Donna L. Leonetti

Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels

OBJECTIVE—We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS—A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI0–30/ΔG0–30). RESULTS—ΔI0–30/ΔG0–30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included −1 for ΔI0–30/ΔG0–30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included −1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI0–30/ΔG0–30 and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS—The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

Visceral Adiposity Is an Independent Predictor of Incident Hypertension in Japanese Americans

Context Central obesity and hypertension are well-established components of the metabolic syndrome, but what exactly is the relationship between visceral adiposity and hypertension? Contribution This prospective study used computed tomography to measure multiple body fat areas of 300 middle-aged, normotensive Japanese Americans. Ninety-two participants developed hypertension within 10 to 11 years. Greater visceral adiposity, independent of other measures of body fat and other risk factors, such as plasma insulin and glucose levels, was associated with increased risk for hypertension. Cautions Relationships between visceral adiposity and the development of hypertension may vary in different ethnic groups. The Editors A central pattern of body fat distribution is now generally considered to play an important role in the metabolic syndrome, which involves obesity, insulin resistance, hyperinsulinemia, dyslipidemia, glucose intolerance, and hypertension (1, 2). In particular, visceral adiposity rather than regional or generalized obesity appears to play a key role in these diseases (3-7). Several cross-sectional and prospective studies have examined associations between hypertension and greater central obesity, as measured by waist circumference, the ratio of waist-to-hip circumference, or the ratio of subscapular-to-triceps skinfold thickness (8-15). The cross-sectional studies have reported a positive association (8, 9), but the prospective studies have been inconclusive (10-15). These studies have posited that visceral adiposity and insulin resistance are the most important factors linking greater abdominal obesity (as assessed by surface measurements) and hypertension. Although visceral fat is thought to affect the prevalence of hypertension, only 3 cross-sectional studies have suggested a possible association between visceral adiposity (measured by using computed tomography [CT]) and blood pressure (3, 4, 16); however, the results of these studies were inconclusive. No prospective studies have examined whether directly measured visceral fat is associated with an increased risk for incident hypertension. Therefore, we prospectively examined the relationship between directly measured visceral adiposity and the risk for incident hypertension, independent of other measurements of total and regional adiposity and fasting plasma insulin. Methods Study Sample Between 1983 and 1988, we enrolled 658 second- and third-generation Japanese Americans who were between 34 and 76 years of age (mean age, 54.2 years) into the Japanese American Community Diabetes Study (17, 18). Participants were chosen from volunteers through community-wide recruitment and were representative of Japanese-American residents of King County, Washington, in age distribution, residential distribution, and parental immigration pattern. A comprehensive mailing list and telephone directory that included almost 95% of the Japanese-American population of King County, Washington, was used. All participants were of 100% Japanese ancestry. Participants returned for follow-up examinations 5 to 6 and 10 to 11 years after a baseline evaluation. For the current analysis, eligible participants had systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg and were not taking antihypertensive or oral hypoglycemic medications or insulin. We excluded 277 of the 658 participants in the original cohort because they did not meet the inclusion criteria. We excluded an additional 67 persons because of death, loss to follow-up, or withdrawal from the study. Another 14 persons who completed follow-up but had missing covariate information were also excluded. The analytic cohort consisted of 300 persons (Figure). The follow-up rate in the present study was 91% (345 of 381) at the 5- to 6-year examination and 80% (304 of 381) at the 10- to 11-year examination (Figure). Figure. Flow of participants through the study. Data Collection All measurements were made in the General Clinical Research Center at the University of Washington, Seattle, Washington. The Human Subjects Review Committee at the University of Washington approved the protocol for this research, and we obtained signed informed consent from all participants. At all examinations, blood pressure was measured to the nearest 2 mm Hg with a mercury sphygmomanometer while the participant was in a recumbent position. Systolic blood pressure was determined by the first perception of sound, and diastolic blood pressure was determined at the disappearance of sounds (fifth-phase Korotkoff). Average blood pressure was calculated from the second and third of 3 consecutive measurements. We