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Endocrine Hypertension Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Annaswamy Raji, M.D., Endocrine-Hypertension Division, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: araji{at}partners.org
Abstract
Previous studies have shown that Asian Indians (AIs) are insulin resistant and at high risk for developing diabetes and coronary heart disease, compared with Caucasians. To examine whether differences in body fat distribution contribute to this risk, 12 healthy AIs and 12 Caucasians matched for age and body mass index (BMI) underwent a 75-g oral glucose tolerance test, 2-h euglycemic hyperinsulinemic clamp, abdominal (L2–3) computed tomography scan, and fasting lipid and plasminogen activator inhibitor-1 (PAI-1) levels. Despite similar fasting plasma glucose levels, AIs exhibited fasting hyperinsulinemia (P = 0.001), higher glucose (P = 0.03) and insulin (P = 0.004) levels during the oral glucose tolerance test, and reduced glucose disposal rate (Rd) (4.7 ± 0.4 vs. 7.5 ± 0.3 mg/kg per min, P < 0.0001) during the clamp. AIs had significantly lower high-density lipoprotein, higher low-density lipoprotein, and significantly higher PAI-1 levels (P = 0.01). Despite similar BMI, AIs had significantly greater total abdominal fat (P = 0.04) and visceral fat (P = 0.04). In all subjects, measures of fat mass were inversely correlated with Rd during the clamp (r = -0.47 to -0.61, P < 0.01–0.001). Visceral fat mass was correlated with triglycerides, low-density lipoprotein, and high-density lipoprotein (P < 0.002–0.0001). PAI-1 was inversely correlated with Rd in AIs (r = -0.70, P < 0.01) and not in Caucasians (r = -0.24, P = 0.44). For comparable BMI and age, healthy AIs have physiologic markers for insulin resistance, dyslipidemia, and increased cardiovascular risk, compared with Caucasians. Alterations in body fat distribution—particularly increased visceral fat—may contribute to these abnormalities.
IT HAS BEEN observed for some time that South Asian (Indian, Pakistani, Bangladeshi, and Sri Lankan) immigrants have a high rate of insulin resistance and hyperinsulinemia (1, 2, 3, 4, 5, 6, 7). They also have a higher incidence of type 2 diabetes (DM) and coronary artery disease (CAD) in comparison with Caucasians and other ethnic groups in the United Kingdom, United States, and South Africa (8). The prevalence of DM in migrant Indians living in the UK, US, and South Africa is as high as 16% (9, 10, 11, 12), and the CAD incidence is estimated to be about 1.5- to 10-fold higher than in the general population of the host country (1, 8, 13, 14). The high prevalence of DM and CAD in migrant and urban Asian Indians is not completely explained by the traditional risk factors of Caucasians such as hypertension, hyperlipidemia, and smoking (8, 9, 10).
Epidemiological studies (1, 15, 16) have shown that South Asians also are more likely to have central obesity, increased waist/hip ratio (WHR), and glucose intolerance, compared with Caucasians. However, data related to increased WHR and prevalence of diabetes in Asian Indians are controversial, and detailed studies of body fat distribution in relation to insulin resistance have not been reported (1, 12, 17). Increased visceral fat in Asian Indians usually has been associated with increased generalized obesity, which often is not apparent from their body mass index (BMI) that is in the normal range as defined by standard weight tables and other readily available criteria.
Increased visceral fat is related to dyslipidemia and increased frequency of insulin resistance and may account for the increased prevalence of DM and CAD in Asian Indians (18). Other abnormalities reported in insulin-resistant Asian Indians are increased plasminogen activator inhibitor-1 (PAI-1), increased platelet activation, and elevated fibrinogen levels (18, 19, 20, 21, 22). All these factors would appear to put them at high risk for atherosclerosis and thrombosis (23).
