A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome
A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome
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DOI：
10.2337/db17-0744
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发表时间：
2018-05-01
期刊：
影响因子：
7.7
通讯作者：
Bornfeldt, Karin E.
中科院分区：
文献类型：
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作者：
Kanter, Jenny E.;Kramer, Farah;Bornfeldt, Karin E.
动脉粥样硬化引起的心血管疾病是2型糖尿病和代谢综合征相关死亡的主要原因。胰岛素治疗通常需要改善血糖控制，但它并不能明显预防动脉粥样硬化。在与胰岛素受体（IR）结合后，胰岛素激活下游信号的不同臂。IR-Akt组与降血糖和有益效果有关，而IR-Erk组可能产生不太理想的效果。我们研究了在代谢综合征小鼠模型中，选择性激活IR-Akt臂，使IR-Erk臂基本失活，是否会导致对动脉粥样硬化的保护。胰岛素模拟肽S597降低血糖，激活胰岛素靶组织中的Akt，模拟胰岛素的作用，但只能弱激活Erk，甚至阻止胰岛素诱导的Erk激活。引人注目的是，S597延缓了动脉粥样硬化病变的进展，这一过程与防止白细胞增多有关，从而减少了炎性Ly6C（hi）单核细胞的病变积累。s597介导的对白细胞的保护伴随着早期骨髓造血干细胞数量的减少和造血干细胞中IR-Erk活性的降低。本研究为代谢综合征和2型糖尿病相关的晚期动脉粥样硬化提供了一种概念性的新治疗策略。
Cardiovascular disease caused by atherosclerosis is the leading cause of mortality associated with type 2 diabetes and metabolic syndrome. Insulin therapy is often needed to improve glycemic control, but it does not clearly prevent atherosclerosis. Upon binding to the insulin receptor (IR), insulin activates distinct arms of downstream signaling. The IR-Akt arm is associated with blood glucose lowering and beneficial effects, whereas the IR-Erk arm might exert less desirable effects. We investigated whether selective activation of the IR-Akt arm, leaving the IR-Erk arm largely inactive, would result in protection from atherosclerosis in a mouse model of metabolic syndrome. The insulin mimetic peptide S597 lowered blood glucose and activated Akt in insulin target tissues, mimicking insulin's effects, but only weakly activated Erk and even prevented insulin-induced Erk activation. Strikingly, S597 retarded atherosclerotic lesion progression through a process associated with protection from leukocytosis, thereby reducing lesional accumulation of inflammatory Ly6C(hi) monocytes. S597-mediated protection from leukocytosis was accompanied by reduced numbers of the earliest bone marrow hematopoietic stem cells and reduced IR-Erk activity in hematopoietic stem cells. This study provides a conceptually novel treatment strategy for advanced atherosclerosis associated with metabolic syndrome and type 2 diabetes.