diagnosed hypertension at baseline or follow-up if the average systolic blood pressure was 140 mm Hg or greater, the average diastolic blood pressure was 90 mm Hg or greater, or the participant was receiving antihypertensive medications. We classified participants as hypertensive if they met these criteria at the follow-up examination at 5 to 6 years or 10 to 11 years (Figure). All patients received a 75-g oral glucose tolerance test after a 10-hour fast. We then used the American Diabetes Association criteria (19) to classify patients as having normal glucose tolerance, impaired glucose tolerance, or type 2 diabetes mellitus. Blood samples were drawn after an overnight 10-hour fast and during an oral glucose tolerance test for measurement of plasma glucose and insulin levels. We used an automated glucose oxidase method to assay plasma glucose. Fasting plasma insulin was measured by radioimmunoassay, as reported previously (5, 7). We measured triglyceride and high-density lipoprotein cholesterol levels in the Northwest Lipid Research Laboratory, according to modified procedures of the Lipid Research Clinics (20). We calculated body mass index (BMI) as the weight in kilograms divided by height in meters squared. For CT scans, we used single slices of the thorax, abdomen (at the umbilicus), and mid-thigh to measure cross-sectional subcutaneous thoracic, abdominal, and right thigh and intra-abdominal fat areas (measured in cm2), as described elsewhere (21). We directly estimated visceral adiposity from the intra-abdominal fat area. This measurement has been reported to have a high correlation with directly ascertained total visceral fat volume measured by using CT or magnetic resonance imaging (22, 23). We calculated total subcutaneous fat area as the sum of subcutaneous thoracic and abdominal fat areas and twice the right thigh subcutaneous fat area. We defined total fat area as total subcutaneous fat area plus intra-abdominal fat area. Among Japanese Americans, total fat area correlates highly with fat mass, as measured by hydrodensitometry (r= 0.89 to 0.94) (24). Waist circumference was measured at the level of the umbilicus to the nearest tenth of a centimeter. Participants were questioned about current use of cigarettes and daily consumption of alcoholic beverages, which was converted into grams of alcohol consumed per day. Usual weekly energy expenditure in kilocalories was estimated from questionnaire data on work and recreational activities, strenuous exercise, distance walked, and stairs climbed, as described elsewhere (25). Statistical Analysis We used multiple logistic regression analysis to estimate the odds ratio for incident hypertension in relation to an increase of 1 SD in baseline variables. For rare outcomes, the odds ratio will approximately equal the relative risk. For more frequent outcomes, such as hypertension, the odds ratio will overestimate the relative risk (26). We evaluated nonlinear effects of continuous independent variables by using quadratic and log transformations (27). The linear trends in odds were evaluated by using the median value for each quartile category of continuous variables. To assess departure from linearity, we included linear and quadratic terms (the median and the value squared) in the model (28). To determine whether interaction was present (that is, the relationship between the risk factor and the outcome varied depending on the value of a third variable) (27, 29, 30), we inserted first-order interaction terms into appropriate regression models. We assessed interaction to determine whether the relationship between hypertension status at follow-up and baseline adipose variables, such as intra-abdominal fat area, subcutaneous abdominal fat area, total subcutaneous fat area, BMI, or waist circumference, differed according to the level of an additional variable (for example, sex) in the model. We used the likelihood ratio test to determine the statistical significance of nonlinear effects of continuous independent variables and interaction terms in the logistic regression models. Multicollinearity was assessed by using the variance inflation factor (31). A variance inflation factor exceeding 10 is regarded as indicating serious multicollinearity, and values greater than 4.0 may be a cause for concern (31). We calculated the 95% CI for each odds ratio. P values were 2-tailed. We performed statistical analyses using Stata SE, version 8.0 (Stata Corp., College Station, Texas). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Among the 300 eligible men and women followed for 10 to 11 years, there were 92 incident cases of hypertension. In univariate logistic regression analysis, intra-abdominal fat area, abdominal subcutaneous fat area, total subcutaneous fat area, total fat area, BMI, and waist circumference were associated with a higher incidence of hypertension. Fasting plasma insulin level, fasting plasma glucose level, 2-hour plasma glucose level, and high-density lipoprotein cholesterol level were also associated with incidence of hypertension (Table 1). Wealso compared the baseline characteristics of participants included in

Association of Elevated Fasting C-Peptide Level and Increased Intra-Abdominal Fat Distribution With Development of NIDDM in Japanese-American Men

