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Division of Endocrinology, Diabetes, and Metabolism (A.R., M.W., D.C.S.), Cardiovascular Division (M.D.G.-H.), and Department of Radiology (S.G.S.), Brigham and Women’s Hospital, Boston, Massachusetts 02115; and Department of Radiology (V.R.), Department of Endocrinology, Diabetes, and Metabolism (C.S.M.), Beth Israel-Deaconess Medical Center, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Annaswamy Raji, M.D., Division of Endocrinology, Diabetes, and Metabolism, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: araji{at}partners.org.
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Abstract |
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Introduction |
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Recent physiological studies have shown that many characteristics of the insulin resistance syndrome are more prevalent in Asian Indians compared with Caucasians (6, 7, 8). Impaired glucose tolerance, elevated fasting plasma glucose and insulin levels, and insulin resistance, as measured by the insulin clamp and other techniques, have all been observed in Asian Indian populations (4, 9, 10, 11). In addition to decreased insulin sensitivity, Asian Indians frequently have lipid abnormalities, including increased triglycerides, low high-density lipoprotein (HDL) cholesterol, and increased lipoprotein(a), all of which may contribute to the excess coronary heart disease (5, 12). Recent studies of body fat distribution have shown that Asian Indians also have increased central obesity and visceral fat (6, 7). Importantly, the increase in central obesity often is not apparent from measurements of body mass index (BMI), which may be in the normal range as defined by standard weight tables and other readily available criteria (13, 14). Other abnormalities reported in this population include higher plasminogen activator inhibitor-1 (PAI-1), increased platelet activation, and elevated fibrinogen levels (12, 15, 16, 17). All of these factors appear to put Asian Indians at high risk for atherosclerosis, thrombosis, and diabetes (8).
Several studies have shown that insulin has a direct vasodilatory action that is mediated by nitric oxide release from endothelial cells (18, 19, 20). Both obese nondiabetic and diabetic subjects have been shown to have endothelial dysfunction and an impaired response to the hemodynamic action of insulin. Abnormalities of endothelial function associated with insulin resistance have the potential to greatly increase the risk for developing CAD. Because nitric oxide accounts for almost all of insulin-induced vasodilation, it is likely that endothelial dysfunction associated with insulin resistance is the result of partial nitric oxide deficiency and/or resistance to its action. This question can be resolved by comparing the vasodilatory response to insulin with another endothelium-dependent vasodilator, such as reactive hyperemia, and with an endothelium-independent vasodilator, such as nitroglycerin.
The present study was designed to examine the relationship between insulin sensitivity (using the euglycemic hyperinsulinemic clamp technique) and endothelial function (assessed by brachial artery ultrasound using reactive hyperemia and nitroglycerin before and during the clamp) in a healthy Asian Indian population and a group of Caucasians of European ancestry matched for age and BMI. Additional factors associated with insulin resistance and vascular risk, including lipid profile, free fatty acids (FFA), adiponectin, PAI-1, C-reactive protein (CRP), vascular cellular adhesion molecules (VCAM), intercellular adhesion molecules (ICAM), and regional fat distribution were also measured and compared.
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Subjects and Methods |
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Fifteen Caucasians of European origin and 25 Asian Indians, between the ages of 20 and 65 and living in the Boston, MA area, participated in the study. The groups were matched for age and BMI. The institutional review board of Brigham and Women’s Hospital approved the study. After obtaining written informed consent, all volunteers were screened for hematological and blood chemistry abnormalities. Subjects had no major underlying medical problems, including diabetes, hypertension, CAD, hyperlipidemia, and liver or kidney disease. Women were studied during the follicular phase of their menstrual cycle to decrease the potential influence of gonadal steroids on insulin action.
Oral glucose tolerance test (OGTT)
A standard 75-gm OGTT (Tru-Glu 75, Custom Laboratories, Inc., Baltimore, MD) was given to the subjects on the day of their physical examination after an 8-h overnight fast. An iv catheter was placed in a forearm vein, and blood was 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 waist to hip circumference ratio (WHR) was performed using a 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 anthropometric and bioelectric impedance measurements to minimize interinvestigator variability.
