Novel Targets for Reducing Atherosclerosis in Type 1 Diabetes

动脉粥样硬化的发病机制是多因素的，涉及高脂血症和炎症，以及高血糖。1型糖尿病患者的心血管疾病风险增加了四倍，尽管用于风险因素管理和胰岛素治疗的药物取得了惊人的进步，但这种风险仍然存在。因此，新的战略和方法是必要的。由于胰岛素被注射给糖尿病患者皮下，而不是进入门静脉，这是生理的，肝脏保持相对较低的胰岛素水平。我们考虑到这可能有助于促进动脉粥样硬化的环境，甚至超过高血糖。该项目的长期目标是开发模仿胰岛素对肝脏的关键动脉粥样硬化保护作用的药物。在我们的初步数据中，我们发现CYP7B1是肝脏中胰岛素的一个极其敏感的靶点：在所有三种情况下，CYP7B1因急性胰岛素刺激而增加；因胰岛素缺乏而减少；因肝脏敲除胰岛素受体而减少；以及仅有的四个基因中的一个在所有三种情况下都发生显著变化。细胞色素P7B1在胆固醇、氧固醇和胆汁酸代谢6-8中起核心作用。基于我们强大的初步数据，我们假设胰岛素诱导CYP7B1维持脂质稳态并抑制炎症，而这一调节在1型糖尿病中丢失，导致动脉粥样硬化。为了验证这一假设，我们将(1)确定在1型糖尿病小鼠模型中恢复CYP7B1可以在多大程度上预防动脉粥样硬化；(2)定义胰岛素调节CYP7B1的信号通路。我们期望发现，CYP7B1通过两种机制减少糖尿病小鼠的动脉粥样硬化：(1)减少氧固醇量和血管炎症；(2)减少饮食中的胆固醇吸收(通过调节胆汁酸分布)和血浆胆固醇。验证我们的假设可能会导致开发出模拟胰岛素对CYP7B1作用的药物。这类药物将恢复1型糖尿病的体内平衡，可能比目前的降脂疗法更有效，因为它们将降低血浆胆固醇和炎症。

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.