This study was designed to examine the relationship of insulin sensitivity (using the insulin clamp technique) to visceral fat [measured by abdominal computed tomography (CT) scan], PAI-1, and lipid profiles in healthy immigrant Asian Indians and Caucasians matched for age and BMI. We also assessed the relationship between the diet and physical activity and insulin sensitivity in the two populations.
Subjects and Methods
Two groups of subjects participated in the study: 12 Asian Indians and 12 Caucasians of European ancestry between the ages of 20 and 65 yr living in eastern Massachusetts. Groups were matched for age, gender, and BMI. All subjects were given a physical activity questionnaire and a 3-d food diary to assess their dietary intake at the time of their initial visit. Women were studied during the follicular phase of their menstrual cycle to decrease the potential influence of gonadal steroids on insulin action. The study was approved by the institutional review board of the Brigham and Women’s Hospital. After obtaining written informed consent, volunteers were screened for hematological and blood chemistry abnormalities, and those enrolled had no underlying medical problems including diabetes, hypertension, CAD, hyperlipidemias, or liver or kidney disease.
Oral glucose tolerance test (OGTT)
A standard 75-g OGTT (Tru-Glu 75, Custom Laboratories, Inc., Baltimore, MD) was given to the subjects after an 8-h overnight fast on the day of their physical examination. An iv catheter was placed in a forearm vein and blood collected for determination of glucose and insulin concentrations before glucose administration and at 30-min intervals for 120 min thereafter.
Anthropometric measurements
Height and weight were measured by standard procedures. The WHR was performed using flexible measuring tape with the subject standing. The waist circumference was measured at the narrowest circumference between the lower costal margin and the iliac crest, and the hip was measured at the maximum circumference at the level of the femoral trochanters. Body composition was measured using bioelectrical impedance (RJL Systems, Clinton Township, MI) to determine total fat and fat free mass. The same investigator performed all the anthropometric and bioelectric impedance measurements to minimize interinvestigator variability.
Computed axial tomography. Intraabdominal fat was determined by CT scan of the abdomen (Somaton 4, Siemens, Erlanger, Germany). Two slices were obtained: one at the lumbar 2–3 level and the other at lumbar 3–4 level using 120 kV and 100 mA. Calculation of area was done by measurements of pixels with density within specific attenuation numbers. Fat was defined as having attenuation number -150 to -15 and soft tissues as -15 to +100 Hounsfield units. The whole area measurement included attenuation values from -150 to +3000 Hounsfield units (including bone).
Euglycemic hyperinsulinemic clamp technique. Insulin sensitivity was measured using the insulin clamp technique as previously described (24, 25). In brief, all subjects were placed on a 200- to 300-g carbohydrate diet for 3 d before the study. The study was performed at the General Clinical Research Center following an overnight fast with the subject remaining supine until the completion of the study. Intravenous lines were placed in one antecubital vein for the administration of test substances and in a hand vein for blood drawing. After basal samples were collected, insulin (Novolin U-100, Novo Nordisk, Princeton, NJ) was infused at a constant rate of 40 mU/m2 per min for 120 min in all subjects (after a priming dose of 80 mU/m2 per min over the first 10 min). Blood samples were obtained every 5 min from a catheter placed retrograde in a dorsal vein of a hand kept in a hand warmer thermostatically controlled at 70 C to arterialize venous blood. Dextrose solution (20%) was infused to maintain plasma glucose at fasting levels throughout clamp procedure, according to the method of Defronzo et al. (24). During the euglycemic clamp procedure, blood samples were also drawn at timed intervals to measure PAI-1 (0, 30, 90, 105, and 120 min). The rate of glucose disposal was calculated as the mean glucose infusion rate during the last 40 min of the clamp after correcting for changes in the plasma glucose concentration during the interval.
Biochemical analyses
Plasma glucose was assayed by the glucose oxidase method (glucose analyzer, Hemacue, Inc., Mission Viejo, CA). Plasma insulin levels were determined by RIA (Linco Research, Inc., St. Louis, MO). Plasma samples were assayed for PAI-1 antigen at Vanderbilt University using a two-site ELISA (Biopool AB, Umea, Sweden).
