Introduction

Adiponectin, an adipocyte-secreted protein with insulin-sensitizing effects, plays an important role in lipid metabolism and glucose homeostasis and has anti-inflammatory properties (1, 2, 3). Adiponectin is decreased in obesity, insulin resistance, and type 2 diabetes and is predictive of type 2 diabetes, including among populations without generalized obesity, such as Japanese and Asian Indians (2, 3, 4, 5, 6).

Ethnic differences in adiponectin concentration independent of obesity have been reported; adiponectin was shown to be significantly lower in non-obese African-American compared with non-obese white women (7) and was lower in African-American than white boys of similar BMI (8). Indian and black women in South Africa were shown to have significantly lower adiponectin levels than whites, after adjusting for age and waist-to-hip ratio (9). Ethnic differences in adiponectin concentration independent of diabetes or insulin resistance have also been observed. Non-diabetic Asian Indian men in Texas had significantly lower adiponectin levels than non-diabetic white men of similar body fat content and distribution (10). African-Americans had significantly lower adiponectin concentration compared with normoglycemic whites and non-diabetic Hispanics (11).

Ghrelin, a peptide hormone secreted by the stomach, regulates hunger and long-term weight gain or loss and is thought to play a role in glucose homeostasis and insulin resistance (12, 13). Plasma ghrelin concentrations are lower in persons with obesity, hypertension, type 2 diabetes, and the metabolic syndrome (14, 15). Postprandial ghrelin concentrations were shown to be elevated among African-American vs. white women, independently of BMI (16). Fasting ghrelin levels were lower among Pima Indians than whites, independently of fasting insulin levels (17), and among Japanese compared with white men after adjusting for metabolic factors (18); however, other ethnic differences, particularly in postmenopausal women, have not been well characterized.

Ethnic differences in adiponectin and ghrelin concentrations may explain some of the ethnic disparities in diabetes prevalence, particularly in Asian populations. Filipino-Americans have a 4-fold higher prevalence of type 2 diabetes and a 3-fold higher risk of the metabolic syndrome compared with whites of similar body size (19, 20, 21). Low adiponectin and ghrelin levels might explain some of their predisposition to type 2 diabetes. Prior studies comparing ethnic differences in adiponectin have included participants with glucose abnormalities, which can complicate discerning ethnic differences because adiponectin levels are lower in those with type 2 diabetes and insulin resistance. Few studies have compared fasting adiponectin and ghrelin concentrations in a multiethnic cohort with normal glucose tolerance; such information may explain why selected ethnic groups are predisposed to type 2 diabetes despite the absence of obesity. We hypothesize that adiponectin and ghrelin concentrations differ by ethnicity even among normoglycemic individuals; however, these differences are not explained by ethnic differences in adiposity. The objectives of this study are 1) to determine whether fasting adiponectin and ghrelin concentrations differ by ethnicity and if so, whether these differences are explained by ethnic differences in adiposity; and 2) to identify covariates associated with adiponectin and ghrelin levels in normoglycemic 40- to 80-year-old Filipino, African-American, and white women.

Research Methods and Procedures

Study Population

The Rancho Bernardo Study, a San Diego community-based longitudinal study of myriad health outcomes since 1972, includes participants who are predominantly non-Hispanic whites (22); periodic follow-up visits have been performed, including an oral glucose tolerance test, lipids, and body fat composition during the 1984 to 1987 visit. Between 1994 and 1999, two ethnic comparison cohorts of African-American and Filipino women were enrolled (21, 23). Population-based sampling was not possible because Filipinos were not identified separately from Asians in the 1990 census; consequently, a convenience sample was recruited, as described elsewhere (21). Data and archived fasting blood samples from white women were obtained from the 1984 to 1987 visit because adiponectin, ghrelin, and body fat composition by bioelectric impedance were measured during the 1984 to 1987 visit, and the younger age of white women in 1984 to 1987 enabled similar age comparisons to Filipino and African-American women. Clinical evaluations for the white and Filipina participants were performed at the Rancho Bernardo Clinic because of close proximity to participants' homes, while clinical evaluations for African-American women were conducted at the clinical research center at University of California-San Diego; all cohorts used the same research protocol and diagnostic laboratories. The study was approved by the University of California-San Diego Human Research Protections Program, and all women provided written informed consent before enrollment.

