carbohydrate, and <300 mg cholesterol) plus stretching exercise three times a week (control group) on BMI, body composition (% fat), and body fat distribution at 6 and 24 months of follow-up in 64 Japanese American men and women with IGT, 58 of whom completed the study., Results: At 6 months, the treatment group showed significantly greater reduction in percent, body fat (-1.4 +/- 0.4 vs. -0.3 +/- 0.3%); BMI (-1.1 +/- 0.2 vs. -0.4 +/- 0.1 kg/m(2)); subcutaneous fat by computed tomography at the abdomen (-29.3 +/- 4.2 vs. -5.7 +/- 5.9 cm(2)), thigh (-13.2 +/- 3.6 vs. -3.6 +/- 3.0 cm(2)), and thorax (-19.6 +/- 3.6 vs. -8.9 +/- 2.6 cm(2)); and skinfold thickness at the bicep (-2.0 +/- 0.6 vs. 1.1 +/- 0.6 mm) and tricep (-3.7 +/- 0.8 vs. -0.9 +/- 0.6 mm), which continued despite moving to home-based exercise for the last 18 months., Conclusions: Diet and endurance exercise improved BMI, body composition, and body fat distribution and, thus, may delay or prevent type 2 diabetes in Japanese Americans with IGT.

Background: Despite having lower average body mass indexes (BMIs) than do whites, Asians are at high risk of type 2 diabetes, possibly because of their greater central adiposity. The criteria for identifying individuals at risk of obesity-related conditions are usually not population specific., Objective: Our goal was to determine whether the National Heart, Lung, and Blood Institute (NHLBI) overweight and obesity guidelines are useful for identifying diabetes risk in Japanese Americans., Design: This was a prospective, cohort study of 466 nondiabetic Japanese Americans [age: 52.2 +/- 0.6 y; BMI (in kg/m(2)): 24.1 +/- 0.2; +/- SEM]. Diabetes status at a 5-y follow-up visit was assessed with an oral-glucose-tolerance test., Results: Among 240 subjects aged < or = 55 y, incident diabetes was strongly associated with overweight (BMI > or = 25) at baseline [relative risk (RR): 22.4; 95% CI: 2.7, 183; adjusted for age, sex, smoking, and family history] and weight gain of > 10 kg since the age of 20 y (adjusted RR: 4.5; 95% CI: 1.4, 14.5). NHLBI definitions of central obesity (waist circumference > or = 88 cm for women and > or = 102 cm for men) were unsuitable for this population because only 15 of 240 subjects met these criteria. A waist circumference greater than or equal to the third tertile was associated with diabetes (adjusted RR: 5.4; 95% CI: 1.7, 17.0). Among 226 subjects aged >55 y, incident diabetes was not associated with BMI, weight gain, or waist circumference., Conclusions: NHLBI definitions are useful for identifying overweight Japanese Americans aged < 55 y who are at high risk of diabetes. Although central adiposity is an important risk factor, the guidelines for waist circumference are insensitive predictors of diabetes risk in this population.

Objective: To compare the American Diabetes Association (ADA) fasting glucose and the World Health Organization (WHO) oral glucose tolerance test (OGTT) criteria for diagnosing diabetes and detecting people at increased risk for cardiovascular disease (CVD)., Research Design and Methods: Study subjects were 596 Japanese-Americans. Fasting insulin, lipids, and C-peptide levels; systolic and diastolic blood pressures (BPs); BMI (kg/m2); and total and intra-abdominal body fat distribution by computed tomography (CT) were measured. Study subjects were categorized by ADA criteria as having normal fasting glucose (NFG), impaired fasting glucose (IFG), and diabetic fasting glucose and by WHO criteria for a 75-g OGTT as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetic glucose tolerance (DGT)., Results: Of 503 patients with NFG, 176 had IGT and 20 had DGT These patients had worse CVD risk factors than those with NGT . The mean values for NGT, IGT, and DGT, respectively, and analysis of covariance P values, adjusted for age and sex, are as follows; intra-abdominal fat area by CT 69.7, 95.0, and 101.1 cm2 (P < 0.0001); total CT fat area 437.7, 523.3, and 489.8 cm2 (P < 0.0001); fasting triglycerides 1.40, 1.77, and 1.74 mmol/l (P = 0.002); fasting HDL cholesterol 1.56, 1.50, and 1.49 mmol/l (P = 0.02); C-peptide 0.80, 0.90, 0.95 nmol/l (P = 0.002); systolic BP 124.9, 132.4, and 136.9 mmHg (P = 0.0035); diastolic BP 74.8, 77.7, and 78.2 mmHg (P = 0.01)., Conclusions: NFG patients who had IGT or DGT had more intra-abdominal fat and total adiposity; higher insulin, C-peptide, and triglyceride levels; lower HDL cholesterol levels; and higher BPs than those with NGT. Classification by fasting glucose misses many Japanese-Americans with abnormal glucose tolerance and less favorable cardiovascular risk profiles.