Analysis
All statistical analyses were carried out using the SAS (Cary,
NC) and STATA (College Station, TX) statistical software.
Standard statistical tests comparing the two groups include
t tests for means, Wilcoxon rank sum test in which ranks are
appropriate, and 
-square tests for categorical variables. Linear and
multiple regression analysis were also performed to examine
associations between insulin sensitivity and key predictor variables.
Baseline demographic data are expressed as mean ±
SD, whereas all other summary data are expressed
as mean ± SE.
Results
The clinical characteristics and the laboratory results of the
subjects are given in Tables 1
and 2.
Despite similar age (34 ± 10 vs. 35 ± 13 yr) and
BMI (23 ± 2 vs. 24 ± 3
kg/m2), Asian
Indians had significantly elevated fasting insulin (P =
0.001) and a slightly higher fasting glucose than Caucasians of
European descent. Moreover, they had higher areas under the curve for
both glucose (P = 0.03) and insulin (P
= 0.004) during the OGTT. There was no significant difference in the
waist circumference or the WHR between the two groups
(P = 0.15). There was also no significant difference in
the fat free mass measured by bioelectric impedance between the two
groups.
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Insulin action and body composition
Despite similar age and BMI, the Asian Indians had significantly
lower glucose disposal rates (P < 0.001) during the
insulin clamp, compared with Caucasians (Fig. 1). Insulin-mediated glucose disposal was
also inversely related to fasting insulin (r = -0.72,
P = 0.0001) and areas under the curve for insulin
(r = -0.66, P = 0.01) during the OGTT in Asian
Indians, confirming a relationship of hyperinsulinemia to insulin
resistance in this population.
|
shows
that insulin-mediated glucose disposal (Rd) was
inversely correlated with all compartments of abdominal adipose tissue
including total (r = -0.61, P < 0.001), sc
(r = -0.47, P < 0.01), and visceral fat (r
= -0.55, P < 0.005). When the two groups were
analyzed individually, the inverse correlations of
Rd with all compartments of fat were maintained,
suggesting that for any given change in the abdominal fat, there is a
proportional change in the Rd rate. The
y-intercepts for both groups were different indicating that there may
be factors (genetic or environmental) other than body fat distribution
contributing to the decreased insulin sensitivity in the Asian Indian
population.
|
Because of the high prevalence of coronary artery disease in Asian
Indians, we measured lipids and PAI-1 in both groups and also
investigated the relationship among lipids, visceral fat, and insulin
action (Table 2
). Asian Indians had significantly increased low-density
lipoprotein (LDL) (P = 0.04) and triglycerides
(P = 0.06) and significantly lower high-density
lipoprotein (HDL) (P = 0.02), compared with Caucasians.
There was a significant inverse correlation among triglycerides, LDL
and Rd (r = -0.56, P <
0.003, and r = -0.44, P < 0.03), and also a
positive correlation with HDL (r = 0.41, P <
0.04). In terms of the relationship between lipids and different
compartments of intraabdominal fat, LDL (r = 0.64,
P < 0.001), triglycerides (r = 0.80,
P < 0.001), and HDL (r = -0.59,
P < 0.02) correlated with visceral fat but not
statistically significantly with sc fat. PAI-1 was increased
significantly in Asian Indians, compared with Caucasians (Table 2,
P < 0.01). PAI-1 was significantly inversely
correlated with glucose disposal in Asian Indians (r = -0.70,
P < 0.01) but not in Caucasians (r = -0.24,
P = 0.44, Fig. 3). In
both groups combined, there was a significant positive correlation
between PAI-1 and different compartments of abdominal fat (total fat:
r = 0.70, P < 0.0001, sc fat: r = 0.46;
P < 0.02; visceral fat: r = 0.62,
P < 0.001). When the two groups were analyzed
individually, strong positive correlation was maintained in Asian
Indians for total and visceral fat, compared with Caucasians who
maintained a very weak correlation. The relationship was similar to
that between Rd and the different compartments of
fat in these two groups.