Clinical Evaluation

Demographic characteristics, lifestyle factors (cigarette smoking, alcohol use, physical activity), physician-diagnosed conditions, and menopausal status were determined using structured questionnaires. Participants who were using prescription or non-prescription medications in the month before the clinic visit brought pills and prescriptions to the clinic to be verified and recorded by a nurse. None of the participants was taking thiazolidinediones, which have been shown to alter adiponectin concentration.

Height and weight were measured in participants wearing lightweight clothing without shoes. BMI (kg/m²) was computed as an estimate of general obesity. Waist circumference was measured at the natural bending point and hip circumference at the iliac crest. Total percentage body fat and lean-to-fat body mass ratio were measured by bioelectric impedance in all African-American and Filipino women and 70% of white women. A 75-g oral glucose tolerance test was administered after a minimum 8-hour fast; blood samples were obtained by venipuncture at 0 and 2 hours. Plasma glucose was measured by the glucose-oxidase method, and insulin was determined by radioimmunoassay in a diabetes research laboratory (21). The homeostasis model assessment was used to estimate insulin resistance (HOMA-IR)¹ (24). Triglyceride and high-density lipoprotein-cholesterol (HDL-C) levels were measured by enzymatic techniques according to the procedures of the Lipid Research Clinics Manual. Fasting adiponectin and ghrelin concentrations were measured by radioimmunoassay (Linco Research, St. Louis, MO) in 2004 using archived samples that were stored frozen at - 70 °C. Normal glucose tolerance was defined as having no prior history of diabetes diagnosis by a physician, no use of oral hypoglycemic agents or insulin, a fasting plasma glucose <100 mg/dL, and 2-hour post-challenge glucose <140 mg/dL (25).

Statistical Analysis

In this cross-sectional analysis, data were analyzed using Statistical Analysis Systems (version 9.0, Cary, NC). ANOVA, general linear models, and ² tests were used for descriptive statistics. Pearson correlation coefficients were computed to assess the correlation between each protein and adiposity markers. As observed in other ethnic groups (16, 26), markers of adiposity that were significantly and most highly correlated with both adiponectin and ghrelin differed by ethnicity in this cohort. Consequently, mean levels of each protein were computed with adjustment for age and adiposity markers, which included BMI, waist, waist-to-hip ratio, total percentage body fat, and lean:fat mass ratio. Adiponectin and ghrelin distributions were skewed and, consequently, log-transformed for statistical analysis. General linear models were used to compare adiponectin and ghrelin concentrations while adjusting for anthropometric markers; Bonferroni adjustment for multiple comparisons was applied. Univariate analysis was conducted to identify putative covariates associated with adiponectin or ghrelin that would be included in multivariable analysis. Multivariable linear regression was performed to identify covariates associated with adiponectin or ghrelin. Statistical significance was designated at p < 0.05 and 95% confidence intervals that excluded 1.

Results

The study population included normoglycemic white (n = 143), Filipino (n = 136), and African-American (n = 212) women. Filipinas were younger and had higher college attainment than white or African-American women (p < 0.001, Table 1). The majority (87% ) of participants were postmenopausal. Reported exercise (3 times/wk) was similar among white and Filipino women (p = 0.06), but was significantly lower in African-Americans (p = 0.037). Current cigarette smoking was significantly higher among whites compared with either Filipino or African-American women (p = 0.003) and more frequent among African-Americans than Filipinas. Alcohol consumption (3 drinks/wk) was reported by almost one half of white women, one fifth of African-Americans, and rarely among Filipinas.

Table 1 - Demographic and age-adjusted anthropometric markers and metabolic variables.