Computed axial tomography
The cross-sectional areas of sc, intraabdominal (visceral), and total fat were determined by CT scans of the abdomen (Sensation 4 and Sensation 16, Siemens, Forcheim, Germany). Sections were obtained at the level of the L3–L4 interspace using 120 kVp and 100 mA. Calculation of area was done by semiautomatic 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 (HU). The whole area measurement included attenuation values from –150 to +3000 HU (including bone).
Euglycemic hyperinsulinemic clamp technique
Insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique as previously described (21, 22). In brief, subjects were placed on a 200–300 gm carbohydrate diet for 3 d before the study. The study was performed in the General Clinical Research Center, after an overnight fast, with the subject remaining supine until the completion of the study; iv lines were placed in one antecubital vein for the administration of test substances and in a hand vein for blood drawing. The hand was kept in a hand warmer thermostatically controlled at 70 C to arterialize venous blood. After basal samples were collected, insulin (Novolin U-100, Novo Nordisk, Princeton, NJ) was infused at a constant rate of 40 mU/m2·min for 180 min, after a priming dose of 80 mU/m2·min over the first 10 min. Blood samples were obtained every 5 min, and a 20% dextrose solution was infused to maintain plasma glucose at fasting levels throughout clamp procedure, according to the method of DeFronzo et al. (21). The rate of glucose metabolism was calculated as the mean glucose infusion rate during the last 20 min of the second hour clamp, after correcting for changes in the plasma glucose concentration during the interval. Brachial artery ultrasound was performed to measure both endothelium-dependent and -independent vasodilation at baseline (before the insulin infusion was initiated) and during the third hour of the clamp.
Brachial artery ultrasound
Noninvasive assessment of flow-mediated dilation was performed using brachial artery ultrasound (23, 24). The studies were performed with the subject resting supine in a quiet, temperature-controlled, low-light setting. A longitudinal image of the brachial artery was obtained using a broadband multifrequency linear array transducer (Toshiba Power Vision 8000; Toshiba, Irvine, CA) with a resolution of 0.01 mm. Images were obtained at baseline, during reactive hyperemia, and after nitroglycerin administration as described below. Longitudinal images were obtained near the antecubital fossa; and a straight segment, free of side branches, was selected for the study. A resting image was acquired, and resting blood flow was estimated by time averaging the pulsed Doppler signal obtained from a midvessel sample volume. A blood pressure cuff was placed proximal to the image site at the beginning of the study. After baseline images, the blood pressure cuff was inflated to a suprasystolic pressure for 5 min and then released. Brachial artery images were recorded continuously for 5 min during the postocclusive reactive hyperemia. After a control period of at least 10 min, images were recorded to confirm that basal conditions had been reestablished. When basal conditions were reestablished, 0.4 mg nitroglycerin was administered sublingually and brachial images recorded for 5 min to assess endothelium-independent vasodilation. This procedure was done before the start of the insulin clamp and was repeated during the third hour of the clamp to assess the effect of insulin on endothelial function. All images were recorded on S-VHS videotape. Individual frames were stored digitally at end diastole during baseline, 1 min after cuff release, at rebaseline, and at 3 min after sublingual nitroglycerin. The digitalized images were then evaluated for analysis using edge detection software (25). Flow-mediated dilation is expressed as the change in poststimulus diameter as a percentage of the baseline diameter.
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). Lipid levels were measured at the Brigham and Women’s Hospital laboratory, which is accredited by the Lipid Standardization Program of the Centers for Disease Control and Prevention. FFA were measured in the laboratory of Dr. Michael Jensen (Mayo Clinic, Rochester, MN) by microfluorometric assay using a COBAS MIRA analyzer (Roche Diagnostic Systems, Somerville, NJ). PAI-1 antigen was measured by ELISA (Diagnostica Stago, Parsipanny, NJ) using an enzymatically amplified two-step sandwich type immunoassay. A sensitive latex-based immunoassay (Dade Behring, Newark, DE) was used to determine the levels of CRP. Serum VCAM and ICAM were measured by an ELISA (R& D Systems, Minneapolis, MN). Serum adiponectin was measured by RIA (Linco Research, Inc., St. Charles, MO), with a sensitivity of 1 ng/ml and an intraassay coefficient of variation of 6.6%.