This is a review of research carried out in Japanese Americans that points towards possible approaches to prevention of type 2 diabetes mellitus. The natural history of type 2 diabetes usually includes both insulin resistance and beta-cell dysfunction. Insulin secretion may compensate for insulin resistance. Alternatively, enhanced insulin sensitivity may mask an insulin secretory defect. Epidemiological data support the view that in the vast majority of cases of type 2 diabetes, insulin resistance is essential to the pathogenesis of hyperglycemia. Increased diabetes prevalence as ethnic groups migrate to more urban or westernized regions has been attributed to increased occurrence of insulin resistance. Research among Japanese Americans in Seattle, Washington, showed a higher prevalence of type 2 diabetes than in Japan, which suggested that factors associated with 'westernization' might be playing a role in bringing out underlying susceptibility to diabetes. Our research has shown that these impressions were correct and that the abnormalities that characterize the metabolic syndrome play a significant role. Due to increased intra-abdominal fat deposition, Japanese Americans were likely to be 'metabolically obese' despite relatively normal BMI. A diet higher in animal fat and lower levels of physical activity were risk factors leading to increased intra-abdominal fat deposition, insulin resistance, and diabetes. Information from epidemiological studies such as these may be used to determine whether diabetes may be prevented through changes in lifestyle or application of specific therapies targeted towards identified metabolic abnormalities.

Japanese Americans have experienced a higher prevalence of type 2 diabetes than in Japan. Research conducted in Seattle suggests that lifestyle factors associated with 'westernization' play a role in bringing out this susceptibility to diabetes. These lifestyle factors include consumption of a diet higher in saturated fat and reduced physical activity. A consequence of this is 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 insulin resistance upon a genetic background of reduced beta-cell reserve results in hyperglycemia and diabetes among Japanese Americans. This article reviews evidence that support this view.

Objective: To identify risk factors for incident coronary heart disease (CHD)., Research Design and Methods: A total of 175 Japanese-American men without CHD were followed for up to 10 years. Baseline variables were blood pressure, weight, BMI, fat areas by computed tomography, skinfold thicknesses, abdominal circumference, plasma insulin, C-peptide, cholesterol, LDL cholesterol, HDL cholesterol, HDL2 cholesterol, and HDL3 cholesterol, triglycerides, apoproteins A1 and B, and diagnosis of diabetes and hypertension. CHD was diagnosed by electrocardiogram and clinical events. Logistic regression was used to estimate odds ratio., Results: There were 50 incident cases of CHD. Using univariate logistic regression analysis, significant risk factors were intra-abdominal fat (P = 0.0090), fasting glucose (P = 0.0002), 2-h glucose (P = 0.0008), fasting HDL cholesterol (P = 0.0086), fasting HDL2 cholesterol (P = 0.030), fasting HDL3 cholesterol (P = 0.018), fasting triglycerides (P = 0.013), systolic (P = 0.0007) and diastolic blood pressure (P = 0.0002), and presence of diabetes (P = 0.0023). Multiple logistic regression models adjusted for BMI and age showed that intra-abdominal fat accounted for the effects of HDL cholesterol or triglycerides. In a multiple logistic regression model that included intra-abdominal fat, all systolic blood pressure and fasting glucose were significant. Substituting diastolic blood pressure for systolic blood pressure and 2-h glucose or diabetes status for fasting glucose produced similar results., Conclusions: Visceral adiposity, blood pressure, and plasma glucose are important independent risk factors for incident CHD in this population of diabetic and nondiabetic Japanese-American men.

