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Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes.

ABSTRACT: The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.

SUBMITTER: Yaghootkar H

PROVIDER: S-EPMC4392920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as "metabolically normal obese" (MNO), but not those defined as "metabolically abnormal obese" (MAO), are protected from the adverse metabolic effects of weight gain. METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m2 who were matched for BMI and fat mass. RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects. CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain-induced metabolic dysfunction. TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170. FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.

Project description:BackgroundPeople with the metabolically obese normal weight (MONW) phenotype have been confirmed to significantly increase the risk of unfavorable health consequences. This study aimed to investigate the relationships between traditional and novel anthropometric indices with the MONW phenotype and compare the predictive ability of different anthropometric indices in identifying individuals with the MONW phenotype.MethodsThis cross-sectional study involved a total of 26,332 participants aged 18 years or older with a normal weight from Nanjing, China. Sociodemographic information, biochemical measurements, and anthropometric indices were collected. The novel body fat anthropometric indices included body shape index (ABSI), body roundness index (BRI), abdominal volume index (AVI), weight-adjusted-waist index (WWI), body adiposity index (BAI), conicity index (CI), waist-hip-height ratio (WHHR), as well as traditional indices such as waist circumference (WC), hip circumference (HC), body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR).The prevalence ratio (PR) from modified poisson regression and area under the receiver-operating characteristic curve (AUC) were conducted to compare the association and predictive capacity of different obesity indicators for the MONW phenotype. All analyses were stratified by sex.ResultsModified poisson regression analyses revealed that weight, WC, HC, BMI, WHR, WHtR, ABSI, BRI, AVI, WWI, BAI, CI, and WHHR were independently associated with higher risk of the MONW phenotype, regardless of whether they were treated as a continuous or categorical variable (P < 0.05). Notably, BRI demonstrated the strongest association in both men (highest quartile VS lowest quartile; PR = 3.14, 95%CI, 2.49, 3.96; P < 0.001) and women (PR = 4.63, 95%CI, 3.81, 5.62; P < 0.001). Receiver operating characteristic analysis indicated that AUC for the different anthropometric indices ranged from 0.50 to 0.80. BRI and WHtR had the largest AUC in both males (both AUC = 0.733; 95% CI, 0.717, 0.750) and females (both AUC = 0.773; 95% CI, 0.761, 0.786). The optimal cut-off points for BRI, determined by maximizing the Youden's index, were 3.102 (sensitivity: 63.2%, specificity: 36.2%) in males and 3.136 (sensitivity: 68.9%, specificity: 44.2%) in females. Moreover, BRI and WHtR exhibited the highest diagnostic accuracy in younger age groups, specifically those aged 18-34 in both sexes.ConclusionsBRI emerged as the optimal predictor and independent determinant of the MONW phenotype, regardless of gender. This association was particularly pronounced in young individuals.

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Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes.

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