The Japanese-American population of King County, Washington, is known to have a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). As part of a community-based study, we reexamined 146 second-generation Japanese-American men who had been initially classified as nondiabetic. At a mean follow-up period of 30 mo, 15 men had developed NIDDM, and 131 remained nondiabetic. The variables measured at the initial visit that distinguished the 15 diabetic men from the 131 nondiabetic men were older age, higher serum glucose level at 2 h after 75 g oral glucose, higher fasting plasma C-peptide level, and increased cross-sectional intra-abdominal fat area as determined by computed tomography. Both older age and higher 2-h glucose levels are variables that have been associated with the development of NIDDM, but the association of higher fasting C-peptide level and greater intra-abdominal fat area with subsequent development of NIDDM were new observations. The elevated fasting C-peptide level persisted after adjustment for fasting serum glucose. The elevated C-peptide level represents hypersecretion of insulin and was interpreted to reflect a compensatory response to an underlying insulin-resistant state that antedates the development of NIDDM. The fasting C-peptide level was correlated with the intra-abdominal fat area, suggesting that the intra-abdominal fat area may be associated with insulin resistance. Thus, in individuals who develop NIDDM, insulin resistance, increased insulin secretion, and increased intra-abdominal fat are present before diabetic glucose tolerance can be demonstrated.

Prevalence of diabetes mellitus and impaired glucose tolerance among second-generation Japanese-American men.

We describe the initial findings from a multidisciplinary, epidemiologic study of diabetes mellitus conducted in a population of secondgeneration Japanese-American (Nisei) men born between 1910 and 1939 who reside in King County, Washington (n = 1746). From this study population, 487 volunteered, and 229 were enrolled to comprise the study sample. A random sample of Nisei men was also drawn from the population to develop a reference sample of 189 men. All subjects participated in a 75-g oral glucose tolerance test; the National Diabetes Data Group (NDDG) and World Health Organization (WHO) diagnostic criteria as well as a modification of the WHO criteria were used to classify individuals with normal glucose tolerance, impaired glucose tolerance (IGT), or diabetes. Within the study sample, 79 men were found to have normal glucose tolerance, 72 had IGT, and 78 had type II diabetes. The mean age of the study sample was 61.4 yr. Based on comparison of the study sample to the reference sample, the study sample was ascertained to be representative of Nisei men in King County. Extrapolating from our observations in the reference sample and in the study sample, we have estimated that ∼56% of Nisei men in the study population have abnormal glucose tolerance. Much of this is undiagnosed because only ∼13% of the reference sample of Nisei men reported a prior diagnosis of diabetes. Of the men who enrolled in the study as nondiabetic subjects, 11.1% had diabetes and 39.2% had IGT; i.e., 50.3% had previously unknown abnormalities in glucose tolerance. We estimate that ∼20% of Nisei men have diabetes (both previously diagnosed and undiagnosed) and ∼36% have IGT.

Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men.

OBJECTIVE: To examine the association between baseline testosterone levels and changes in visceral adiposity in Japanese-American men.DESIGN: Prospective observational study.SUBJECTS: Second-generation Japanese-American males enrolled in a community-based population study.MEASUREMENTS: At baseline, 110 men received a 75 g oral glucose tolerance test (OGTT), and an assessment of body mass index (BMI); visceral adiposity measured as intra-abdominal fat area (IAF) using computed tomography (CT); fasting insulin and C-peptide levels; and total testosterone levels. IAF was re-measured after 7.5 y. Subcutaneous fat areas were also measured by CT in the abdomen, thorax and thigh. The total fat (TF) was calculated as the sum of IAF and total subcutanous fat areas (SCF).RESULTS: After 7.5 y, IAF increased by a mean of 8.0 cm2 (95% CI: 0.8, 15.3). Baseline total testosterone was significantly correlated with change in IAF (r=−0.26, P=0.006), but not to any appreciable degree with change in BMI, TF, or SCF. In a linear regression model with change in IAF as the dependent variable, baseline testosterone was significantly related to this outcome while adjusting for baseline IAF, SCF, BMI, age, diabetes mellitus status (OGTT by the WHO diagnostic criteria) and fasting C-peptide (regression coefficient for baseline testosterone [nmol/l;[equals;−107.13, P=0.003).CONCLUSIONS: In this Japanese-American male cohort, lower baseline total testosterone independently predicts an increase in IAF. This would suggest that by predisposing to an increase in visceral adiposity, low levels of testosterone may increase the risk of type 2 diabetes mellitus.