Full table

Table 1 shows that age-adjusted BMI, waist circumference, and total percentage body fat were significantly higher, while lean-to-fat body mass ratio was lower, in African-Americans compared with Filipino or white women (p < 0.0001). Filipinas and whites had similar BMI (p = 0.33), waist (p = 0.26), percent body fat (p = 0.29), and lean-to-fat body mass ratio (p = 0.16); however, waist-to-hip ratio was significantly lower in whites (p < 0.0001) and was similar among Filipinas and African-Americans (p = 0.77, Table 1).

Age-adjusted fasting plasma glucose did not differ between Filipino and white women (p = 0.56) but was significantly lower among African-Americans (p = 0.004). Two-hour post-challenge glucose was significantly higher among Filipinas compared with both other ethnic groups (p < 0.001) and was higher among African-Americans compared with whites (p = 0.011). Fasting insulin, post-challenge insulin, and HOMA-IR were significantly higher among whites compared with Filipinas (p = 0.026; p = 0.037; p = 0.017) but did not differ between African-Americans and both other ethnic groups.

Triglyceride levels did not differ between whites and African-Americans (p = 0.25) but were significantly higher among Filipinas (p < 0.001). Filipinas had significantly lower HDL-C levels than white (p < 0.0001) or African-American (p = 0.003) women, and HDL-C levels were lower among African-Americans than whites (p = 0.0005).

Age-adjusted mean adiponectin and ghrelin concentrations are presented in Table 2; statistical comparisons are based on log-transposed values. Adiponectin concentration was significantly lower among Filipinas (8.90 g/mL) and African-Americans (9.67 g/mL) compared with whites (15.6 g/mL, p < 0.0004), and this observation persisted after adjustment for each anthropometric marker as well as simultaneous adjustment for HOMA-IR and waist-to-hip ratio. Adiponectin levels were significantly lower among Filipinas compared with African-Americans after adjustment for either BMI, waist, percent body fat, or lean-to-fat mass ratio (p < 0.001) but did not differ after adjustment for waist-to-hip ratio or simultaneous adjustment for HOMA-IR and waist-to-hip ratio. Bonferroni adjustment for multiple comparisons showed that these observations persisted (p < 0.002) except for BMI-adjusted adiponectin levels between Filipinas and African-Americans. Age-adjusted adiponectin levels did not differ between premenopausal and postmenopausal (11.3 vs. 11.2 g/mL, p = 0.63) women.

Table 2 - Age-adjusted fasting adiponectin and ghrelin levels in normoglycemic Filipino, white, and African-American women.

Full table

Figure 1 shows age-adjusted adiponectin levels by ethnicity, body size, and HOMA-IR. Adiponectin declined with increasing tertiles of BMI, waist girth, waist-to-hip ratio, and HOMA-IR for all ethnic groups. However, whites had significantly higher adiponectin levels than Filipinas or African-Americans at every tertile of BMI, waist girth, waist-to-hip ratio, and HOMA-IR (p < 0.001).

Figure 1.

Age-adjusted adiponectin by tertiles of BMI, waist girth, waist-to-hip ratio, and HOMA-IR

Full figure and legend (125K)

Age-adjusted fasting plasma ghrelin levels were significantly lower in Filipinas (1147.6 pg/mL) compared with African-American women [ 1490.3 pg/mL, p < 0.0001 (log-ghrelin)] after adjustment for BMI, waist, or waist-to-hip ratio (Table 2) but did not differ between whites and the other ethnic groups. Adjusting for total percentage body fat or lean-to-fat body mass ratio showed lower ghrelin levels in both whites and Filipinas compared with African-Americans. Whites and Filipinas had similar ghrelin concentration when adjusted for HOMA-IR and BMI simultaneously; however, ghrelin levels remained lower in Filipinas compared with African-American women. Bonferroni adjustment showed that all of these observations persisted at p 0.002.

Multivariable Analysis

Adiponectin.

