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Cited by 1,189Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic Diseases

Lipid-induced insulin resistance: unravelling the mechanism

Open access
Samuel, Varman T, Petersen, Kitt Falk, Shulman, Gerald I·2010·The Lancet
DOI 10.1016/s0140-6736(10)60408-4PMC PMC2995547
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Abstract

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that lipid-induced insulin resistance in muscle and liver is caused by intracellular diacylglycerol accumulation activating novel protein kinase C isoforms, which impair insulin signalling and glucose transport. It synthesizes human and rodent evidence to propose a unifying mechanism for obesity, type 2 diabetes, lipodystrophy, and ageing.

Key findings

  • Lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity, not from Randle’s proposed inhibition of glycolysis; lipid infusion reduced muscle G6P concentrations and attenuated intracellular glucose accumulation, implicating glucose transport.
  • In muscle, diacylglycerol accumulation activates novel PKCs such as PKCθ, leading to reduced IRS1 tyrosine phosphorylation and increased IRS1 serine-307 phosphorylation, which impairs insulin signalling.
  • In liver, steatosis and diacylglycerol accumulation activate PKCε; in high-fat-fed rats, a PKCε antisense oligonucleotide improved hepatic insulin sensitivity and insulin signalling even though diacylglycerol accumulation was equal across groups.
  • Thiazolidinedione treatment for 3 months reduced hepatic triglyceride content by almost 40% and increased extramyocellular triglyceride by roughly 40%; in obese patients with type 2 diabetes, average 8 kg weight loss reduced hepatic triglyceride from nearly 12% to 2% with improved hepatic insulin sensitivity.

Methods

  • Narrative review of human and rodent studies examining mechanisms linking lipid accumulation to insulin resistance in skeletal muscle and liver.
  • The authors searched PubMed from January 1963 to February 2010 using terms including “insulin resistance” combined with “skeletal muscle,” “liver,” “lipids,” or “diacylglycerol,” and also searched “protein kinase C” and “diacylglycerol”; papers were restricted to English-language publications.
  • Evidence includes in vivo magnetic resonance spectroscopy studies in humans, hyperinsulinaemic-normoglycaemic clamps, lipid infusions, muscle biopsies, genetic mouse models, and antisense oligonucleotide experiments.

Limitations

  • The paper states that further studies are needed to understand how tissue-specific diacylglycerol accumulation activates specific novel PKCs, whether the intracellular distribution of this lipid pool differs between insulin-sensitive and insulin-resistant states, and how novel PKC activation impairs insulin signalling.
  • The paper notes that other proposed mechanisms—inflammation, endoplasmic-reticulum stress, adipokines, and lipokines—are only briefly discussed because other reviews are available.
  • Evident from the text: this is a narrative review, not a systematic review or meta-analysis, and it relies heavily on rodent models and selected human studies; the authors’ search strategy describes preference for recent and relevant reports rather than comprehensive systematic inclusion.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s0140-6736(10)60408-4

Cites

148 of 148 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 55 cited sources checked · 0 supported · 0 flagged

  • Interpretationcitation

    Insulin resistance develops with the accumulation of fatty-acid metabolites (namely diacylglycerols) within insulin-responsive tissues.

    “Insulin resistance develops with the accumulation of fatty-acid metabolites (namely diacylglycerols) within insulin-responsive tissues.46”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Shulman, 2000, Cellular mechanisms of insulin resistance, J Clin Invest source

      Not checked in the free run.

  • Interpretationreasoning

    Lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity.

    “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.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The steatotic liver is resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis.

    “The steatotic liver is also resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In healthy individuals, high plasma fatty acid concentrations cause insulin resistance associated with a defect in glucose transport or phosphorylation activity, not an impairment in glycolysis.

