Elsevier

The Lancet

Volume 375, Issue 9733, 26 June–2 July 2010, Pages 2267-2277
The Lancet

Seminar
Lipid-induced insulin resistance: unravelling the mechanism

https://doi.org/10.1016/S0140-6736(10)60408-4Get rights and content

Summary

Insulin resistance has long been associated with obesity. More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past two decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatotic liver is also resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis. In muscle and liver, the intracellular accumulation of lipids—namely, diacylglycerol—triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing; and the insulin-sensitising effects of thiazolidinediones.

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

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

References (138)

  • JR Goudriaan et al.

    CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice

    J Lipid Res

    (2003)
  • KL Hoehn et al.

    Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity

    Cell Metab

    (2010)
  • RS Lindsay et al.

    Adiponectin and development of type 2 diabetes in the Pima Indian population

    Lancet

    (2002)
  • AV Chibalin et al.

    Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance

    Cell

    (2008)
  • A Rodriguez et al.

    Contribution of impaired glucose tolerance in subjects with the metabolic syndrome: Baltimore Longitudinal Study of Aging

    Metabolism

    (2005)
  • PW Wilson et al.

    Epidemiology of diabetes mellitus in the elderly. The Framingham Study

    Am J Med

    (1986)
  • AJ McCullough

    The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease

    Clin Liver Dis

    (2004)
  • SF Previs et al.

    Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2

    J Biol Chem

    (2000)
  • MF Abdelmalek et al.

    Nonalcoholic fatty liver disease as a complication of insulin resistance

    Med Clin North Am

    (2007)
  • S He et al.

    A sequence variation (I148M) in PNPlA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis

    J Biol Chem

    (2010)
  • VT Samuel et al.

    Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease

    J Biol Chem

    (2004)
  • AM Prentice et al.

    Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release?

    Int J Obes (Lond)

    (2008)
  • JL Harris et al.

    A crisis in the marketplace: how food marketing contributes to childhood obesity and what can be done

    Annu Rev Public Health

    (2009)
  • Diet, nutrition and the prevention of chronic diseases

    World Health Organ Tech Rep Ser

    (2003)
  • B Sherry et al.

    Trends in state-specific prevalence of overweight and underweight in 2- through 4-year-old children from low-income families from 1989 through 2000

    Arch Pediatr Adolesc Med

    (2004)
  • G Perseghin et al.

    Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study

    Diabetes

    (1997)
  • M Krssak et al.

    Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study

    Diabetologia

    (1999)
  • G Perseghin et al.

    Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents

    Diabetes

    (1999)
  • DA Pan et al.

    Skeletal muscle triglyceride levels are inversely related to insulin action

    Diabetes

    (1997)
  • R Taylor et al.

    Validation of 13C NMR measurement of human skeletal muscle glycogen by direct biochemical assay of needle biopsy samples

    Magn Reson Med

    (1992)
  • DL Rothman et al.

    Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus

    Proc Natl Acad Sci USA

    (1995)
  • GI Shulman et al.

    Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy [see comments]

    N Engl J Med

    (1990)
  • DL Rothman et al.

    31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus

    J Clin Invest

    (1992)
  • K Brechtel et al.

    Fast elevation of the intramyocellular lipid content in the presence of circulating free fatty acids and hyperinsulinemia: a dynamic H-MRS study

    Magn Reson Med

    (2001)
  • JP Felber et al.

    Pathways from obesity to diabetes

    Int J Obes Relat Metab Disord

    (2002)
  • M Roden et al.

    Mechanism of free fatty acid-induced insulin resistance in humans

    J Clin Invest

    (1996)
  • G Boden

    Role of fatty acids in the pathogenesis of insulin resistance and NIDDM

    Diabetes

    (1997)
  • G Boden et al.

    Mechanisms of fatty acid-induced inhibition of glucose uptake

    J Clin Invest

    (1994)
  • A Dresner et al.

    Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity

    J Clin Invest

    (1999)
  • GW Cline et al.

    Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes

    N Engl J Med

    (1999)
  • H-G Joost et al.

    The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members

    Mol Membr Biol

    (2001)
  • PR Shepherd et al.

    Glucose transporters and insulin action—implications for insulin resistance and diabetes mellitus

    N Engl J Med

    (1999)
  • TP Ciaraldi et al.

    Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects

    J Clin Invest

    (1995)
  • WT Garvey et al.

    Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance

    J Clin Invest

    (1998)
  • MJ Saad et al.

    Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats

    J Clin Invest

    (1993)
  • F Folli et al.

    Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus

    J Clin Invest

    (1993)
  • AC Newton

    Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm

    Biochem J

    (2003)
  • RE Lewis et al.

    Threonine 1336 of the human insulin receptor is a major target for phosphorylation by protein kinase C

    Biochemistry

    (1990)
  • TS Pillay et al.

    Phorbol ester-induced downregulation of protein kinase C potentiates insulin receptor tyrosine autophosphorylation: evidence for a major constitutive role in insulin receptor regulation

    Biochem Soc Trans

    (1990)
  • C Schmitz-Peiffer et al.

    Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat

    Diabetes

    (1997)
  • Cited by (0)

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