Intergenerational Wealth Transmission and the Dynamics of Inequality in Small-Scale Societies

Origins of Egalitarianism Wealthy contemporary societies exhibit varying extents of economic inequality, with the Nordic countries being relatively egalitarian, whereas there is a much larger gap between top and bottom in the United States. Borgerhoff Mulder et al. (p. 682; see the Perspective by Acemoglu and Robinson) build a bare-bones model describing the intergenerational transmission of three different types of wealth—based on social networks, land and livestock, and physical and cognitive capacity—in four types of small-scale societies in which livelihoods depended primarily on hunting, herding, farming, or horticulture. Parameter estimates from a large-scale analysis of historical and ethnographic data were added to the model to reveal that the four types of societies display distinctive patterns of wealth transmission and that these patterns are associated with different extents of inequality. Some types of wealth are strongly inherited and, hence, contribute to long-term economic inequality. Small-scale human societies range from foraging bands with a strong egalitarian ethos to more economically stratified agrarian and pastoral societies. We explain this variation in inequality using a dynamic model in which a population’s long-run steady-state level of inequality depends on the extent to which its most important forms of wealth are transmitted within families across generations. We estimate the degree of intergenerational transmission of three different types of wealth (material, embodied, and relational), as well as the extent of wealth inequality in 21 historical and contemporary populations. We show that intergenerational transmission of wealth and wealth inequality are substantial among pastoral and small-scale agricultural societies (on a par with or even exceeding the most unequal modern industrial economies) but are limited among horticultural and foraging peoples (equivalent to the most egalitarian of modern industrial populations). Differences in the technology by which a people derive their livelihood and in the institutions and norms making up the economic system jointly contribute to this pattern.

Visceral Adiposity, not Abdominal Subcutaneous Fat Area, Is Associated with an Increase in Future Insulin Resistance in Japanese Americans

OBJECTIVE—Visceral adiposity is generally considered to play a key role in the metabolic syndrome. We sought to determine whether greater visceral adiposity directly measured by computed tomography (CT) is associated with increased future insulin resistance independent of other adipose depots. RESEARCH DESIGN AND METHODS— We followed 306 nondiabetic Japanese Americans over 10–11 years. Baseline variables included BMI; waist circumference; and abdominal, thoracic, and thigh fat areas measured by CT. Total fat area was estimated by the sum of all of these fat areas. Visceral adiposity was measured as intra-abdominal fat area at the umbilicus level. Total subcutaneous fat area was defined as total fat area minus intra-abdominal fat area. Insulin resistance was evaluated by homeostasis model assessment for insulin resistance (HOMA-IR), fasting plasma insulin level, Matsuda index, and area under the oral glucose tolerance test curve (AUC) of insulin. RESULTS— Both baseline intra-abdominal fat area (P = 0.002) and HOMA-IR (P < 0.001) were independently associated with increased HOMA-IR at 10–11 years in a multiple linear regression model after adjustment for abdominal subcutaneous fat area, age, sex, 2-h plasma glucose level, and incremental insulin response. Intra-abdominal fat area remained a significant predictor of increased HOMA-IR at 10–11 years even after adjustment for total subcutaneous fat area, total fat area, BMI, or waist circumference, but no other measure of CT-measured regional or total adiposity was significantly related with HOMA-IR at 10–11 years in models that contained intra-abdominal fat area. Similar results were obtained for predicting future fasting plasma insulin level, Matsuda index, and AUC of insulin. CONCLUSIONS— Greater visceral adiposity is associated with an increase in future insulin resistance.

Abnormal Body Fat Distribution Detected by Computed Tomography in Diabetic Men

Previous studies of body fat using tape measurement of body circumference and hand-held caliper skinfold measurements have suggested abnormal fat distribution in patients with diabetes mellitus. These methods, however, have high interobserver variability and cannot assess intra-abdominal fat independent of subcutaneous fat. We used computed tomography to evaluate body fat distribution in a group of 53 Japanese-American men of similar age and body mass index (weight divided by height squared). As determined by a 75-g oral glucose tolerance test, 29 subjects had type II diabetes and 24 were normal. Computed tomography cuts were obtained at three body levels to measure thorax, abdomen, and thigh subcutaneous fat area as well as intra-abdominal fat area. We found greater intra-abdominal fat in men with diabetes than in those without (123.74 vs. 95.54 cm2, P = 0.034) and a greater ratio of thorax to thigh subcutaneous fat (2.55 vs. 1.88, P = 0.016). These findings support the hypothesis that fat in different areas of the body differs metabolically. Computed tomography can be a useful tool for investigating whether abnormal body fat distribution is associated with the pathogenesis of abnormal glucose tolerance.