Analyses
Power was determined using differences in insulin sensitivity and endothelium-dependent vasodilation measured by brachial artery ultrasound as primary end points. All statistical analyses, including correlation and linear regression, were carried out using the STATA statistical software version 8.0 (STATA Corporation, College Station, TX). Standard statistical tests comparing the two groups included t tests for means, Wilcoxon rank sum test when nonparametric analyses were appropriate, and 
2 tests for categorical variables. Linear and multiple regression analyses 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. All tests were conducted using a two-sided 
-level of 0.05.
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Results |
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Clinical characteristics of the study subjects and baseline laboratory results are given in Tables 1
and 2. Despite similar age and BMI, Asian Indians had significantly elevated fasting insulin (P = 0.007) and area under curve for insulin (P = 0.03) during the OGTT. Glucose levels in the fasting state and during the OGTT were slightly higher in Asian Indians but did not meet statistical significance. There were no significant differences between the two groups in the waist circumference, WHR, and fat mass measured by bioelectric impedance. The Asian Indians had a higher prevalence of family history of diabetes (28 vs. 20%) and CAD (32 vs. 7%) and a similar prevalence of family history of hypertension (20 vs. 20%), compared with the Caucasian subjects.
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). PAI-1 (P = 0.04) and FFA (P = 0.02) were significantly higher, and adiponectin was significantly lower (P = 0.05), in Asian Indians than Caucasians, but there were no consistent differences in CRP, VCAM, ICAM, or blood pressure between the groups (Table 2). Insulin action
Despite similar age and BMI, Asian Indians had a significantly lower glucose disposal rate during the clamp compared with Caucasians (4.5 ± 0.3 vs. 7.5 ± 0.4 mg/kg·min, P < 0.0001) (Fig. 1). Because plasma insulin levels during the clamp were slightly higher in Asian Indians [60.5 ± 2.9 vs. 53.1 ± 2.8 µU/ml, P = not significant (NS)], the glucose disposal rate divided by the mean insulin concentrations (M/I ratio) was calculated and was also significantly lower in Asian Indians compared with the Caucasians [(8.1 ± 0.8 vs. 14.6 ± 1.3 mg/kg·min·µU/ml) x 100, P = 0.0001]. Insulin-mediated glucose disposal was significantly correlated with fasting insulin (r = –0.58, P = 0.009) and area under curve for insulin during the OGTT (r = –0.44, P = 0.04) in Asian Indians, demonstrating a consistent relationship between hyperinsulinemia and insulin resistance in this population.
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Total, sc, and visceral abdominal fat were higher in Asian Indians compared with Caucasians, although the differences did not reach statistical significance (Table 3). Insulin-mediated glucose disposal was inversely correlated with all compartments of fat, including total (r = –0.46, P = 0.01), sc (r = –0.45, P = 0.01), and visceral fat (r = –0.33, P = 0.06) (Fig. 2). When the two groups were analyzed individually, the correlations of glucose disposal with total fat (r = –0.54, P = 0.01), sc fat (r = –0.46, P = 0.04) and visceral fat (r = –0.55, P = 0.01) were maintained in Asian Indians but not in Caucasians.
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). When the groups were analyzed individually, again only Asian Indians maintained the correlation with triglycerides (r = –0.47, P = 0.03) and HDL (r = 0.54, P = 0.01). PAI-1 was inversely correlated with glucose disposal (r = –0.47, P = 0.006) and positively correlated with visceral fat (r = 0.38, P = 0.03) and total fat (r = 0.40, P = 0.02) when both groups were combined.