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The results of our study demonstrate that healthy, normal-weight Asian Indians are profoundly insulin resistant and hyperinsulinemic, compared with age- and BMI-matched Caucasians. Moreover, Asian Indians have greater amounts of total, visceral, and sc fat by CT scan, compared with Caucasians matched for BMI, and the measures of fat were inversely related to Rd. Asian Indians also have lower HDL and higher LDL and triglycerides, compared with Caucasians, and triglycerides and LDL correlated significantly with visceral fat. PAI-1 levels were also significantly elevated and were correlated with Rd in Asian Indians. These data support the hypothesis that altered body composition is associated with insulin resistance, hyperinsulinemia, and dyslipidemia in Asian Indians, and this may explain their increased risk for diabetes and CAD.
The two groups studied had an average BMI of 23–24 kg/m2, which is not in a range considered to be obese or at risk for diabetes and other complications related to obesity in the general population. Despite the normal BMIs, however, Asian Indians were profoundly insulin resistant, suggesting the possibility that insulin resistance in this population is related more to regional than general adiposity. These features of Asian Indians are reminiscent of a term described by Ruderman (26): "metabolically obese," normal-weight individuals. He proposed that metabolically obese individuals with a history of diabetes, hypertension, and hypertriglyceridemia might be characterized by hyperinsulinemia and also have increased fat cell size. In a previous study, McKeigue et al. (1) examined the relationship between central adiposity and insulin resistance in migrant Asian Indians in the UK and found for similar BMI the 4-fold increase in diabetes in Asian Indians was associated with higher WHR, compared with Europeans living in the UK. Also, for every level of WHR, migrant Asian Indians had higher fasting insulin levels and were more insulin resistant, compared with their European counterparts. Studies from India comparing rural and urban populations also showed that a 5-fold increased prevalence of diabetes in urban populations was associated with an increase in BMI but not WHR (12).
Our measurement of abdominal adiposity using the more precise CT scan may help to clarify some discrepancies seen in the literature. Our findings suggest that Asian Indians have more total, sc, and visceral fat for similar BMI and age, compared with Caucasians, and all compartments of fat were inversely correlated with glucose disposal measured by the insulin clamp. We did not find a difference in the WHR, suggesting that this method may not be sensitive enough to detect important differences in body composition in this population. The high abdominal fat in Asian Indians may explain the hyperinsulinemia and high risk for diabetes and cardiovascular disease in this population. Our results are consistent with those of Banerji et al. (18), who in a study of healthy nonobese Asian Indian men, found them to be insulin resistant with a high percentage of body fat relative to their BMI and muscle mass and showed that their insulin resistance correlated with visceral but not sc adipose tissue volume.
Studies have shown that anthropometric measures, such as BMI, WHR, and waist circumference, are not comparable across different racial populations (28). This raises an important issue regarding the use of BMI across different races in the definition of obesity and predicting risk associated with obesity on the basis of BMI. There are many indications, however, that in some ethnic groups (particularly of Asian origin), the risk of diabetes starts to increase rapidly at levels of BMI or waist circumference well in the acceptable range for Europeans (29). This may imply that cut-off points, as recommended for European Caucasian populations (BMI > 30kg/m2 or waist larger than 88 cm for women and 102 cm for men) have little value in identifying Asian individuals at high risk. Our data suggest that, even at lower BMI, Asian Indians are profoundly insulin resistant and have increased total abdominal fat, which may explain their predilection for increased diabetes and coronary heart disease. Lowering the cut-off points, especially in Asian populations, may be beneficial in identifying individuals at high risk for developing diabetes and its complications. Large-scale studies need to be undertaken to address the above issue.