Waist-to-hip ratio was significantly and most highly correlated with adiponectin (r = - 0.330, p < 0.0001) in the combined cohort compared with other anthropometric markers and was, therefore, used in multivariable analysis. As shown in Table 3, multivariable linear regression showed that adiponectin levels were significantly lower in Filipinas [ = - 5.06; 95% confidence interval (CI), - 6.90 to - 3.21, p < 0.0001 (log-adiponectin)] and African-American women [ = - 6.85; 95% CI, - 8.24 to - 5.46, p < 0.0001 (log-adiponectin)] compared with whites, in multivariable models that adjusted for age, waist-to-hip ratio, and other factors associated with adiponectin in univariate analysis, including HOMA-IR, HDL-C, triglycerides, exercise, and alcohol. Multivariable analysis limited to Filipinas and African-Americans showed that ethnicity [ = - 0.035; 95% CI, - 0.924 to 0.853, p = 0.736 (log adiponectin)] was not associated with adiponectin concentration.

Table 3 - Multivariable linear regression analysis: fasting adiponectin and ghrelin levels in normoglycemic women.

Full table

When stratified by ethnicity, differences were observed in covariates associated with log-adiponectin. In each ethnic group age, waist-to-hip ratio and HDL-C were independently associated with log-adiponectin levels (Table 4). Alcohol use was associated with log-adiponectin in African-Americans but not in whites or Filipinas. Triglycerides were independently and inversely associated with log-adiponectin in whites and Filipinas, but only a marginal association was observed among African-Americans (p = 0.052). HOMA-IR was independently and inversely associated with log-adiponectin in whites and African-Americans but not in Filipinas (p = 0.81). This observation persisted in regression models in which fasting insulin replaced HOMA-IR; fasting insulin was also independently and inversely associated with log-adiponectin in whites and African-Americans, but not in Filipinas (p = 0.73).

Table 4 - Multivariable regression analyses: covariates associated by ethnicity with log-adiponectin and log-ghrelin.

Full table

Ghrelin.

BMI was most highly correlated with log-ghrelin (r = - 0.112, p = 0.013) in the combined cohort and was used in multivariable analysis. Ghrelin levels were significantly lower in Filipinas [ = - 245.4; 95% CI, - 362.4 to - 128.5, p < 0.001 (log ghrelin)] but similar in whites [ = 84.3; 95% CI, - 235.8 to 67.2, p = 0.077 (log ghrelin)] compared with African-Americans, in regression models that adjusted for age, BMI, HOMA-IR, HDL-C, triglycerides, exercise, and alcohol use (Table 3). Percent body fat may serve as a more accurate measure of general obesity than BMI, and these observations persisted in multivariate regression where total percentage body fat replaced BMI(Filipinas: = - 299.6; 95% CI, - 434.6 to - 164.6, whites: = - 178.4; 95% CI, - 370.6 to 13.7).

Multivariable analysis limited to whites and Filipinas showed that ethnicity was not associated (p = 0.22) with ghrelin levels. Differences in the covariates associated with ghrelin were observed when stratified by ethnicity and included younger age in whites, older age and lower BMI in Filipinas, and lower BMI and HOMA-IR in African-Americans (Table 4). Regression models in which total percentage body fat replaced BMI showed similar results as above.

Discussion

This multi-ethnic comparison of normoglycemic women showed that body size did not explain the significantly higher adiponectin levels in white compared with Filipino or African-American women. Previous studies have shown that adiponectin is negatively associated with obesity and insulin resistance (26). These normoglycemic Filipinas had similar BMI, waist girth, percent body fat, and lean-to-fat ratio and lower insulin levels and HOMA-IR than normoglycemic whites and would have been expected to have similar adiponectin levels, but instead, Filipinas had one half the adiponectin concentration of whites. Although Filipinas had larger waist-to-hip ratio and dyslipidemia than whites, differences in abdominal obesity, triglycerides, or HDL-C did not explain their lower adiponectin levels. Adiponectin levels were also lower, by 40% , in African-American women than in white women, even after adjusting for markers of obesity and insulin resistance. Our observations are consistent with a prior report of lower adiponectin levels in normoglycemic African-American compared with white women (11) and is the first, to our knowledge, to report lower levels of adiponectin in normoglycemic Filipino-American women. Additionally, fasting adiponectin levels in our sample of normoglycemic African-American women were similar to those in normal glucose tolerant African-Americans in Ohio, suggesting that our findings are generalizable to another African-American cohort (27).