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.

OBJECTIVE To identify risk factors for development of non-insulin-dependent diabetes mellitus (NIDDM) during a 5-year longitudinal follow-up of second-generation Japanese-American (Nisei) men. RESEARCH DESIGN AND METHODS For 5 years, 137 initially nondiabetic Nisei men were followed with 75-g oral glucose tolerance tests at the initial visit and at 2.5- and 5-year follow-up visits. Body fat distribution was assessed by computed tomography (CT) and body mass index (BMI) calculated at each visit. Fasting insulin and C-peptide, the increment of insulin and C-peptide at 30 min after the oral glucose load, intra-abdominal and total subcutaneous fat by CT, and BMI were compared between those who remained nondiabetic (non-DM) and those who had developed NIDDM at 2.5 years (DM-A) and 5 years (DM-B). RESULTS At baseline, the DM-A group had significantly increased intra-abdominal fat, elevated fasting plasma C-peptide, and lower C-peptide response at 30 min after oral glucose. At the 2.5-year follow-up, this group had markedly increased fasting plasma insulin and decreased 30-min insulin and C-peptide response to oral glucose. The DM-B group also had significantly lower insulin response at 30 min after oral glucose at baseline but no significant difference in intra-abdominal fat or fasting plasma insulin and C-peptide levels. When this group developed NIDDM by 5-year follow-up, however, an increase of intra-abdominal fat was found superimposed on the pre-existing lower insulin response. Fasting plasma insulin and C-peptide remained low. CONCLUSION In DM-A, lower 30-min insulin response to oral glucose (an indicator of β-cell lesion) and increased intra-abdominal fat and fasting C-peptide (indicators of insulin resistance) were the risk factors related to the development of NIDDM. DM-B subjects had a lower 30-min insulin response to oral glucose at baseline and increased intra-abdominal fat at 5-years, when they were found to have NIDDM. Thus, both insulin resistance and impaired β-cell function contribute to the development of NIDDM in Japanese-Americans, and impaired β-cell function may be present earlier than visceral adiposity in some who subsequently develop NIDDM.

Proinsulin as a Marker for the Development of NIDDM in Japanese-American Men

Disproportionate hyperproinsulinemia is one manifestation of the B-cell dysfunction observed in non-insulin-dependent diabetes mellitus (NIDDM), but it is unclear when this abnormality develops and whether it predicts the development of NIDDM. At baseline, measurements of proinsulin (PI) and immunoreactive insulin (IRI) levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM, and, by using World Health Organization criteria, subjects were categorized as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, they were recategorized as NGT, IGT, or NIDDM using the same criteria. After 5 years, 16 subjects had developed NTODM, while 71 had NGT or IGT. Individuals who developed NIDDM were more obese at baseline, measured as intra-abdominal fat (IAF) area on computed tomography (P = 0.046) but did not differ in age from those who continued to have NGT or IGT. At baseline, subjects who subsequently developed NIDDM had higher fasting glucose (P = 0.0042), 2-h glucose (P = 0.0002), fasting C-peptide (P = 0.0011), and fasting PI levels (P = 0.0033) and disproportionate hyperproinsulinemia (P = 0.056) than those who continued to have NGT or IGT after 5 years of follow-up. NIDDM incidence was positively correlated with the absolute fasting PI level (relative odds = 2.35; P = 0.0025), even after adjustment for fasting IRI, IAF, and body mass index (relative odds = 2.17; P = 0.013). Because 12 of the 16 subjects who developed NTODM had IGT at baseline, the 38 IGT subjects were also examined separately. In this cohort, the same risk factors (fasting and 2-h glucose, fasting C-peptide, and fasting PI levels) were predictive for the development of NIDDM. We conclude that Japanese-American men who subsequently develop NIDDM have more IAF and increased glucose, C-peptide, and PI levels. These data suggest that alterations in PI may be a new marker for the subsequent development of NTODM.