A Pilot Study of Moderate Hyperbilirubinemia in Type 1 Diabetes Mellitus

Diabetes mellitus (DM) is associated with a markedly increased risk of both macro- and microvascular disease. Excess pro-oxidants and insufficient antioxidants each contributes to oxidant stress in DM. Oxidant stress induces endothelial dysfunction, a major determinant of vascular damage. In DM, hyperglycemia and elevated free fatty acids (FFAs) induce generation of reactive oxygen species (ROS) by stimulating protein kinase C (PKC) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Figure 1). In addition, hyperglycemia activates the renin-angiotensin system, and angiotensin II (Ang II) additively stimulates PKC and NADPH oxidase.

Bilirubin, long regarded as metabolic waste, is, in fact, a potent antioxidant scavenger of ROS. It also directly inhibits both protein kinase C and the NADPH oxidase system, augmenting its antioxidant activity (Figure 1). Moreover, bilirubin inhibits Ang II-mediated vasoconstriction and ROS generation. Experimental models suggest that hyperbilirubinemia may preserve diabetes-associated endothelial function and prevent vasculopathy. Furthermore, epidemiological studies demonstrate that higher bilirubin levels are associated with a reduced risk of vascular disease in DM. Bilirubin therefore emerges as a potentially critical molecule to protect against diabetic vascular and renal damage. However, limited translational research has addressed raising bilirubin levels as a preventive therapy for vascular disease in DM.

Accordingly, the investigators seek to establish the feasibility of studying the change in endothelial function caused by induced moderate hyperbilirubinemia in type 1 diabetes. the investigators will take advantage of the recently described use of atazanavir to safely achieve moderate hyperbilirubinemia. Atazanavir is a protease inhibitor used to treat HIV infection that competitively inhibits hepatic 1A1 isoform of uridine diphosphoglucose glucuronosyltransferase (UGT1A1), limiting bilirubin clearance and inducing hyperbilirubinemia (Figure 2). This mimics Gilbert's syndrome, a benign unconjugated hyperbilirubinemia due to partial genetic deficiency of UGT1A1.

This work has the potential to identify iatrogenic moderate hyperbilirubinemia as a strategy to interrupt key mechanisms of type 1 diabetes-associated macro- and microvascular disease.

This is a physiologic study. The design is a single arm and open label. There are three study visits: a screening visit, a baseline visit, and a final visit. The treatment is atazanavir 300 mg PO bid. The treatment period is 4 days. The primary study outcome is forearm vascular function. The principal secondary outcomes are serum antioxidant defense capacity and measures of oxidant stress.