The few clinical studies among Filipinas have shown similar HOMA-IR and fasting insulin levels compared with whites and African-Americans despite significantly higher prevalence of type 2 diabetes among Filipinas (32% ) compared with African-Americans (12% ) or whites (5.8% ) (28). However, in this study of women without glucose abnormalities, both HOMA-IR and fasting insulin were significantly lower among Filipinas compared with white women. Nevertheless, fasting insulin and HOMA-IR values in this cohort of normoglycemic women were within normal limits.

Among non-diabetic Japanese women, adiponectin was shown to be inversely associated with insulin resistance, independently of age and adiposity (29). Similar findings were observed in white and African-American women, in whom HOMA-IR and fasting insulin were inversely and independently associated with adiponectin in multivariable regression, but these observations were not found in Filipinas. However, both 2-hour post-challenge glucose (p = 0.002) and 2-hour insulin (p = 0.03) were both independently and inversely associated with log-adiponectin among normoglycemic Filipinas in multivariable analysis that adjusted for age, waist-to-hip ratio, triglycerides, HDL-C, and exercise.

Prior studies have reported an association between adiponectin and hypertension, coronary heart disease, smoking, and medications that could induce insulin resistance. However, the inclusion of hypertension, smoking, and thiazide use to the multivariable analysis showed no association with adiponectin concentration in this cohort and did not account for ethnic differences in adiponectin levels.

The high molecular weight form of adiponectin is associated with glucose intolerance (30), and pregnant Asian Indian women have lower levels of high molecular weight adiponectin compared with white women (31). However, we could not discern the different isoforms of adiponectin and could measure only total adiponectin concentration. It remains unclear if an association between either HOMA-IR or fasting insulin and the high molecular weight form of adiponectin would have been observed among Filipinas, if we had had the ability to measure this isoform.

Adiponectin is associated with visceral fat, and waist-to-hip ratio, waist, or BMI may imprecisely estimate visceral fat. Filipinas and African-Americans had contrasting BMI and waist girth but similar waist-to-hip ratio and adiponectin levels and, presumably, similar visceral fat volume. Visceral adipose tissue (VAT) was measured by computed tomography in a subset of these participants without known cardiovascular disease to measure coronary artery calcification (28). This subset included 45 normoglycemic Filipinas and 104 normoglycemic African-Americans from the current analysis. In this subset, BMI and waist girth were also significantly larger in African-Americans, but neither VAT nor waist-to-hip ratio nor adiponectin levels differed by ethnicity (data not shown). However, multivariable analysis in this small subset of 45 normoglycemic Filipinas showed that computed tomography-defined VAT fat was inversely associated with log-adiponectin, but neither HOMA-IR ( = - 0.03, p = 0.74) nor fasting insulin ( = - 0.18, p = 0.72) was associated with log-adiponectin. In contrast, among the 104 African-Americans with available VAT measurements, the inverse association between HOMA-IR ( = - 0.0097, p = 0.04) and log adiponectin persisted in multivariable analysis.

Our observations of lower adiponectin concentration in normoglycemic Filipino and African-American women even after adjustment for waist-to-hip ratio are consistent with a South African study in which whites had significantly higher adiponectin levels compared with Indian and African-American women (9). Hypoadiponectinemia may be an unrecognized factor that increases the risk of type 2 diabetes in selected populations. These findings suggest that there may be ethnically determined differences in adiponectin production or action. Adiponectin concentrations in non-diabetic Pima Indians are heritable, with 39% of the variance of age- and sex-adjusted adiponectin potentially accounted for by additive genetic influences. Further, quantitative trait loci on chromosomes 2, 3, 9, and 10 may influence circulating adiponectin concentrations in Pima Indians (32). Single nucleotide polymorphisms in the adiponectin gene are associated with lower adiponectin concentration and an increased risk of type 2 diabetes in Japanese (33). Similar mechanisms may affect Filipinos and African-Americans, resulting in lower adiponectin concentration and paralleling a higher predisposition for type 2 diabetes.

