Abstract
Obesity-driven Type 2 diabetes (T2D) is a systemic inflammatory condition associated with cardiovascular disease. However, plasma cytokines and tissue inflammation that discriminate T2D risk in African American women with obese phenotypes are not well understood. We analyzed 64 circulating cytokines and chemokines in plasma of 120 African American women enrolled in the Black Women’s Health Study. We used regression analysis to identify cytokines and chemokines associated with obesity, co-morbid T2D and hypertension, and compared results to obese women without these co-morbidities, as well as to lean women without the co-morbidities. We then used hierarchical clustering to generate inflammation signatures by combining the effects of identified cytokines and chemokines and summarized the signatures using an inflammation score. The analyses revealed six distinct signatures of sixteen cytokines/chemokines (P = 0.05) that differed significantly by prevalence of T2D (P = 0.004), obesity (P = 0.0231) and overall inflammation score (P < E-12). Signatures were validated in two independent cohorts of African American women with obesity: thirty nine subjects with no metabolic complications or with T2D and hypertension; and thirteen breast reduction surgical patients. The signatures in the validation cohorts closely resembled the distributions in the discovery cohort. We find that blood-based cytokine profiles usefully associate inflammation with T2D risks in vulnerable subjects, and should be combined with metabolism and obesity counselling for personalized risk assessment.
Highlights
Unresolved, low level inflammation is a defining feature of Type 2 diabetes (T2D), in which specific pro-inflammatory cytokines drive disease pathogenesis [1,2]
Subjects were classified as either normal weight (BMI < 24 kg/m2) without either T2D or hypertension (‘lean, healthy’: Group I); obese (BMI ! 30 kg/m2) without either T2D or hypertension (‘obese, healthy’: Group II); obese with both T2D and hypertension, not treated with metformin (‘obese, unhealthy, no metformin’: Group III); and obese with both T2D and hypertension, and treated with metformin (‘obese, unhealthy, metformin-treated’: Group IV) (Table 1)
Preliminary analyses showed that use of metformin and non-steroidal anti-inflammatory medications were significantly associated with cytokine levels and could confound the effects of Body Mass Index (BMI) and T2D
Summary
Unresolved, low level inflammation is a defining feature of Type 2 diabetes (T2D), in which specific pro-inflammatory cytokines drive disease pathogenesis [1,2]. The healthy obese population is a significant fraction of the U.S adults with obesity, and depending on how metabolic health is measured, can represent about a quarter of subjects, including among U.S racial and ethnic minority populations [25] The purpose of this investigation was to identify new cytokines associated with metabolic disease. The approach identified specific signatures that are associated with lower mortality, morbidity and physical function, and were distinct from signatures with higher risks for morbidity and mortality We considered that this approach might be well suited to cross sectional analysis of cytokines of a different group, participants in the Black Women’s Health Study with different subtypes of obesity defined by the presence or absence of T2D
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