Abstract
ObjectiveAlthough previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model.MethodBody fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues.ResultsIn the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice.ConclusionsBilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation.
Highlights
Obesity is a risk factor for type 2 diabetes mellitus [1, 2], and recent studies have shown that body fat distribution may be more important than overall adiposity
Univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower high-density lipoprotein-cholesterol (HDL-C)
Bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area
Summary
Obesity is a risk factor for type 2 diabetes mellitus [1, 2], and recent studies have shown that body fat distribution may be more important than overall adiposity. While biliverdin reductase-A (BVRA) protected against hepatic steatosis via PPARα activation [11], BVRA knockout mice on a HFD were glucose insensitive [11] and BVRA was lower in obese humans with insulin resistance [12]. Previous studies suggested that bilirubin functions as an antioxidant [13] and an important modulator of chronic inflammation in metabolic syndrome and diabetes [14], the underlying mechanism of the relationships between bilirubin and insulin resistance, body fat distribution, and adipose tissue inflammation in diabetes mellitus have not been fully characterized. In this study we elucidated these relationships in patients with type 2 diabetes mellitus and in an animal model
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