A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome.
Jenny E KanterFarah KramerShelley BarnhartJeffrey M DugganMasami Shimizu-AlbergineVishal KothariAlan ChaitStephan D BoumanJessica A HamermanBo F HansenGrith S OlsenKarin E BornfeldtPublished in: Diabetes (2018)
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 Ly6Chi 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.
Keyphrases
- glycemic control
- blood glucose
- type diabetes
- metabolic syndrome
- cardiovascular disease
- signaling pathway
- insulin resistance
- cell proliferation
- stem cells
- bone marrow
- mouse model
- weight loss
- pi k akt
- cardiovascular risk factors
- blood pressure
- adipose tissue
- cell therapy
- binding protein
- smoking cessation
- combination therapy
- diabetic rats