Ghrelin is decreased in obesity (17), and BMI was, indeed, associated with lower ghrelin concentration among Filipinas and African-Americans. Paradoxically, African-American women had the highest BMI and total percentage body fat and would have been expected to have the lowest fasting ghrelin concentration, but instead, they had the highest ghrelin levels. Filipinas had significantly smaller BMI and percentage body fat than African-Americans and were expected to have high ghrelin levels; but contrary to expectations, Filipinas had the lowest ghrelin concentration. Ethnic differences were also observed in the covariates associated with ghrelin. BMI was inversely associated with ghrelin among Filipinas and African-Americans, but not among whites. HOMA-IR was independently and inversely associated with ghrelin levels in African-American women, which is consistent with prior reports (34), but this association was absent in Filipinas and whites.

To our knowledge, this is the first study to compare ethnic differences in fasting ghrelin concentration in a predominantly postmenopausal cohort of normoglycemic women. Unlike observations of lower ghrelin levels among Japanese and Pima Indians compared with whites (17, 18), we found that whites had similar ghrelin levels to Filipinas and African-Americans, despite disparate body size. Our observations were similar to those for prepubertal white and African-American children, who had similar fasting ghrelin concentration, despite discordant body size (35). The reasons for elevated fasting ghrelin concentration among African-American compared with Filipino women are not clear and beyond the scope of this study. Polymorphisms in the ghrelin gene have been identified and are hypothesized to modify ghrelin secretion and/or activity; however, none was associated with fasting ghrelin concentration (36), and ethnic differences were not evaluated. Low fasting ghrelin concentration is independently associated with type 2 diabetes, insulin secretion, and insulin resistance (14); our observations of lower ghrelin levels might explain the elevated risk of type 2 diabetes among Filipinos.

The strengths of this study include a multiethnic cohort of women from the same geographic area, using the same research protocol and diagnostic laboratories. Further, restricting the analyses to normoglycemic women who were not taking thiazolidinediones enabled comparisons by ethnicity, without the confounding effects of glucose abnormalities or medications that can alter adiponectin or ghrelin levels. Limitations of this study include the absence of body fat measurements for 30% of the white women and our inability to measure the high molecular weight form of adiponectin. It is unknown if the high molecular-to-total adiponectin ratio differs among white, Filipino, and African-American women and, if so, if the observed ethnic differences in fasting total adiponectin levels would persist in comparisons of the high molecular weight isoform. Measurement of insulin sensitivity by euglycemic hyperinsulinemic clamp was not performed and might have better characterized the association between insulin sensitivity and these proteins.

In summary, this study of normoglycemic women demonstrated ethnic differences in fasting adiponectin and ghrelin, independent of indices of anthropometry or insulin resistance, HDL-C, or triglycerides. Specifically, adiponectin was significantly lower in Filipinas and African-Americans compared with whites, and fasting ghrelin was significantly lower in Filipinas. Hypoadiponectinemia in normoglycemic African-Americans and Filipinos and low ghrelin levels in Filipinas might contribute to the elevated prevalence of type 2 diabetes in these populations. Future studies should evaluate mechanisms that contribute to adiponectin and ghrelin secretion or action in ethnically diverse populations.

Notes

¹ Nonstandard abbreviations: HOMA-IR, homeostasis model assessment-insulin resistance; HDL-C, high-density lipoprotein-cholesterol; VAT, visceral adipose tissue.

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Acknowledgments

This study was supported by NIH/NIDDK R01 DK-31,801, R03 DK 60,576 Grants and NIH/NCMHD P60 MD00220 Grants from the San Diego EXPORT Center.