We searched PubMed with the search terms “insulin resistance” in combination with “skeletal muscle”, “liver”, “lipids”, or “diacylglycerol” from January, 1963, until February, 2010. We also searched with “protein kinase C” and “diacylglycerol”. Papers were restricted to those published in the English language. We gave preference to recent and relevant reports, and important papers that addressed the main themes reviewed in this Seminar. Relevant review articles were selected to provide
SeminarLipid-induced insulin resistance: unravelling the mechanism
Introduction
Obesity is now a pandemic that is largely caused by a combination of our genetics, evolutionary pressures that favour metabolic efficiency,1 and a modern environment in which highly palatable, calorie-dense food is widely available and inexpensive.2 There are now more overweight than underweight people worldwide, and children are increasingly at risk of becoming obese.3, 4, 5 In tandem with the obesity epidemic, the prevalence of related disorders, such as metabolic syndrome, non-alcoholic fatty liver disease, and type 2 diabetes mellitus, is also rising. Insulin resistance plays a crucial part in the pathogenesis of all these disorders, yet the cellular mechanisms are still poorly understood. Here, we review studies in human beings and rodents that have informed our current understanding of the mechanistic links between lipid accumulation and insulin resistance. We first discuss some of the pioneering studies in this specialty.
Section snippets
Glucose-fatty-acid cycle
Randle and colleagues6 postulated a mechanism more than 40 years ago by which fatty acids could impair insulin-stimulated glucose oxidation in muscle. They reported that incubation of preparations of the rat heart with fatty acids increased intracellular concentrations of glucose-6-phosphate (G6P) and glucose, and incubation of preparations of diaphragm increased intracellular concentrations of glycogen (figure 1). According to Randle and colleagues' theory, fat oxidation increased the ratios
Testing Randle and colleagues' hypothesis
Investigation of the association between fatty acids and insulin resistance is difficult in individuals who are already obese or diabetic because of the confounding effects of other co-morbidities. These effects are avoided by investigation of the mechanisms of insulin resistance in the offspring of patients with type 2 diabetes mellitus, who are young, lean, and insulin resistant. When Perseghin and colleagues7 compared such individuals with controls matched for age and body-mass index (BMI),
Diacylglycerol-induced insulin resistance
The coordinated intracellular response to insulin requires an intricate relay of signals. In skeletal muscle, insulin binds to its receptor, activating the receptor tyrosine kinase activity, with subsequent phosphorylation and activation of insulin-receptor substrate 1 (IRS1; figure 2). When phosphorylated, IRS1 activates 1-phosphatidylinositol 3-kinase (PI3K). This enzyme, through signalling intermediates, activates Akt2, which phosphorylates and inactivates AS160, a protein that prevents
Diacylglycerol hypothesis
Insulin resistance develops with the accumulation of fatty-acid metabolites (namely diacylglycerols) within insulin-responsive tissues.46 Genetic murine models have been invaluable in establishing this theory—eg, tissue-specific overexpression of lipoprotein lipase promotes tissue-specific lipid accumulation and selective insulin resistance.47 By contrast, prevention of lipid entry into muscle by removal of lipoprotein lipase,48 or other proteins involved in fat transport (CD3649, 50 or FATP151
Mechanisms of hepatic insulin resistance
Ectopic lipid accumulation in the liver is now widely known as non-alcoholic fatty liver disease. Formerly thought of as benign steatosis, this liver disease is now the most common chronic cause of raised serum concentrations of liver-derived enzymes in adults and children,79 and it is closely associated with obesity, insulin resistance, and type 2 diabetes mellitus.80, 81, 82 Insulin action in the liver has many similarities with insulin action in muscle. In the liver, insulin activates the
PKCɛ, hepatic steatosis, insulin resistance
Wild-type mice and rats develop hepatic steatosis after a few days of high-fat feeding that is associated with hepatic insulin resistance, without much change in muscle lipid content or peripheral insulin action.100 Moreover, by promotion of mitochondrial fatty acid oxidation with low doses of the mitochondrial uncoupler 2,4-dinitrophenol, rats were protected from fat-induced hepatic steatosis and hepatic insulin resistance.100 In this model, hepatic steatosis was associated with proximal
Insulin resistance and lipodystrophy
One challenge in the assessment of the specific role of non-alcoholic fatty liver disease in the development of hepatic insulin resistance is the close association between obesity and non-alcoholic fatty liver disease. Thus, the changes in liver insulin action due to steatosis and those attributable to adiposity and associated changes, such as inflammation, are difficult to ascertain.108, 109, 110 The lipodystrophies offer an opportunity to assess the role of ectopic lipid deposition without
Other hypotheses
The data presented so far have supported a unifying theme—namely, that the accumulation of diacylglycerol within insulin-sensitive tissues activates novel PKCs that interfere with insulin signalling and cause insulin resistance. However, other mechanisms have been proposed to explain insulin resistance in obesity. These are only briefly discussed here, since other reviews are available.117, 118
Though we have endeavoured to show how accumulation of diacylglycerol leads to insulin resistance, not
Correction of hepatic steatosis
Thiazolidinediones, which are potent PPARγ agonists, can effectively reduce hepatic steatosis.133 Though PPARγ is mainly expressed in adipocytes, it has effects on hepatic and muscle insulin sensitivity. On the basis of this discordance between the site of PPARγ expression and the site of drug effects, the hypothesis was that thiazolidinediones redistribute fat from the liver and muscle into the adipocyte.46 Mayerson and colleagues133 tested this hypothesis, using rosiglitazone in patients with
Way forward
Achievement of sustainable weight loss, without bariatric surgery, is an enormously difficult task and, although small steps are being taken for the prevention of obesity, many hurdles remain. Until societal, political, and economic forces align to promote healthy lifestyles, the incidence of obesity, and consequently insulin resistance and type 2 diabetes mellitus, will probably increase. The development of new effective treatments for insulin resistance requires an elucidation of the
Search strategy and selection criteria
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