Postprandial insulin resistance as an early predictor of cardiovascular risk

Abstract

Insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia and oxidative stress are risk factors related to cardiovascular diseases including congestive heart failure, myocardial infarction, ventricular hypertrophy, endothelial nitric oxide impairment in systemic blood vessels and the heart, atherosclerosis, and hypercoagulability of blood. The traditional focus on insulin sensitivity and blood levels of markers of risk determined in the fasted state is inconsistent with the large volume of recent data that indicates that the metabolic defect in the pre-diabetic and diabetic condition relates more strongly to postprandial deficiency than to the fasting state. Risk factors for adverse cardiovascular events can be detected in the pre-diabetic insulin-resistant subject based upon the metabolic response to a test meal even in the absence of altered fasting parameters. The normal response to a mixed meal includes a doubling of insulin action secondary to insulin-induced release of a putative hepatic insulin sensitizing substance (HISS) that acts selectively on skeletal muscle. HISS is released only in the fed state and accounts for meal-induced insulin sensitization. Blockade of HISS release leads to a condition referred to as HISS-dependent insulin resistance, which is suggested as the primary postprandial metabolic defect, accounting for postprandial hyperglycemia, hyperinsulinemia, hyperlipidemia, and increased oxidative stress in the pre-diabetic and diabetic condition. HISS-dependent insulin resistance represents a novel hypothesis and suggests a new diagnostic and therapeutic target.

Keywords:

• HISS
• hyperglycemia
• hyperlipidemia
• hyperinsulinemia
• oxidative stress

Acknowledgements

The HISS-related work of the author cited here has been supported by operating grants from the Canadian Institutes of Health Research and the Canadian Diabetes Association. The HISS-related studies were carried out mainly by graduate students, technologists and trainees in the laboratories of Lautt (Winnipeg, Canada) and Macedo (Lisbon, Portugal). Manuscript preparation was by Karen Sanders. The author discloses that intellectual property related to diagnosis, prevention, and therapy of HISS-dependent insulin resistance has been licensed by the University of Manitoba to DiaMedica Inc.