Insulin Resistance In African Americans Research Articles

An epigenome-wide association study of insulin resistance in African Americans

BackgroundAfrican Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study.ResultsWe identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel—cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans.ConclusionsThe findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.

1703-P: Altered DNA-Methylation Modulates Adipose Tissue Gene Expression and Is Associated with Insulin Resistance in African Americans

Altered DNA-methylation has a well-documented mechanistic role in modulating gene expression. However, its contribution in modulating adipose tissue gene expression and insulin sensitivity (SI) in African Americans (AAs) is unknown. To understand the role of differential DNA methylation in determining SI we selected 12 insulin resistant (IR) and 12 insulin sensitive (IS) individuals from a cohort 253 nondiabetic AAs. IR and IS individuals were selected from the extremes of the distribution of SI (1.49±0.69 vs. 8.23±4.48), and expression levels of insulin resistance-associated transcripts in AAGMEx cohort. Reduced representation bisulfite sequencing (RRBS; >30M read) was used to quantify epigenome-wide DNA methylation levels in adipose DNA samples. To determine differentially methylated sites (DMS) linear regressions adjusting for age and sex were used to test for DMS at 774,095 CpG sites (≥ 10X coverage) passing quality control. We identified 8387 hypermethylated and 2532 hypomethylated autosomal DMS in IR individuals (mean methylation difference ≥5% and genomic control corrected-p ≤0.05). Among these DMS, 6414 were annotated to exon, intron or promoter regions of 3923 genes. Highest number of DMS (22, including 20 hypermethylated (5.5-30.2%) DMS) were annotated to PRDM16, a transcription co-factor critical for the development of brown adipocytes. We merged the DMS 3923 genes with 663 differentially expressed transcripts (GC-p≤0.05 and fold change ≥1.2) and identified 123 IR-associated genes with DMS. Genes containing hypermethylated CpG sites and downregulated expression in IR were enriched for long-chain fatty-acyl-CoA biosynthetic process (B-H p=0.0013, includes ELOVL6, ACSF2, ACOT2, FASN, and TECR), and mitochondrion (B-H p=0.0016, 14 genes). In summary, differential DNA-methylation of a subset of genes in adipose tissue modulate expression of transcripts in key biological pathways and may determine insulin sensitivity. Disclosure N.K. Sharma: None. M.E. Comeau: None. C.D. Langefeld: None. S.K. Das: None. Funding American Diabetes Association (1-18-ICTS-113 to S.K.D.); National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance, β-cell function, and diabetes in Hispanics and African Americans

ObjectiveThe TG/HDL-C ratio is used as a marker of insulin resistance (IR) in Caucasians; however, there is limited data in other ethnic groups. We hypothesized that the TG/HDL-C ratio is associated with IR in Hispanics and African Americans (AA). Research design and methodsData from the Insulin Resistance Atherosclerosis Family Study was examined for associations between TG/HDL-C ratio and IR, β-cell function and incident diabetes in non-diabetic Hispanics (n = 872, 63% female) and AA (n = 371, 61% female). Insulin sensitivity index (SI) and disposition index (DI) from frequently-sampled intravenous glucose tolerance tests were used as markers of IR and β-cell function respectively. Incident type 2 diabetes was determined by fasting glucose ≥ 126 mg/dl or initiation of anti-hyperglycemia agents over 5 year follow-up. ResultsHigher TG/HDL-C ratio was associated with IR in Hispanic and AA men and women (P < 0.0002), as well as β-cell function in Hispanic women and AA men and women (P < 0.02). TG/HDL-C predicted incident type 2 diabetes in women (area under the curves 0.703 and 0.795 for Hispanics and AA respectively). ConclusionsSimilar to Caucasians, the TG/HDL-C ratio can be used to identify IR in Hispanics and AA, and may predict type 2 diabetes in women.