    “Thus, in healthy individuals, exposure to high concentrations of plasma fatty acids caused insulin resistance associated with an induced defect in either glucose transport or phosphorylation activity, not an impairment in glycolysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Roden, 1996, Mechanism of free fatty acid-induced insulin resistance in humans, J Clin Invest source

      Not checked in the free run.

  • Interpretationcitation

    In muscle and liver, intracellular accumulation of diacylglycerol triggers activation of novel protein kinases C with subsequent impairments in insulin signalling.

    “In muscle and liver, the intracellular accumulation of lipids—namely, diacylglycerol—triggers activation of novel protein kinases C with subsequent impairments in insulin signalling.”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Interpretationcitation

    Activation of novel PKCs and serine phosphorylation of IRS1 are important for the development of insulin resistance.

    “The importance of activation of novel PKCs and serine phosphorylation of IRS1 for the development of insulin resistance was shown in mice without PKCθ,40 and in those with serine-to-alanine mutations in key residues of IRS1 (thereby preventing serine phosphorylation).41”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Kim, 2004, PKC-theta knockout mice are protected from fat-induced insulin resistance, J Clin Invest source

      Not checked in the free run.

    • cites [41] Morino, 2008, Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In rodents, a high-fat diet increases the concentration of diacylglycerol in muscles and activates novel PKCs.

    “In rodents, a high-fat diet increased the concentration of diacylglycerol in muscles and activated novel PKCs.36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Schmitz-Peiffer, 1997, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Samuel, 2004, Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin-resistant individuals had a large increase in liver triglyceride content, attributable to a roughly two-fold increase in hepatic de-novo lipogenesis.

    “Furthermore, insulin-resistant individuals had a large increase in liver triglyceride content, attributable to a roughly two-fold increase in hepatic de-novo lipogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Petersen, 2007, The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A reduction in mitochondrial content in muscle reduces mitochondrial fatty acid oxidation, promoting accumulation of diacylglycerol within the muscle and contributing to skeletal muscle insulin resistance in young, lean, insulin-resistant offspring of parents with type 2 diabetes mellitus.

    “Irrespective of whether the reduction in mitochondrial content in the muscles is a primary defect, at the very least it reduces the mitochondrial fatty acid oxidation that promotes the accumulation of diacylglycerol within the muscle and contributes to the development of skeletal muscle insulin resistance in young, lean, insulin-resistant offspring of parents with type 2 diabetes mellitus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PKCε antisense oligonucleotide improves hepatic insulin sensitivity and insulin signalling in rats fed a high-fat diet for 3 days, despite equal fat and diacylglycerol accumulation.

    “Though fat accumulation, and specifically diacylglycerol accumulation, was equal in all groups, the PKCε antisense oligonucleotide improved hepatic insulin sensitivity and insulin signalling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Crooke, 2004, Progress in antisense technology, Annu Rev Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intrahepatic triglyceride content, not visceral adiposity, is associated with insulin resistance and increased triglyceride secretion.

    “Fabbrini and colleagues91 similarly reported that intrahepatic triglyceride content, not visceral adiposity, was associated with insulin resistance and increased triglyceride secretion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Fabbrini, 2009, Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the liver, insulin activates the insulin receptor kinase, which phosphorylates IRS1 and IRS2, leading to activation of PI3K and ultimately Akt2; Akt2 activation promotes glycogen synthesis and inhibits gluconeogenesis.

    “In the liver, insulin activates the insulin receptor kinase, which phosphorylates IRS1 and IRS2, leading to activation of PI3K and ultimately Akt2 (figure 2).83 At this point, Akt2 activation promotes glycogen synthesis and inhibits gluconeogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Previs, 2000, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Substantial weight loss in patients after bariatric surgery is associated with both improvements in insulin sensitivity and reduction in markers of endoplasmic-reticulum stress.

    “Substantial weight loss in patients after bariatric surgery has also been associated with both improvements in insulin sensitivity and reduction in markers of endoplasmic-reticulum stress.132”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Gregor, 2009, Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice overexpressing DGAT1 in skeletal muscle accumulate triglycerides in their muscles but are protected from fat-induced muscle insulin resistance.

