Novel Targets for Reducing Atherosclerosis in Type 1 Diabetes

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Atherosclerosis pathogenesis is multifactorial, involving hyperlipidemia and inflammation, as well as hyperglycemia. Individuals with type 1 diabetes show a four-fold increase in cardiovascular disease risk that has persisted despite the spectacular advances in drugs for risk factor management and insulin therapy4. Thus, new strategies and approaches are necessary. Because insulin is administered to diabetic patients subcutaneously, rather than into the portal vein, which is physiological, the liver remains relatively under-insulinized. We considered the possibility that this could contribute to the pro-atherogenic milieu, even beyond hyperglycemia. The long-term goal of this project is to develop drugs that mimic key atheroprotective effects of insulin on the liver. In our preliminary data, we identify Cyp7b1 as an exquisitely sensitive target of insulin in the liver: Cyp7b1 was increased by acute insulin stimulation; reduced by insulin deficiency; reduced by hepatic knockout of the insulin receptor; and one of only four genes significantly altered in all three conditions. CYP7B1 plays a central role in cholesterol, oxysterol and bile acid metabolism6-8. Based on our strong preliminary data, we hypothesize that insulin induces CYP7B1 to maintain lipid homeostasis and suppress inflammation, and that this regulation is lost in type 1 diabetes, leading to atherosclerosis. To test this hypothesis, we will (1) determine the extent to which restoration of Cyp7b1 in a mouse model of type 1 diabetes can prevent atherosclerosis; and (2) define the signaling pathways by which insulin regulates Cyp7b1. We expect to find that CYP7B1 reduces atherosclerosis in diabetic mice via two mechanisms: (1) reducing oxysterols and vascular inflammation; and (2) reducing dietary cholesterol absorption (via modulation of the bile acid profile) and plasma cholesterol. Validation of our hypothesis could lead to the development of drugs that mimic insulin action on CYP7B1. Such drugs, which would restore homeostasis in type 1 diabetes, could be more effective than present lipid-lowering therapies as they would lower both plasma cholesterol and inflammation.