Abstract P321: Insulin Resistance is Associated with Incident Coronary Heart Disease but Not Stroke Among African Americans: The Jackson Heart Study

Background: The association between the homeostasis model assessment for insulin resistance (HOMA-IR) and CVD varies by race/ethnicity and is often non-existent or weaker in African Americans (AAs). Triglyceride levels (110-149 mg/dl) below the current metabolic syndrome threshold are associated with insulin resistance in AAs, suggesting that the McAuley index (MA index ), based on insulin and triglycerides, may predict CHD and stroke better than HOMA-IR. We investigated this association in the Jackson Heart Study, a large longitudinal cohort of AAs. Methods: Insulin resistance was estimated for 3565 participants without diabetes and CVD at baseline using the MA index (exp [2.63-0.28 In(insulin in mU/l) - 0.31 In(triglycerides in mmol/l)]) and its association with incident CHD and stroke (composite outcome) was compared against that of the HOMA-IR index. A lower MA index and higher HOMA-IR are indicative of insulin resistance. Cox regression analysis was used to estimate adjusted hazard ratios (HR) for incident CHD and stroke, individually and as a composite. Results: There were 158 events (89 CHD-only, 58 stroke-only, and 11 CHD/stroke) over a median follow-up of 8.4 years. After adjustment for demographic factors, the risk of the composite outcome decreased with each SD increase in the MA index (HR 0.80; 95% CI: 0.67 - 0.96), with no attenuation following further control for CHD and stroke risk factors. When considered individually, the MA index was associated with CHD (HR 0.71, 95% CI: 0.55 - 0.92), but not stroke (HR 0.96, 95% CI: 0.74 - 1.25) risk. The log(HOMA-IR)-CHD association was comparable to that observed with the MA index (Table 1). For both indices, an association was present in men, but not in women (P interaction = 0.01 and 0.2 for log(HOMA-IR) and MA index , respectively). Conclusions: The performance of the MA index in predicting CHD and stroke risk in AAs is comparable to the widely used HOMA-IR index. Our findings suggest a role of insulin resistance in CHD but not stroke risk in this population.

Abstract MP37: The Triglyceride to High-density Lipoprotein Cholesterol Ratio, an Estimate of Insulin Resistance, is Associated with Incident Coronary Heart Disease. The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Insulin resistance (IR), a metabolic dysregulation predictive of various clinical sequelae, is reportedly associated with the risk of coronary heart disease (CHD). The invasive nature of direct measures of IR limits their use in clinical practice and population research, motivating the need for a suitable tool to signal the presence of IR. Its correlation with insulin action, simplicity, and wide availability of standardization in its assay properties, promotes the ratio of fasting plasma triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C). However, there is no consensus for TG/HDL-C ratio thresholds to index IR, whether the ratio relates to IR in African Americans, nor the ratio’s ability to predict coronary heart disease (CHD) risk. Objectives: To: 1) optimize race and gender-specific TG/HDL-C ratio cut-points indicative of IR in white and African American males and females; 2) compare cardio-metabolic profiles of the dichotomies created by these cut-points within each race-gender subgroup; and 3) estimate associations of IR indexed by the TG/HDL-C ratio with incident CHD by race and gender. Methods: Data from 10,031 white and 3,076 African American non-diabetic participants aged 45-64 years in the population-based ARIC Study were examined. Race and gender-specific TG/HDL-C ratio cut-points with optimal performance against the upper quartile of fasting insulin were calculated at baseline (1987-1989) using Youden indices. Cardio-metabolic profiles were compared by IR categories in each race-gender subgroup. Competing risk (of death) Cox models, adjusted for age, hypertension, cigarette smoking, BMI, and LDL-C, were fit by race and gender to quantify the risk of incident CHD events by 2012 independently attributed to IR. Incident CHD events were ascertained from cohort examinations, follow-up of hospital admissions and fatal events records, and classified according to a standardized protocol. Results: A total of 1,886 (18%) and 429 (14%) validated CHD events accrued by 2012 in whites and African Americans, respectively. Optimized values of the TG/HDL-C ratio thresholds to index IR were ≥3.4 for white males, ≥2.3 for white females, ≥2.2 for African American males, and ≥1.8 for African American females. Applying these thresholds, individuals denoted as having IR had noticeably poorer cardio-metabolic risk profiles than those not having IR in each race-gender subgroup. IR, as defined by the above cut-points, was associated with the following adjusted hazard ratios (95% confidence intervals) of incident CHD by 2012: 1.35 (1.21, 1.52) in white males; 1.52, (1.27, 1.83) in white females; 1.69 (1.28, 2.22) in African American males; and 1.44 (1.08, 1.92) in African American females. Conclusion: The TG/HDL-C ratio, a clinically useful indicator of IR, independently predicts coronary heart disease in non-diabetic white and African American men and women.