Objective: Plasma leptin levels correlate strongly with increased total adipose tissue, a known risk factor for type 2 diabetes, yet the role of leptin in the etiology of diabetes remains unclear. We sought to determine whether leptin is a risk factor for development of diabetes in Japanese Americans., Research Design and Methods: We compared baseline leptin levels in 370 nondiabetic Japanese Americans who remained nondiabetic for 5-6 years of follow-up with those of 40 nondiabetic Japanese Americans who developed diabetes during follow-up. All participants had computed tomography measurements of baseline subcutaneous chest, abdomen, thigh, and intra-abdominal fat, with total fat defined as the sum of all these measurements., Results: The mean age was 51.7 +/- 11.7 years for men and 51.9 +/- 12.0 years for women. The 23 men who developed diabetes had significantly higher leptin levels than the 212 men who remained nondiabetic (P < 0.01). Among men, baseline leptin levels predicted diabetes risk independent of baseline total fat, insulin, insulin resistance, glucose, or age in separate multiple logistic regression models (relative risk adjusted for baseline total fat = 1.80 per SD increase [2.7 ng/ml], 95% CI 1.02-3.17). This association was particularly strong among men in the top decile for intra-abdominal fat. In contrast, the 17 women who developed diabetes had leptin levels similar to those of the 158 women who remained nondiabetic (P = 0.31)., Conclusions: Among Japanese Americans, increased baseline leptin levels are associated with increased risk of developing diabetes in men but not in women.

Although the hormone leptin seems to play a role in ensuring the maintenance of adequate energy stores and thereby protects against starvation, its role in the regulation of body weight and adiposity under normal circumstances is unclear. Overweight individuals have markedly elevated circulating leptin levels, suggesting that leptin's effect on food intake and thermogenesis is diminished or absent in obesity. Recent evidence, though, indicates that weight gain in Pima Indians is associated with relatively decreased levels of the hormone. Because it is important to understand whether a deficiency in circulating leptin contributes to the development of obesity, we sought to determine whether there is a relationship between leptin levels and subsequent changes in adiposity in a more typical population. We compared baseline plasma leptin concentrations to changes over 5 years in body weight, BMI, and computed tomography-determined total fat in 492 second- and third-generation Japanese Americans. Subjects were of 100% Japanese ancestry; male subjects had a mean BMI at baseline of 25.4 kg/m2 and a mean age of 54 years; female subjects had a mean BMI of 23.1 kg/m2 and a mean age of 53 years. Changes in weight (men: r = 0.17, P < 0.05; women: r = 0.20, P < 0.05), BMI (men: r = 0.17, P < 0.05; women: r = 0.18, P < 0.05), and total fat (men: r = 0.19, P < 0.05; women: r = 0.20, P < 0.01) were positively correlated with baseline leptin levels adjusted for baseline adiposity, fasting insulin, and age. In Japanese Americans, then, relatively increased leptin levels are associated with greater subsequent gains in weight and adiposity. We concluded that in this population, fat accumulation is associated not with leptin deficiency but possibly with leptin resistance and is preceded by increased leptin levels.

Studies to determine the efficacy of antiepileptic drugs often use seizure frequency as an outcome measure. Time to kth seizure (k up to 12) was investigated as an alternative endpoint. Monte Carlo simulations, based on seizure behavior in previous clinical trials, were used to evaluate crossover studies with these endpoints. exhibited the highest power. However, tests on time to the 12th seizure, for a sample size of 50, approached the power of tests on seizure frequency with a sample size of 20. Including patients with less severe epilepsy (two vs four seizures per month) did not change the power of tests on time to the kth seizure and lowered it only moderately for tests on seizure frequency. The simulation methodology presented can be adapted to evaluate other design variations.