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Adiponectin was significantly inversely correlated with visceral fat (r = –0.41, P = 0.02) and total fat (r = –0.36, P = 0.04) and positively correlated with insulin sensitivity (r = 0.31, P = 0.06). When the two groups were analyzed individually, stronger correlations were maintained in Asian Indians compared with Caucasians. Asian Indian women had a significantly higher adiponectin level compared with men (30.8 ± 3.9 vs. 21.2 ± 1.7 µg/ml, P = 0.01).
Vascular reactivity
Results of the vascular reactivity measurements are shown in Table 5. In the basal state (before the insulin clamp) the brachial artery diameter was similar in Caucasians and Asian Indians (3.81 ± 0.17 vs. 3.68 ± 0.16 mm, P = NS). The percent changes in brachial artery diameter in response to both reactive hyperemia and nitroglycerin also were not significantly different between the two groups of subjects. After 2 h of hyperinsulinemia, there were no significant changes in the responses to these vascular stimuli, and there continued to be no difference in the responses between groups. However, the vasodilatory response to insulin per se, i.e. the percent increase in resting brachial artery diameter from before the clamp to after the clamp, was significantly reduced in the Asian Indians compared with Caucasians (2.6 ± 1.0 vs. 5.7 ± 1.0%, P = 0.04). The percent change in brachial artery diameter was also positively correlated with glucose disposal rate during the insulin clamp (r = 0.38, P = 0.04) (Fig. 3).
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Discussion |
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Both groups studied had an average BMI of 25 kg/m2, which is not considered to be obese in the general population. Despite the fact that Asian Indians were nonobese, they were significantly insulin resistant and hyperinsulinemic and had features suggestive of metabolic syndrome. These results are consistent with other studies in the literature (6, 26), including our previous report (7). Other investigators have examined the relationship between central adiposity and insulin resistance in migrant Indians and have shown that Asian Indians have higher WHR compared with Caucasians living in the United Kingdom (5). Moreover, at every level of WHR, Asian Indians had higher insulin concentrations and were more insulin resistant compared with Caucasians. Other studies from India suggest that the increase in the prevalence of diabetes in the urban areas is more closely related to increasing BMI than to increasing WHR (13, 27). In our study, we did not see any difference in WHR, waist circumference, or BMI between the two groups. Given the relatively small sample size and the fact that we selected individuals with normal BMI and matched the two groups on this variable, this is not unexpected. However, this finding does provide support for the hypothesis that insulin resistance develops at a very early stage in Asian Indians, when many conventional measures of metabolic and cardiovascular risk factors may still be in the normal range.
Because WHR may not be a sensitive marker for detecting central obesity in this population given their normal BMI, we did more precise measurement of body fat distribution using a CT scan. We found that Asian Indians tended to have higher total, visceral, and sc fat compared with Caucasians, and that only in Asian Indians was a strong correlation maintained between visceral fat and insulin sensitivity, again suggesting an early etiologic link between the two. Our results also are consistent with others in the literature demonstrating that Asian Indians have a higher percentage of fat at a range of BMI and WHR that is considered normal in Caucasians (6, 7, 26). Thus, the use of standard BMI and WHR values derived in predominantly European Caucasian populations does not accurately reflect the excess adiposity, insulin resistance, and risk of diabetes and CAD in Asian Indians.
Abnormalities of lipolysis, FFA turnover, and triglyceride metabolism are characteristic of insulin resistance. Misra et al. (28) have shown that Asian Indians have higher intramyocellular lipids that are pathophysiologically correlated with insulin sensitivity. Forouhi et al. (29) as well found higher intramyocellular lipids in Asian Indians compared with Caucasians, but it was not correlated with insulin sensitivity. However, they did find stronger associations of insulin sensitivity with fasting plasma triglycerides. It is also plausible that the increased insulin resistance observed in Asian Indians at the level of skeletal muscle is mediated by increased circulating FFA. Indeed, we found that FFA was highly correlated both with visceral fat and, inversely, with glucose disposal. Defects in suppression of FFA have been demonstrated in patients with impaired glucose tolerance, in patients with DM, and in nondiabetic South Asians in the United Kingdom compared with Caucasians of European origin (30, 31), although we did not observe such an impairment during the insulin clamp in the present study. Finally, it is possible that the increased insulin resistance in nonobese Asian Indians may result from genetic differences between this population and European Caucasians. We and others have shown that there are potentially other factors independent of abdominal fat that may contribute to decreased insulin sensitivity in Asian Indians compared with Caucasians (6, 7, 12), but a genetic basis for these differences has not been established.