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of β-cell function in African American women

BackgroundThe TG/HDL-C ratio is used as a marker of insulin resistance (IR) in Caucasians. However, there are conflicting data on TG/HDL-C ratio as a predictor of IR in African Americans. Compared to Caucasians, African Americans have lower TG levels and increased insulin levels despite a greater risk for diabetes. We hypothesized that the TG/HDL-C ratio is predictive of IR and/or β-cell function in African American (AA) women. MethodsNon-diabetic AA women (n=41) with a BMI>25kg/m2 underwent frequently sampled intravenous glucose tolerance test (FSIGTT). Insulin sensitivity (SI) and the acute insulin response to glucose (AIRg) were measured using minimal model and β-cell function was determined by disposition index (DI=SI*AIRg). IR was defined as the lowest tertile of SI (<1.8×10−4min−1/μU/ml) and inadequate β cell compensation was defined as the lowest tertile of DI (<900). Data were analyzed using logistic regression models and area under the receiver operating characteristic curve (AUC-ROC). An AUC-ROC>0.70 was defined as significant discrimination. ResultsThe mean (± SD) age was 38.5±11.3years, with BMI of 33.5±6.7kg/m2 and fasting glucose of 86.5±10.5mg/dL. The AUC-ROC for the prediction of DI<900 was 0.74 indicating that a higher TG/HDL-C ratio was associated with decreased DI. However, the AUC-ROC for prediction of IR or low AIRg (<335 μU/ml) was not significant. ConclusionThis study confirmed that the TG/HDL-C ratio is a poor predictor of IR in AA women. However, we did show an inverse association between the TG/HDL-C ratio and β-cell function, suggesting that this simple tool may effectively identify AA women at risk for DM2.

Association between serum vitamin D and insulin resistance in African Americans with type 2 diabetes (1030.3)

The purpose of the study was to determine the association between serum vitamin D and insulin resistance measured by HOMA2‐IR index in a sample of African Americans with type 2 diabetes residing in South Florida. Subjects were recruited by community outreach. One hundred and eleven subjects (n=111) were included in the study. Fasting plasma insulin and glucose were used to calculate HOMA2‐IR. Serum vitamin D was measured with an enzyme‐immunoassay kit by absorbance. HOMA2‐IR values were log transformed to achieve normality. Unadjusted and adjusted multilinear regressions were used to determine the association between log HOMA2‐IR and serum vitamin D. Log HOMA2‐IR was the dependent variable. The mean age, BMI, A1C, energy intake, serum vitamin D, and log HOMA2‐IR values were 54.73 ± 10.21 years, 35.90 ± 8.22 kg/m2, 7.61 ± 1.92 (%), 2088.47 ± 1116.58 kcal, 19.12 ± 8.86 (ng/mL), and 0.22 ± 0.29 respectively. In the unadjusted model, serum vitamin D was associated with log HOMA2‐IR (β=‐0.203, P=0.030). However, the association did not hold after adjusting for covariates (P=0.109). Age (P=0.020), BMI (P=0.001), and A1C (P=0.002) were strongly associated with HOMA2‐IR. The association among serum vitamin D and HOMA2‐IR was confounded by age, BMI and A1C.Grant Funding Source: Supported by NIH/NIDDK sponsored grant. JE was supported by NIH/NIGMS R25 GM061347.