    “Mice overexpressing DGAT1 in skeletal muscles (MCK-DGAT1)61 accumulate tri glycerides in their muscles, but are protected from fat-induced muscle insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Liu, 2007, Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Age-associated reductions in mitochondrial function might play a part in the impairment of β-cell function associated with ageing, and promote progression to impaired glucose tolerance and type 2 diabetes mellitus in elderly people.

    “Because mitochondria have a key role in the regulation of glucose-stimulated β-cell insulin secretion, age-associated reductions in mitochondrial function might also play a part in the impairment of β-cell function associated with ageing, and promote progression to impaired glucose tolerance and type 2 diabetes mellitus in elderly people.78”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Harris, 1998, Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Visceral fat mass was identical in normal-weight, insulin-sensitive and insulin-resistant individuals, suggesting features of the metabolic syndrome can develop independently of increased visceral adiposity.

    “Notably, visceral fat mass, as measured with abdominal MRI, was identical in these cohorts of normal-weight, insulin-sensitive and insulin-resistant individuals, which suggests these features of the metabolic syndrome can develop independently of increased visceral adiposity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Petersen, 2007, The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PNPLA3 polymorphism rs738409 is prevalent in the Hispanic population and is highly associated with non-alcoholic fatty liver disease.

    “Use of genetic screening has identified a polymorphism rs738409 within patatin-like phospholipase domain containing 3 (PNPLA3 population or adiponutrin) that is prevalent in the Hispanic population, and is highly associated with non-alcoholic fatty liver disease.96”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Romeo, 2008, Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease, Nat Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In man, a single bout of exercise increases DGAT1 expression in muscle, associated with increased triglyceride, reduced diacylglycerol, and improved insulin sensitivity.

    “In man, a single bout of exercise was sufficient to induce similar changes, in which increased DGAT1 expression in muscle was associated with increased concentrations of triglyceride, reduced concentrations of diacylglycerol, and improved insulin sensitivity.64”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Schenk, 2007, Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endoplasmic-reticulum stress pathways are activated in rodent models of obesity and in human obesity.

    “Their activation has been shown in rodent models of obesity129 and in human obesity.130”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [129] Ozcan, 2004, Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes, Science source

      Not checked in the free run.

    • cites [130] Boden, 2008, Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals, Diabetes source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The review's literature search used PubMed with specified terms and date range, restricted to English-language papers, with preference for recent and relevant reports.

    “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”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Inflammation, endoplasmic-reticulum stress, adipokines, and lipokines are probably secondary in nature, becoming manifest later in the course of disease, and are associated with the development of obesity.

    “However, because these do not change in lean insulin-resistant young and elderly individuals, they are probably secondary in nature, becoming manifest later in the course of disease, and are associated with the development of obesity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Inflammation, endoplasmic-reticulum stress, adipokines, and lipokines do not change in lean insulin-resistant young and elderly individuals.

  • May combine two claims.

    Premisecitation

    Rosiglitazone improved insulin-mediated whole-body glucose disposal, consistent with improvements in muscle insulin sensitivity.

    “Though no reductions in the concentration of intramyocellular triglyceride were noted in this study, rosiglitazone improved insulin-mediated whole-body glucose disposal, consistent with improvements in muscle insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Mayerson, 2002, The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inflammation, endoplasmic-reticulum stress, adipokines, and lipokines have roles in the pathogenesis of insulin resistance in liver and skeletal muscle.

    “Inflammation, endoplasmic-reticulum stress, adipokines, and lipokines have roles in the pathogenesis of insulin resistance in liver and skeletal muscle.”
    Quote in the paperSubstantial claim
20 of 20

  • The paper relies on this without support.

    PPARγ is mainly expressed in adipocytes but has effects on hepatic and muscle insulin sensitivity.

