Bilirubin belongs to the superfamily of tetrapyrrolic compounds, which is one of the most highly conserved groups of molecules. These compounds have evoked to have pluripotent roles, starting from the role as light harvesting and energy generating pigments in a photosynthetic process in algae and plants. For decades bilirubin has been believed to be a toxic waste product of heme catabolism in human, while in recent years accumulating evidence has shown that bilirubin has beneficial effects upon various oxidative stress-associated diseases. In this commentary, we show that serum bilirubin may be an important biomarker and a potential therapeutic target in diabetes and metabolic syndrome.

Bilirubin is formed by the ubiquitously expressed heme oxygenase (HO), the rate-limiting enzyme involved in heme catabolism. HO participates in heme breakdown to generate biliverdin, free ferrous iron and carbon monoxide. Bilverdin is rapidly converted to bilirubin by biliverdin reductase. Bilirubin is further processed in the liver, where it is conjugated with glucuronic acid by uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) to a water-soluble form for elimination. Recently, clinical and experimental evidence has increasingly shown that HO and its reaction product bilirubin may serve as an important endogenous agent with cytoprotective activity against oxidative stress-induced injury. We found for the first time that diabetic patients with Gilbert syndrome, who have a genetic variant in UGT1A1 and moderately elevated levels of serum bilirubin levels, had a lower prevalence of vascular complications including retinopathy, nephropathy and cardiovascular disease, comparing to the patients without the syndrome, along with reduced markers of oxidative stress and inflammation [1]. This evidence strongly suggested that sustained moderate hyperbilirubinemia may inhibit oxidative stress and prevent the diabetic vascular complications. Such protective effects of bilirubin have been supported by increasing number of studies on both clinical and laboratory outcomes of diabetic patients. Serum bilirubin concentrations were demonstrated to be negatively associated with albuminuria in patients with type 2 diabetes [2]. The Hisayama Study group reported that comparing to the lowest bilirubin quartile, those with the highest bilirubin levels had a four times lower prevalence of diabetic retinopathy [3]. In a large Korean cross-sectional study on 94,000 subjects, high serum bilirubin was found to be associated with the reduced risk of both diabetes mellitus and diabetic nephropathy [4]. Recent report showed a significant and graded inverse association between baseline serum bilirubin levels and the progression of diabetic nephropathy in a post hoc analysis in the RENNAL trial [5]. Data from this study were independently verified using the IDNT [5]. In a both trail, the renal endpoint was examined over 2.5-year follow-up period and defined as doubling of serum creatinine or endo-stage renal disease requiring dialysis or transplantation.

We also found the inverse associations of serum bilirubin with high sensitivity C-reactive protein, HbA1c and the prevalence of type 2 diabetes in approximately 12,500 middle-aged and elderly Japanese subjects [6], suggesting that bilirubin may prevent the development of type 2 diabetes. Consistent with this data, higher serum bilirubin levels were reported to protect from diabetes mellitus in the US National Health and Nutrition Examination Survey (NHANES) on almost 16,000 subjects [7]. Importantly, recent report showed that genetically elevated bilirubin levels are causally protective against the development of type 2 diabetes using Mendelian randomization in a cohort study [8].

In diabetes, the protective properties of bilirubin are likely due to its potent antioxidant properties [9]. Bilirubin has been shown to be more effective at protecting lipids from oxidation than water-soluble antioxidant glutathione, and almost 30 times more potent toward the prevention of LDL oxidation compared to a lipid-soluble vitamin E analog. Moreover, serum bilirubin has been shown to be a major contributor to the total antioxidant capacity in blood. In addition, bilirubin was reported to inhibit NAD(P)H oxidase, which is a major source for reactive oxygen species (ROS) production in various tissues including vascular tissues and phagocytes. In rodents, we reported that bilirubin and biliverdin inhibited albuminuria and the progression of renal mesangial expansion in diabetes, as well as normalization of oxidative stress and the expression of NAD(P)H oxidase subunits in the kidney [10]. In addition, we also reported that biliverdin treatment partially prevented a worsening of glucose tolerance in db/db mice via inhibition of oxidative stress-induced pancreatic β cell damage, accompanied by normalization of the expression of NAD(P)H oxidase subunits in β cells [11]. Notably, more recent studies have shown that bilirubin has anti-inflammatory properties, and also has the potential properties in activation of Akt and eNOS and synthesis of NO [12], which improves endothelial cell function and insulin resistance as well. In recent years, chronic inflammation is considered to play an important role in multiple organ damage in obesity, metabolic syndrome, and diabetes. These organs include adipose tissue, liver, aorta, heart, kidney, and pancreatic islets. It is very likely that ant-inflammatory effect as well as anti-oxidative effect may contribute to the protective effect of bilirubin on vascular damage. Of interest, HO-1 induction was reported to reduce visceral and subcutaneous obesity in diabetic and obese mice through mechanism involving the attenuation of the inflammation process, as well as modulation of PPAR γ signaling [13]. Bilirubin was also reported to increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation in adipose tissues and liver [14]. Collectively, serum bilirubin may serve as an important physiological modulator of oxidative stress and chronic inflammation in metabolic syndrome and diabetes (Fig. 1).

Fig. 1
figure 1

The possible protective role of bilirubin on oxidative stress- and chronic inflammation-associated multiple organ dysfunction in metabolic syndrome and diabetes. FFA free fatty acid, NAFLD non-alcoholic fatty liver disease, CKD chronic kidney disease

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Given the increasing understanding of the protective properties of bilirubin and its profound association with diabetes and its complications, it is strongly suggested that serum bilirubin may be an important biomarker for the development of diabetes and its complications. Further studies should be done to clearly define how we should use serum bilirubin levels in estimating the disease state for the purpose of treatment planning. More importantly, it is also suggested that elevating serum bilirubin levels may be a feasible therapeutic strategy. This may include administration of HO-1 inducers, supplementation with bilirubin or biliverdin, and administration of drugs which decrease UGT1A1 activity. HO-1 can be upregulated by many common drugs including non-steroidal anti-inflammatory drugs and PPAR α agonists, and also by natural inducers originating from plants such as polyphenols, curcumin and silymarin. However, there has been no established evidence yet showing the beneficial effect of these drugs and natural inducers. We reported that supplementation of phycocyanobilin extracted from Spirulina platensis a blue-green algae prevented the progression of diabetes nephropathy in db/db mice by inhibiting oxidative stress [15]. Notably, the feasibility of targeting UGT1A1 is supported by a report that atazanavir, which has an inhibitory effect of UGT1A1, elevated serum unconjugated bilirubin levels and improved endothelial function in patients with diabetes [16]. This suggests that UGT1A1 inhibitor could be used to induce an “iatrogenic Gilbert syndrome” [17] to prevent the development of diabetes and its complications. This concept may be favored by findings that subjects with Gilbert syndrome or relatively higher serum bilirubin levels in normal range might have lower mortality from any cause in a large scale population-based cohort study [18, 19].

In conclusion, bilirubin is an old molecule, but accumulating evidence suggests that bilirubin may be important physiological modulator of oxidative stress and chronic inflammation in metabolic syndrome and diabetes. Studies should be done to further explore the potential of bilirubin as a new biomarker and a therapeutic target.