Abstract 367: Insulin Resistance is Associated with Increased Sympathetic Activity and Decreased Baroreflex Function in Obese African American Women

Obesity has a greater detrimental impact on the health of African American (AA) women than any other racial or gender group. Nearly 80% of AA women are overweight or obese and have higher incidence of insulin resistance compared to Caucasian women. The sympathetic nervous system (SNS) is increased in obesity and previous studies have reported that it may contribute to insulin resistance. However, most of these studies were performed in Caucasians. Thus, the contribution of the SNS to insulin resistance in African Americans remains unknown.The aim of this study was to determine if sympathetic activity is increased in obese AA women with insulin resistance. A total of 35 obese AA women with metabolic syndrome were studied (age 43±9 years, body mass index 38.7±5.5 Kg/m 2 , percentage body fat 48±4). Insulin sensitivity (SI) was evaluated by frequently sampled intravenous tolerance test and analyzed with Bergman's minimal model (MINMOD). Measurement of sympathetic regulation of vasomotor tone and baroreflex gain were determined with baroreflex-cross spectral analysis. Our results showed that SI was directly associated with baroreflex sensitivity, Figure. Subjects with insulin resistance (SI&lt;3) had lower baroreflex sensitivity compared with those with normal SI (6.2±2.8 vs 10.4±4.5 ms/mm Hg, P=0.009). Subjects with insulin resistance tended to have elevated sympathetic activity as measured by low frequency variability of systolic blood pressure (LF SBP ; 5.9±3.4 vs 3.7±2.0 mm Hg 2 , P=0.057). In conclusion, insulin resistance is associated with decreased baroreflex gain and increased sympathetic activity in obese AA women.

The Association of the Triglyceride-to-HDL Cholesterol Ratio with Insulin Resistance in White European and South Asian Men and Women

IntroductionThere is recent interest surrounding the use of the triglyceride-to-HDL cholesterol ratio as a surrogate marker of insulin resistance in clinical practice, as it may identify people at high risk of developing diabetes or its complications. However, it has been suggested using this lipid ratio may not be appropriate for measuring insulin resistance in African-Americans, particularly women. We investigated if this inconsistency extended to South Asian women in a UK multi-ethnic cohort of White Europeans and South Asians.MethodsCross-sectional analysis was done of 729 participants from the ADDITION-Leicester study from 2005 to 2009. The association between tertiles of triglyceride-to-HDL cholesterol ratio to fasting insulin, homeostatic model of assessment for insulin resistance (HOMA1-IR), quantitative insulin sensitivity check index (QUICKI) and glucose: insulin ratio was examined with adjustment for confounding variables.ResultsIncremental tertiles of the triglyceride-to-HDL cholesterol ratio demonstrated a significant positive association with levels of fasting insulin, HOMA1-IR, glucose: insulin ratio and a negative association with QUICKI in White European men (n = 255) and women (n = 250) and South Asian men (n = 124) (all p<0.05), but not South Asian women (n = 100). A significant interaction was demonstrated between sex and triglyceride-to-HDL cholesterol ratio tertiles in South Asians only (p<0.05). The area under the receiver operating characteristic curve for triglyceride-to-HDL cholesterol ratio to detect insulin resistance, defined as the cohort HOMA1-IR≥75th percentile (3.08), was 0.74 (0.67 to 0.81), 0.72 (0.65 to 0.79), 0.75 (0.66 to 0.85) and 0.67 (0.56 to 0.78) in White European men and women, South Asian men and women respectively. The optimal cut-points for detecting insulin resistance were 0.9–1.7 in mmol/l (2.0–3.8 in mg/dl) for the triglyceride-to-HDL ratio.ConclusionIn South Asian women the triglyceride-to-HDL cholesterol ratio was not associated with insulin resistance; therefore there may be limitations in its use as a surrogate marker in this group.

Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans

Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10(-6) in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10(-8) and 2.9 × 10(-8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10(-9) and 4.9 × 10(-10) for FI and IR, respectively). In silico replication in the MAGIC study (n = 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes.

