Lipid mediators and inflammation in glucose intolerance and insulin resistance

Clinical and epidemiological studies suggest that patients who are overweight or obese are at greater risk to develop glucose intolerance and insulin resistance leading to type II diabetes and cardiovascular disease. Despite many hypotheses, it has been difficult to pin-point the precise causes of insulin resistance or impaired glucose tolerance. This commentary aims to stimulate debate by providing some mechanistic insights into a unifying hypothesis by which disturbed lipid metabolism, increased circulating lipid-derived mediators and excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contribute to inflammation, insulin resistance and beta cell dysfunction in type II diabetes. This understanding will direct future drug discovery research to identify and develop novel compounds that can regulate both metabolic and immune/inflammatory systems to provide a dual strategy to combat metabolic disease, especially insulin resistance and type II diabetes.

Introduction

As glucose is a major source of energy for cells, precise control of glucose concentrations by the hormone, insulin, is essential. Impaired glucose tolerance is a delayed normalisation of blood glucose concentrations after glucose intake despite adequate insulin concentrations. The combination of increased glucose and insulin concentrations defines insulin resistance, typically characterised as the insensitivity to insulin in peripheral tissues such as skeletal muscle, liver and adipose and reduced function of the pancreatic beta cells [1]. In patients, insulin resistance is characterised by obesity, type II diabetes mellitus and the associated metabolic and cardiovascular dysfunction, a major cause of morbidity and mortality throughout the world [1, 2, 3]. The metabolic syndrome, also termed the insulin resistance syndrome, combines the clinical signs of fasting and post-prandial hyperglycaemia, centrally distributed abdominal fat, dyslipidaemia and hypertension [4, 5, 6]. Clinical and epidemiological studies suggest that patients who are overweight or obese are more at risk in developing glucose intolerance and insulin resistance leading to type II diabetes and cardiovascular disease.

Many hypotheses have been proposed to explain the underlying mechanisms of insulin resistance. Traditionally, insulin resistance and type II diabetes have been rationalised as a dysfunction of glucose metabolism and this has been the primary therapeutic target in type II diabetes. This glucocentric view then changed towards an emphasis on induction of the dysfunction of glucose homeostasis by free fatty acids and other lipid mediators [7]. Activation of inflammatory lipid mediators associated with the altered release of adipokines and cytokines to alter adipocyte and immune cell function has now become the prevailing hypothesis to explain the mechanisms of insulin resistance [2]. This commentary aims to stimulate debate by providing some mechanistic insights into a unifying hypothesis by which disturbed lipid metabolism, increased circulating lipid-derived mediators and excess accumulation of toxic lipid metabolites in adipose, muscle, liver and pancreatic beta cells contribute to inflammation, insulin resistance and beta cell dysfunction in type II diabetes.