The Relationship of the Anti-Oxidant Bilirubin with Free Thyroxine Is Modified by Insulin Resistance in Euthyroid Subjects

BACKGROUND: The strong anti-oxidative properties of bilirubin largely explain its cardioprotective effects. Insulin resistance is featured by low circulating bilirubin. Thyroid hormone affects both bilirubin generation and its biliary transport, but it is unknown whether circulating bilirubin is associated with thyroid function in euthyroid subjects. Aim is to determine relationships of bilirubin with TSH, free T4 and free T3 in euthyroid subjects without type 2 diabetes mellitus (T2DM), and to assess whether such a relationship would be modified by the degree of insulin resistance. METHODS: Total bilirubin, TSH, free T4, free T3, glucose, insulin, lipids and transaminases were measured in 1854 fasting euthyroid subjects without T2DM, recruited from the general population (PREVEND cohort). Insulin resistance was assessed by homeostasis model assessment. RESULTS: Bilirubin was positively related to free T4 (β = 0.116, P<0.001) and free T3 (β = 0.078, P = 0.001), but bilirubin was unrelated to TSH. The relationship of bilirubin with free T4 was modified by insulin resistance with a larger effect in more insulin resistant individuals (adjusted for age and sex: β = 0.043, P = 0.056 for interaction; additionally adjusted for smoking, alcohol intake, transaminases and total cholesterol (β = 0.044, P = 0.044 for interaction). The association of bilirubin with free T4 was also modified by high density lipoprotein cholesterol (age- and sex-adjusted: β = 0.040, P = 0.072). CONCLUSIONS: Low bilirubin relates to low free T4 in euthyroid non-diabetic subjects. Low normal free T4 may particularly confer low bilirubin in more insulin resistant individuals

High sensitive C-reactive protein and serum amyloid A are inversely related to serum bilirubin:effect-modification by metabolic syndrome

<p>Background: Bilirubin has been implicated in cardiovascular protection by virtue of its anti-inflammatory and anti-oxidative properties. The metabolic syndrome is featured by enhanced low-grade systemic inflammation and oxidative stress. Serum amyloid A (SAA) impairs anti-oxidative properties of high-density lipoprotein (HDL). We determined relationships of high sensitive C-reactive protein (hs-CRP) and SAA with bilirubin in subjects with and without metabolic syndrome (MetS).</p><p>Methods: Serum total bilirubin, hs-CRP, SAA and homeostasis model assessment-insulin resistance (HOMA-IR) were documented in 94 subjects with and in 73 subjects without MetS (26 and 54 subjects with type 2 diabetes mellitus (T2DM), respectively).</p><p>Results: Bilirubin was lower in MetS (P = 0.013), coinciding with higher hs-CRP (P <0.001) and SAA levels (P = 0.002). In all subjects combined, hs-CRP was inversely related to bilirubin (r = -0.203, P = 0.008), irrespective of the presence of MetS or T2DM (interaction terms: P >= 0.75). The inverse relationship of bilirubin with SAA was confined to subjects without MetS (r = -0.267, P = 0.009). Furthermore, the presence of either MetS or T2DM modified the relationship of bilirubin with SAA (interaction terms: beta = 0.366, P = 0.003 and beta = 0.289, P = 0.025, respectively) in age-and sex-adjusted analyses. Effect modification was also found for HOMA-IR (beta = 0.790, P = 0.020). Of the individual MetS components, the strongest interaction of bilirubin on SAA was observed with low HDL cholesterol (beta = 0.435, P <0.001).</p><p>Conclusions: hs-CRP is inversely related to bilirubin, suggesting that low bilirubin is implicated in enhanced low-grade systemic inflammation. The inverse relationship of SAA with bilirubin was found to be absent in MetS, which could be attributable to MetS-associated abnormalities in HDL characteristics.</p>

Low-normal free thyroxine confers decreased serum bilirubin in type 2 diabetes mellitus