The Roles of IL-6, IL-10, and IL-1RA in Obesity and Insulin Resistance in African-Americans

The aim of the study was to investigate the associations between IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, measures of obesity, and insulin resistance in African-Americans. Nondiabetic participants (n = 1025) of the Howard University Family Study were investigated for associations between serum IL (IL-1RA, IL-6, IL-10), measures of obesity, and insulin resistance, with adjustment for age and sex. Measures of obesity included body mass index, waist circumference, hip circumference, waist-to-hip ratio, and percent fat mass. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Data were analyzed with R statistical software using linear regression and likelihood ratio tests. IL-1RA and IL-6 were associated with measures of obesity and insulin resistance, explaining 4-12.7% of the variance observed (P values < 0.001). IL-1RA was bimodally distributed and therefore was analyzed based on grouping those with low vs. high IL-1RA levels. High IL-1RA explained up to 20 and 12% of the variance in measures of obesity and HOMA-IR, respectively. Among the IL, only high IL-1RA improved the fit of models regressing HOMA-IR on measures of obesity. In contrast, all measures of obesity improved the fit of models regressing HOMA-IR on IL. IL-10 was not associated with obesity measures or HOMA-IR. High IL-1RA levels and obesity measures are associated with HOMA-IR in this population-based sample of African-Americans. The results suggest that obesity and increased levels of IL-1RA both contribute to the development of insulin resistance.

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10−7≤P≤1.1*10−5) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10−6). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10−4) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans.

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

The Triglyceride/High-Density Lipoprotein Cholesterol Ratio Fails to Predict Insulin Resistance in African-American Women: An Analysis of Jackson Heart Study

Compared to whites, insulin-resistant African Americans have worse outcomes. Screening programs that could identify insulin resistance early enough for intervention to affect outcome often rely on triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels. Racial differences in TG and HDL-C may compromise the efficacy of these programs in African Americans. A recommendation currently exists to use the TG/HDL-C ratio ≥2.0 to predict insulin resistance in African Americans. The validity of this recommendation needs examination. Therefore, our aim was to determine the ability of TG/HDL-C ratio to predict insulin resistance in African Americans. In 1,903 African Americans [895 men, 1,008 women, age 55 ± 12 years, mean ± standard deviation (SD), range 35-80 years, body mass index (BMI) 31.0 ± 6.4 kg/m(2), range 18.5-55 kg/m(2)] participating in the Jackson Heart Study, a population-based study of African Americans, Jackson, Mississippi tricounty region, insulin resistance was defined by the upper quartile (≥4.43) of homeostasis model assessment of insulin resistance (HOMA-IR). An area under the receiver operating characteristic curve (AUC-ROC) of >0.70 was required for prediction of insulin resistance by TG/HDL-C. The optimal test cutoff was determined by the Youden index. HOMA-IR was similar in men and women (3.40 ± 2.03 vs. 3.80 ± 2.46, P = 0.60). Women had lower TG (94 ± 49 vs. 109 ± 65 mg/dL P < 0.001) and TG/HDL-C (1.9 ± 1.4 vs. 2.7 ± 2.1, P < 0.001). For men, AUC-ROC for prediction of insulin resistance by TG/HDL-C was: 0.77 ± 0.01, mean ± standard error (SE), with an optimal cutoff of ≥2.5. For women, the AUC-ROC was 0.66 ± 0.01, rendering an optimal cutoff indefinable. When women were divided in two groups according to age, 35-50 years and 51-80 years, the results did not change. In African-American men, the recommended TG/HDL-C threshold of 2.0 should be adjusted upward to 2.5. In African-American women, TG/HDL-C cannot identify insulin resistance. The Jackson Heart Study can help determine the efficacy of screening programs in African-Americans.

Relationships Among Obesity, Inflammation, and Insulin Resistance in African Americans and West Africans

Several research studies in different populations indicate that inflammation may be the link between obesity and insulin resistance (IR). However, this relationship has not been adequately explored among African Americans, an ethnic group with disproportionately high rates of obesity and IR. In this study, we conducted a comparative study of the relationship among adiposity, inflammation, and IR in African Americans and West Africans, the ancestral source population for African Americans. The associations between obesity markers (BMI and waist-to-hip ratio (WHR)), inflammatory markers (high-sensitivity C-reactive protein (hsCRP), haptoglobin, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha), and IR (homeostasis model assessment of insulin resistance (HOMA(IR))) were evaluated in 247 West Africans and 315 African Americans. In average, African Americans were heavier than the West Africans (by an average of 1.6 BMI units for women and 3 BMI units for men). Plasma hsCRP, haptoglobin, and IL-6 (but not TNF-alpha level) were higher in African Americans than in West Africans. In both populations, BMI was associated with markers of inflammation and with HOMA(IR), and these associations remained significant after adjusting for sex and age. However, the pattern of associations between measured inflammatory markers and IR was different between the two groups. In West Africans, hsCRP was the only inflammatory marker associated with IR. In contrast, hsCRP, haptoglobin, and IL-6 were all associated with IR in African Americans. Interestingly, none of the associations between markers of inflammation and IR remained significant after adjusting for BMI. This finding suggests that in African Americans, the relationship between inflammatory markers and IR is mediated by adiposity.