Dyslipidemia also is a characteristic feature of the insulin resistance syndrome. In previous studies, Asian Indians have been shown to have hypertriglyceridemia, low levels of HDL, and high levels of small dense LDL (32, 33, 34). This constellation of lipoprotein abnormalities is conducive to atherogenesis and has been termed atherogenic dyslipidemia (35). We did find triglycerides to be higher and HDL to be lower in Asian Indians compared with Caucasians, but the differences were not statistically significant. This may be due to the relatively normal weight and young age of our population, as well as the small sample size. It is noteworthy, however, that only in Asian Indians were both of these abnormalities significantly correlated with insulin sensitivity, again suggesting a relationship between the two in this population. We did not measure the LDL fractions in our study, so we cannot determine whether our subjects had a more atherogenic LDL profile despite normal LDL levels. Finally, PAI-1 also was significantly elevated in Asian Indians and was correlated with insulin sensitivity, confirming other studies in the literature (36, 37). All of these abnormalities are likely to contribute to the higher risk of CAD in this population.
It is known that both visceral and sc adipose tissue are major sources of cytokines (adipokines), and these substances may contribute to insulin resistance (38). At least one study from India has reported that Asian Indians have high levels of TNF- and IL-6 (39). Another adipokine, adiponectin, has gained significant attention recently as a mediator of insulin sensitivity (40). Many studies have reported lower levels of adiponectin in insulin resistance states, and plasma adiponectin is inversely associated with overall and central fat distribution (41). Furthermore, lower levels of adiponectin have been shown to be predictive of future development of DM in Asian Indians (42). This suggests the presence of an important link between adiponectin, visceral adiposity, and insulin resistance (38). Our current findings are consistent with these other studies, in that Asian Indians had a lower adiponectin level that was significantly correlated with visceral fat and insulin sensitivity. Further exploration of this relationship might be helpful in understanding the underlying mechanism of insulin resistance in this population.
Endothelial dysfunction is an integral part of the syndrome of insulin resistance, independent of hyperglycemia. It contributes to impaired vascular reactivity (43) and predisposes to macrovascular disease. Endothelial dysfunction is an early physiological event in atherogenesis (44), and endothelial injury predisposes to thrombosis, leukocyte adhesion, and proliferation of smooth muscle cells in the arterial wall (45). Studies evaluating the relation between CAD and endothelial dysfunction clearly demonstrate that reduced endothelium-dependent vasodilation is an early functional disturbance in the development of atherosclerotic lesions. Balletshofer et al. (46) have revealed a loss in endothelial function from a prediabetic stage to overt DM. Furthermore, there was a significant correlation between endothelial dysfunction and insulin resistance in normoglycemic young first-degree relatives of DM patients, independent of other classic risk factors.
Previous studies have shown that brachial artery flow-mediated vasodilation is endothelium-dependent and, in large part, mediated by nitric oxide (19, 20). Because brachial artery flow-mediated vasodilation is correlated with coronary artery vasomotor responses, this noninvasive method of assessing endothelial function may be used as a surrogate for early CAD (47). Chambers et al. (48) demonstrated that healthy nondiabetic Asian Indians in the United Kingdom had a significant impairment in flow-mediated endothelium-dependent vasodilation assessed by brachial artery ultrasound. This abnormality was associated with early CAD and was independent of other traditional risk factors and insulin sensitivity (48).