    “Though PPARγ is mainly expressed in adipocytes, it has effects on hepatic and muscle insulin sensitivity.”

  • The paper relies on this without support.

    Inflammation, endoplasmic-reticulum stress, adipokines, and lipokines do not change in lean insulin-resistant young and elderly individuals.

    “However, because these do not change in lean insulin-resistant young and elderly individuals, they are probably secondary in nature, becoming manifest later in the course of disease, and are associated with the development of obesity.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • High-dose triglyceride infusion is a common method of inducing acute insulin resistance in mice and humans.

    “High-dose triglyceride infusion is a common method of inducing acute insulin resistance in mice and humans (37), so it is possible that chronic hyperlipidemia resulting from accelerated VLDL secretion exacerbated the insulin resistance phenotype caused by the WD.”

    From Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion (2025) · cites this paper as [37]

    In “Testing Randle and colleagues’ hypothesis” (page unavailable), the paper reports that lipid infusions induced insulin resistance in healthy people within about three hours. “Other hypotheses” (page unavailable) mentions rodents developing insulin resistance after acute lipid infusion, but does not specify mice. The copy does not establish that high-dose triglyceride infusion, specifically, is a common method in both mice and humans. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • These molecules activate proinflammatory and nutrient-sensing pathways that lead to the impairment of insulin action.

    “These molecules activate proinflammatory and nutrient-sensing pathways that lead to the impairment of insulin action ([Fig. 6A](#f6)) [for further information, readers are referred to additional reviews ([144](#B144), [159](#B159))].”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [144]

  • Free fatty acids and their metabolites (such as DAG and ceramides) are important contributors to lipid-induced insulin resistance in skeletal muscle.

    “The lipotoxic hypothesis proposes that FAs and their metabolites (such as DAG and ceramides) are important contributors to lipid-induced insulin resistance in SkM.”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [144]

  • A decrease in fatty acid oxidation induces the buildup of ceramide and diacylglycerol, which impair the insulin signal transduction pathway.

    “In support of this notion, a decrease in fatty acid oxidation induces the buildup of ceramide and diacylglycerol, which have been shown to impair the insulin signal transduction pathway (Samuel et al., 2010).”

    From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Samuel et al., 2010

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Related

Authors
Samuel, V. T., Petersen, K. F., & Shulman, G. I.
Affiliations
  • Veterans Health Administration (US)
  • Yale University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Shulman, Gerald I
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2010-06
Volume
375
Issue
9733
Pages
2267-2277
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(10)60408-4
PMC
PMC2995547
OpenAlex
W2111645882
Semantic Scholar
89c2041ac90d7e5a29fdc97e4a9dadd828997373
Cited by
1,189
References
148
Citations by year
2026: 34 · 2025: 55 · 2024: 62 · 2023: 60 · 2022: 57 · 2021: 78 · 2020: 59 · 2019: 63 · 2018: 62 · 2017: 82 · 2016: 76 · 2015: 64 · 2014: 89 · 2013: 117 · 2012: 123
FWCI
9.66
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute on Aging (R01-AG-23686, R56AG023686, R01AG023686)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01DK049230, R01-DK40936, U24DK59635, R01DK040936, U24DK059635, R01 DK-49230, P30DK045735, P01DK068229)
  • National Center for Research Resources (K23RR017404, UL1RR024139, K23 RR-17404)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
lipid-induced insulin resistance, skeletal muscle insulin resistance, hepatic insulin resistance, insulin-stimulated glucose transport, diacylglycerol, protein kinase C, insulin signaling, hepatic glucose production, glycogen synthesis, obesity, type 2 diabetes, lipodystrophy, aging, thiazolidinediones
MeSH terms
Animals, Diabetes Mellitus, Type 2, Diglycerides, Fatty Acids, Fatty Liver, Glucose, Humans, Insulin, Insulin Resistance, Lipids, Obesity, Protein Kinase C, Muscle, Skeletal

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