Metabolic Syndrome Racial Differences in Adolescents

The metabolic syndrome consists of obesity, insulin resistance, dyslipidemia, atherosclerosis, and hypertension. Its clinical outcomes are stroke, myocardial infarction, and type 2 diabetes. Each of these is more frequent in African-Americans than in Caucasians. This is surprising since most studies indicate that the incidence of the metabolic syndrome is lower in African-American than Caucasian adults. There is growing evidence that adult cardiovascular disease has its origin in childhood and adolescents. Thus, it is important that we understand differences in the pathophysiological precursors to metabolic and cardiovascular disease in this age group. Many studies, but not all, have demonstrated that African-American children and adolescents are insulin resistant compared to similar age Caucasians. The increased insulin resistance occurs in spite of lower triglyceride levels. Low triglyceride levels are usually associated with increased insulin sensitivity. There is evidence that the relationship between triglycerides and insulin sensitivity differs between the two races. African-Americans compensate for the increased insulin resistance by increasing insulin secretion and insulin clearance. Interestingly, those studies that have not found increased insulin resistance in African-Americans have found increased insulin secretion suggesting the increased secretion may precede the insulin resistance. Hyperinsulinism and insulin resistance are linked to endothelial dysfunction in adults and African-American adolescents have poorer endothelial function than do Caucasians. In African-American adolescents, endothelial function decreases as insulin secretion increases. It is likely that the hyperinsulinism, insulin resistance and endothelial dysfunction in adolescent African-American adolescents play an important role in the increased rates of cardiovascular disease and type 2 diabetes. Future research should focus on the mechanisms of these abnormalities and ways to prevent their development in this age group.

Should triglycerides and the triglycerides to high-density lipoprotein cholesterol ratio be used as surrogates for insulin resistance?

The aims of the present study were to examine whether triglycerides (TG) and the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) could predict insulin resistance in healthy African Americans and whites. This cross-sectional study included 99 African American and 50 white men and women between 18 and 45 years of age with body mass indexes between 18.5 and 38.0 kg/m 2. Anthropometric measures were obtained; and overnight fasting blood was collected for TG, HDL-C, glucose, and insulin. Insulin resistance was defined by fasting insulin concentration of at least 13.13 μU/mL and homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5. Receiver operating characteristic curves were used to analyze the data. African Americans and whites had comparable demographic and anthropometric measures. Fasting insulin was higher in African Americans (12.4 ± 7.8 μU/mL) than whites (10.2 ± 7.5 μU/mL), but HOMA-IR did not differ significantly (African Americans, 2.9 ± 2.0; whites, 2.4 ± 1.9). Triglycerides and TG/HDL-C were significantly lower in African Americans (TG, 68.2 ± 43.3 mg/dL; TG/HDL-C, 1.8 ± 2.1) compared with whites (TG, 105.4 ± 55.2 mg/dL; TG/HDL-C, 2.8 ± 1.8). Area under the receiver operating characteristic curves revealed that both TG and TG/HDL-C were acceptable markers of insulin resistance, as defined by fasting insulin concentration, in whites, 0.770 and 0.765, respectively, but poor predictors in African Americans, 0.633 and 0.651, respectively. Similarly, TG and TG/HDL-C were acceptable in predicting insulin resistance, as measured by HOMA-IR, in whites, 0.763 and 0.770, respectively, but poor in predicting HOMA-IR in African Americans, with areas of 0.625 and 0.639, respectively. In conclusion, the relationship between TG and TG/HDL-C with insulin resistance differs by ethnicity; and using TG and TG/HDL-C to predict insulin resistance in African Americans would not be appropriate.