Baron et al. (49) and others have studied, in detail, the role of insulin as a vasodilator. They have shown that the vasodilating action of insulin serves to both amplify the effect of insulin-stimulated skeletal muscle uptake and modulate vascular tone. There also is evidence to show that insulinresistant states like obesity, hypertension and DM are associated with impaired insulin-augmented flow-mediated vasodilation (IAFMV) and endothelial dysfunction, and the degree of insulin resistance is proportional to the extent of impairment in IAFMV (50). We found in our study that insulin-augmented vasodilation, as measured by the change in brachial artery diameter from the basal to the hyperinsulinemic state during clamp, was significantly impaired in Asian Indians. Moreover, the severity of the defect in insulin-mediated vasodilation was closely correlated with the reduction in glucose uptake during the clamp. However, we did not find any difference in the flow-mediated vasodilation (reactive hyperemia) or endothelium-independent vasodilation (nitroglycerin) between the two groups, suggesting the presence of a specific defect in the vascular response to insulin, either at the insulin receptor or subsequent pathways in the signaling cascade. The differences between our findings and those of Chambers et al. (48), who found a more generalized impairment in vascular function, may be due to differences in the patient populations, particularly the severity of insulin resistance.
Recent studies have suggested that the defect in IAFMV in insulin-resistant states like obesity may be due to reduced muscle capillary recruitment (50, 51) resulting from either impaired insulin action in the vascular endothelium or the muscle itself, but this remains to be demonstrated in the Asian Indian population. It also will be of interest to determine whether interventions that improve insulin sensitivity and vascular function, including diet, exercise, or thiazolidinedione therapy (52), can reverse this dysfunction at an early stage, thereby preserving endothelial function and decreasing future risk of cardiovascular disease.
We acknowledge that there are limitations to our findings. This was a cross-sectional observational study with a small sample size. To more accurately define the etiologic relationships among insulin resistance, body fat distribution, dyslipidemia, and impaired insulin-mediated vasodilation would require a larger longitudinal study. However, the strengths of the associations among these variables in an apparently healthy and normal weight population suggest that the defects are occurring early in the evolution of the disease process. It also is not known whether these metabolic and vascular abnormalities are genetic in origin or whether the adoption of a more Western diet in immigrant populations might contribute to their expression. Because we did not measure hepatic glucose production, we cannot determine the relative contributions of decreased glucose uptake into muscle vs. impaired suppression of hepatic glucose production to the overall insulin resistance evident during the clamp. However, the magnitude of the defect in glucose metabolism during the clamp suggests that muscle is likely to be quantitatively the more important site of the insulin resistance. There also are some limitations to using ultrasound of the brachial artery (a medium sized vessel) as an indicator of coronary artery reserve but, as discussed above, these measurements generally are closely correlated.
In summary, we have shown that Asian Indians are profoundly insulin resistant and have elevated levels of several markers of cardiovascular risk, altered vascular responses to insulin, and a trend toward fat redistribution, compared with healthy European Caucasians matched for age and BMI. We know from epidemiological studies that Asian Indians are at increased risk for diabetes and cardiovascular disease at a younger age, and our results suggest that insulin resistance and its consequences may play a central role in this process. The underlying reason for the insulin resistance and endothelial dysfunction is not clear, and may include either primary genetic differences from European Caucasians in areas such as body composition, intracellular insulin action, or FFA and lipid metabolism or environmental differences such as diet and level of physical activity. Future studies should be directed toward determining whether lifestyle changes or pharmacological interventions are capable of reversing the multiple defects in insulin action.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; CAD, coronary artery disease; CRP, C-reactive protein; DM, type 2 diabetes; FFA, free fatty acid(s); HDL, high-density lipoprotein; IAFMV, insulin-augmented flow-mediated vasodilation; ICAM, intercellular adhesion molecules; LDL, low-density lipoprotein; NS, not significant; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; VCAM, vascular cellular adhesion molecules; WHR, waist to hip circumference ratio.
Received January 19, 2004.
Accepted May 4, 2004.
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