Our data further indicate that the increase in total, visceral, and sc abdominal fat were inversely correlated to Rd in both Asian Indians and Caucasians. There have been several mechanistic and population studies highlighting the association of visceral and sc fat with insulin resistance (18, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38). There is some controversy as to which compartment of fat is metabolically important and associated with insulin resistance. The reasons for this may be attributed in part to variations in race, gender, and degree of obesity or the fact that there is a close correlation among all the different adipose tissue compartments. Despite the recognized importance of visceral fat with regard to abnormal glucose metabolism, there has been little research on whether directly measured intraabdominal fat is prospectively related to the incidence of diabetes. Recently Boyko et al. (39) have shown that greater visceral adiposity precedes the development of type 2 diabetes in Japanese Americans. Moreover, this effect was independent of fasting insulin, insulin secretion, glycemia, and total and regional adiposity.
We also found that the linear relationship between Rd and different compartments of fat was similar in both Asian Indians and Caucasians. This does not allow us to specifically determine which compartment of fat is of primary importance in the etiology of insulin resistance. However, in our data the intercepts of the regression lines in both groups were significantly different (P < 0.0001), suggesting that there may be factors (genetic, metabolic, or environmental) other than body fat distribution contributing to the increased insulin resistance seen in Asian Indians. Therefore, it is conceivable that ethnic differences in the manifestations of insulin resistance are likely the result of genetic susceptibility and variable interaction between genetic and acquired factors.
We know that PAI-1, a potent inhibitor of fibrinolysis, is raised in
diabetes and that it may contribute to excess cardiovascular disease.
Our results show that there is a statistically significant inverse
relationship between glucose disposal and PAI-1 in Asian Indians but
not in Caucasians. This may suggest that there is some true mechanistic
difference between Asian Indians and Caucasians in terms of their
relationship between PAI-1 and Rd. From
inspection, we cannot determine with certainty whether the two groups
differ in their relationship between PAI-1 and Rd
because Caucasians had less variability in their insulin sensitivity
and had minimal overlap with the Asian Indian subjects (Fig. 3).
However, it has been shown that in other populations with increased
insulin resistance, PAI-1 differs among racial groups
(22). Thus, there may be a unique relationship between
insulin resistance and PAI-1 in Asian Indians that may explain their
predisposition to CAD at a much younger age than other populations.
We acknowledge that there are limitations to our study. This was an observational cross-sectional study and our sample size was small. In addition, because metabolic tracers were not used to measure hepatic glucose production, we cannot determine whether insulin resistance was predominantly in the muscle or liver. Nevertheless, the results of our study are consistent with larger epidemiological studies and physiologic mechanisms linking visceral fat, insulin resistance, and cardiovascular risk factors such as lipids and PAI-1. Larger studies are needed to explore the mechanisms of insulin resistance and its relationship to heart disease in Asian Indians and to determine whether appropriate interventions can reduce this risk.
In conclusion, clustering of cardiovascular risk factors or the components of the insulin resistance syndrome occurs in apparently healthy Asian Indians with normal BMI.
Altered body composition with greater abdominal fat is associated with insulin resistance, hyperinsulinemia, and dyslipidemia in this population. Insulin resistance with resultant dyslipidemia and increased visceral fat may be responsible for the increased prevalence of diabetes and coronary artery disease in Asian Indians. This finding underscores the need for preventive approaches to metabolic disorders and coronary artery disease in this population. Pharmacological or nonpharmacological approaches to alter body fat distribution may play a role in reducing insulin resistance and its adverse consequences in Asian Indians.
Acknowledgments
We are grateful to the staff at the General Research Clinical Center at the Brigham and Women’s Hospital and Dr. Vassilios Raptopoulos for his expertise in reading the CT scans.
Footnotes
This work was supported by GCRC funding by a grant from the National Institutes of Research Resources (M01RR02635) and an unrestricted educational grant from Aventis Pharmaceuticals.
Abbreviations: BMI, Body mass index; CAD, coronary artery disease; CT, computed tomography; DM, type 2 diabetes; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; Rd, glucose disposal; WHR, waist/hip ratio.
Received March 20, 2001.
Accepted July 20, 2001.
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