Association of a Polymorphic Variant of the Adiponectin Gene with Insulin Resistance in African Americans

Hypertension, type 2 diabetes, and obesity are common complex disorders that contribute to cardiovascular (CV) disease. Insulin resistance increases CV risk and is present in these disorders. Adiponectin, a protein secreted by adipocytes with metabolic and vascular protective effects, is lower in obesity and insulin resistance. Several single nucleotide polymorphisms (SNP) have been identified in the adiponectin (ADIPOQ) gene. Associations of ADIPOQ polymorphisms with diabetes and obesity have been described in Caucasians and Asians. The purpose of this study was to determine if genetic variants of ADIPOQ are associated with insulin resistance and CV risk in African Americans. Metabolic traits (lipids, glucose, insulin, and insulin sensitivity) and blood pressure were measured in 273 African Americans. DNA was examined by DNA sequence analysis and SNPs of candidate genes including ADIPOQ were studied. Statistica analyses were performed by regression of the quantitative trait phenotypes on the groups defined by the SNP genotypes, adjusting for age, sex, and body mass index (BMI). SNP 712 (rs3774261) ofthe/lD/POQgene showed significant association with insulin resistance (p= 0.001). Despite the relatively small sample, our results indicate that genes that regulate adipocyte function may have a regulatory role in the expression of metabolic traits in obesity-associated chronic disease.

Adiponectin Receptor 1 Variants Associated with Lower Insulin Resistance in African Americans

Adiponectin has been shown to have a role in insulin resistance. However, little is known about the contribution of genetic variation in the adiponectin receptor 1 gene (ADIPOR1) in this regard. We hypothesized that variation in ADIPOR1 would be associated with significant changes in insulin resistance and tested this hypothesis in a cohort of 483 African-American adolescents. Seven single nucleotide polymorphisms (SNPs) of ADIPOR1 spanning from the promoter to the 3'-untranslated region were genotyped. We analyzed single SNPs and haplotypes for associations with insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] in the full cohort as well as lean (BMI < 85%) and non-lean (BMI >or= 85%) subsets. There was no evidence of ADIPOR1 variant effects on HOMA-IR in the full cohort or in the lean subset. However, in the non-lean subset, SNP +5843 (A allele), and haplotypes including SNPs -8505/-5692/+3002/+5843 (ATTA and AGTG) showed significant associations with decreased HOMA-IR after adjustment for sex, puberty, adiponectin, and waist z-score. Our findings suggest not only that ADIPOR1 variants influence insulin resistance in the presence of adiposity, but also that these variants and haplotypes are protective in African Americans.

Plasma lipid concentrations in nondiabetic African American adults: associations with insulin resistance and the metabolic syndrome

Despite higher rates of cardiovascular disease, African Americans have a more favorable lipid profile. The purpose of the study was to examine the association between plasma lipid concentrations and insulin resistance in African Americans and to determine if insulin resistance is present at a lower triglyceride (TG) threshold than is used for metabolic syndrome criteria. Data were examined on 185 nondiabetic African American men (n = 61) and women (n = 124), mean age, 39.8 years. Measurements included blood pressure, anthropometrics, oral glucose tolerance test, and insulin sensitivity ( M) by insulin clamp. The relationship between lipids and insulin sensitivity was analyzed by correlation analysis and by comparing TG levels among tertiles of M. Despite relatively low mean (± SD) TG level (87.8 ± 55.2 mg/dL), there were statistically significant correlations of M with TG ( r = −0.23, P < .002), high-density lipoprotein cholesterol (HDL-C; r = 0.19, P < .01), and TG/HDL-C ratio ( r = −0.23, P < .002). The correlations were strongest in men. Subjects with TG in an intermediate range (110-149 mg/dL) had insulin resistance equivalent to that of the high-TG group (≥150 mg/dL). In African Americans, TG levels below the current metabolic syndrome threshold criterion are associated with insulin resistance.