[Frontiers in Bioscience S4, 916-931, January 1, 2012]

Insulin resistance, metabolic stress, and atherosclerosis

Meghana Pansuria1, 2, Hang Xi1, 2, Le Li1, 4, Xiao-Feng Yang1, 2, Hong Wang1, 2, 3

1Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, 19140, 2Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA, 19140, 3Thrombosis Research Center of Temple University School of Medicine, Philadelphia, PA, 19140, 4School of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR, China

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Insulin receptor signaling
4. Insulin signaling in metabolic tissues
4.1. Pancreas
4.2. Skeletal muscle, adipose tissue, and liver
5. Relevance of metabolic stress with insulin resistance (IR) and atherosclerosis
5.1. Hyperglycemia
5.2. Dyslipidemia
5.3. Hyperhomocysteinemia
6. Insulin signaling in vascular cells
6.1. Endothelial cells
6.2. Vascular smooth muscle cells
7. Relevance of IR in vascular cells with atherosclerosis
8. Insulin signaling in immune cells
8.1. Monocytes/ macrophages
8.2. T lymphocytes
9. Relevance of IR in immune cells with atherosclerosis
10. Summary
11. References

1. ABSTRACT

Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome.