Format

Send to

Choose Destination
Diabetes. 2018 May;67(5):946-959. doi: 10.2337/db17-0744. Epub 2018 Feb 26.

A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome.

Author information

1
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, WA.
2
Department of Immunology, University of Washington, Seattle, WA.
3
Benaroya Research Institute, Seattle, WA.
4
Insulin Pharmacology, Novo Nordisk A/S, Måløv, Denmark.
5
Insulin Biology Department, Novo Nordisk A/S, Måløv, Denmark.
6
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, WA bornf@uw.edu.
7
Department of Pathology, UW Medicine Diabetes Institute, University of Washington, Seattle, WA.

Abstract

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.

PMID:
29483182
PMCID:
PMC5909997
[Available on 2019-05-01]
DOI:
10.2337/db17-0744
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center