Background: Bilirubin may confer cardiovascular protection because of its strong antioxidative properties. Both thyroid dysfunction and the diabetic state affect bilirubin metabolism. Here we tested whether low-normal thyroid function affects serum bilirubin among euthyroid subjects with and without type 2 diabetes mellitus (T2DM). Methods: Serum total bilirubin, thyrotropin and free thyroxine (free T4), transaminases, insulin sensitivity (homeostasis model assessment), and lipids were measured in 74 T2DM and 82 nondiabetic subjects with thyrotropin and free T4 levels within the euthyroid range. Results: Bilirubin was positively related to free T4 in T2DM subjects (r=0.370,

Multivariable linear regression models demonstrating the interaction between free T₄ and insulin resistance on bilirubin.

<p>HOMA-IR, Homeostasis model assessment-insulin resistance; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; β, standardized regression coefficient. Bilirubin, HOMA-IR, AST and ALT were log transformed.</p

Clinical characteristics, glucose, insulin, insulin resistance, lipids, transaminases, and thyroid hormones in 1854 subjects.

<p>Data in mean ± SD or in median (interquartile range). BMI, body mass index; HOMA-IR, homeostasis model assessment-insulin resistance; HDL, high density lipoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; β, standardized regression coefficient. <i>P</i>-values for linear trend are shown. Bilirubin, glucose, insulin, HOMA-IR, triglycerides, TSH, AST and ALT were log transformed.</p

Bilirubin and Progression of Nephropathy in Type 2 Diabetes:A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

Bilirubin, a potent endogenous antioxidant, was found to protect against the development of diabetic nephropathy (DN) in rodents. In humans, cross-sectional studies found an inverse relation between bilirubin and DN. We prospectively investigated whether bilirubin is associated with progression of DN toward end-stage renal disease (ESRD). To this end, we performed a post hoc analysis in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial with independent replication in the Irbesartan Diabetic Nephropathy Trial (IDNT). Subjects with type 2 diabetes and nephropathy with alanine aminotransferase, aspartate aminotransferase (AST), and bilirubin level

Age- and sex-adjusted linear regression analyses demonstrating relationships of bilirubin with thyroid hormones, components of the metabolic syndrome, insulin, insulin resistance and total cholesterol.

<p>HDL, high density lipoprotein; HOMA-IR, homeostasis model assessment-insulin resistance; β, standardized regression coefficient. Bilirubin, TSH, glucose, insulin and HOMA-IR and triglycerides were log transformed.</p

Plasma bilirubin and late graft failure in renal transplant recipients

Exogenous bilirubin has been shown to protect against oxidative stress in ischemia-reperfusion injury. Oxidative stress has been implicated in the pathophysiology of chronic transplant dysfunction leading to late graft failure after renal transplantation. We prospectively investigated whether high endogenous bilirubin is protective against development of late graft failure in renal transplant recipients (RTR). Baseline data were collected between August 2001 and July 2003 in nonicteric outpatient RTR with a functioning graft for >1 year. At baseline, bilirubin and liver enzymes were measured using routine assays on a Merck Mega analyzer. Graft failure was prospectively recorded until May 19 2009. During follow-up for 7.1[6.27.2] years, 55 RTR developed graft failure. We found that circulating levels of bilirubin are inversely associated with late graft failure in RTR (HR = 0.29 [95% CI: 0.160.52], P <0.001). This association was independent of potential confounders, including creatinine clearance, urinary protein excretion, calcineurin inhibitors, and gender (HR = 0.31 [95% CI: 0.150.62] P = 0.001). Our findings are consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in RTR. If our findings are confirmed by other studies, intervention with endogenous or exogenous bilirubin may be of interest for long-term preservation of renal function in RTR

Graphical presentation of the interaction of free T₄ with insulin resistance on bilirubin.

<p>The standardized regression coefficients of the interaction term obtained by multivariable linear regression analysis as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090886#pone-0090886-t003" target="_blank">Table 3</a>, model 3 is used.</p