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Etiology of Insulin Resistance
Open accessAbstract
Type 2 diabetes mellitus is a major cause of morbidity and mortality worldwide, and the prevalence is set to increase dramatically over the coming decades. Understanding the metabolic pathways that lead to type 2 diabetes is therefore an important healthcare objective. Novel investigational techniques based on magnetic resonance spectroscopy (MRS) have allowed real-time insight into the molecular defects in patients with type 2 diabetes, revealing that insulin resistance is a product of decreased insulin-stimulated skeletal muscle glycogen synthesis, which can mostly be attributed to decreased insulin-stimulated glucose transport (Glut 4) activity. This defect appears to be a result of intracellular lipid-induced inhibition of insulin-stimulated insulin-receptor substrate (IRS)-1 tyrosine phosphorylation resulting in reduced IRS-1-associated phosphatidyl inositol 3 kinase activity. The hypothesis that insulin resistance is a result of accumulation of intracellular lipid metabolites (e.g., fatty acyl CoAs, diacylglycerol) in skeletal muscle and hepatocytes is supported by observations in patients and mouse models of lipodystrophy. Furthermore, the increase in hepatic insulin sensitivity observed in patients with type 2 diabetes following weight loss is also accompanied by a significant reduction in intrahepatic fat without any changes in circulating adipocytokines (interleukin-6, resistin, leptin). Finally, recent MRS studies in healthy, lean, elderly subjects and lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial activity may also lead to increased intramyocellular lipid content and insulin resistance in skeletal muscle in these individuals. In summary, in vivo MRS has proved to be an important tool for elucidating the causal chain of events that causes insulin resistance. Understanding the cellular mechanism(s) of insulin resistance in turn offers the prospect of better targeted and more effective therapeutic interventions for treatment and prevention of type 2 diabetes.
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“an increased intramyocellar fat content and fatty acid metabolites have been shown to play a pivotal role in the development of insulin resistance in skeletal muscle [11–15].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [13]
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“Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [13]
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Nelson, V. L., Ballou, L. M., & Lin, R. Z. (2014) · Adipocyte · doi:10.4161/21623945.2014.955397 · Cited by 6
“PI3K activity is decreased in the muscle, liver and adipose tissue in almost all type 2 diabetic patients.(6) Therefore, many researchers have examined the actions of PI3K and the contributions of this enzyme to metabolic dysfunction.”
BackgroundThe future of inpatient diabetes management: glucose as the sixth vital sign
Rendell, M., Saiprasad, S., Trepp-Carrasco, A. G., & Drincic, A. (2013) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.13.1 · Cited by 6
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Maldonado‐Hernández, J., Martínez-Basila, A., Macías, M. E. R., & López‐Alarcón, M. (2019) · Acta Diabetologica · doi:10.1007/s00592-019-01318-5 · Cited by 6
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“F01 Ectopic Fat Deposition In addition to the well-documented association between abdominal fat mass accumulation and insulin sensitivity, ectopic fat deposition in tissues such as muscle, liver, and the pancreatic β-cell may be important in the pathogenesis of insulin resistance and type 2 diabetes mellitus [”
Hespel, P. (2010) · International Journal of Molecular Medicine · doi:10.3892/ijmm_00000421 · Cited by 7
“Furthermore, physical inactivity promotes the development of insulin resistance, whilst exercise training clearly improves muscular insulin sensitivity (3).”
BackgroundOvereating: A Conundrum of Lipid Metabolism and Inflammation in Obesity and Cancer
Surumbayeva, A., Saiman, Y., & Astsaturov, I. A. (2025) · Journal of Cellular Physiology · doi:10.1002/jcp.70104 · Cited by 5
“Similarly, in skeletal muscle, transient insulin resistance may prevent the excessive accumulation of lipid intermediates that would otherwise impair mitochondrial function (Petersen and Shulman 2006).”
Sazdova, I., Gagov, H., Hadzi‐Petrushev, N., Konaktchieva, M. N., Konakchieva, R., & Mladenov, M. I. (2026) · Applied Sciences · doi:10.3390/app16063027 · Cited by 5
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“IR is widely considered a hallmark of MetS and refers to a state in which normal levels of circulating insulin are insufficient to induce a regular insulin response in the muscle, fat, and hepatic cells (Petersen and Shulman 2006, Khan et al. 2018).”
Hypertriglyceridemia is associated with impaired fasting glucose in normal-weight children
Simental‐Mendía, L. E., Rodríguez‐Morán, M., Aradillas-García, C., & Guerrero‐Romero, F. (2018) · Pediatric Research · doi:10.1038/s41390-018-0027-7 · Cited by 5
Insulin resistance and laminitis in broodmares
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“The fact that the accumulation of fat in tissues, such as muscle and liver, is associated with insulin resistance throughout the whole animal is widely accepted(48).”
BackgroundAlzheimer’s Disease and Diabetes
Brent, D. A., Gary, L., Aboud, Z., & Gordon, W. (2013) · InTech eBooks · doi:10.5772/54913 · Cited by 6
“FFAs generated by increased activity of hormone-sensitive lipase that contribute to and result in insulin resistance [54-56].”
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Czech, A., Taton, J., & Piątkiewicz, P. (2010) · PubMed · Cited by 5
Listya, H., Sulchan, M., Murbawani, E. A., Puruhita, N., & Sukmadianti, A. (2020) · Diponegoro International Medical Journal · doi:10.14710/dimj.v1i2.9559 · Cited by 5
Screening for Cardiometabolic Risk Profile in Middle Aged Premenopausal Indian women
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Overview of Metabolic Syndrome
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Type 2 Diabetes and Genetics, 2010: Translating Knowledge into Understanding
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“Since the 1960 s, when insulin levels were first measured in humans, controversy has existed over what the dominant and heritable defects in T2D were likely to be (reviewed in [ 32 ]).”
BackgroundResistin Is a Novel Biomarker for a Risk of Heart Failure
Silver, Y. B. M. (2013) · Journal of Cardiovascular Diseases & Diagnosis · doi:10.4172/2329-9517.1000122 · Cited by 5
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BackgroundSignalisation insulinique et résistance à l’insuline
Ferré, P. (2007) · Therapies · doi:10.2515/therapie:2007052 · Cited by 5
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The Goldilocks for chronic weight management—Balancing quantity with quality of weight loss
Henriksen, K., Chakravarthy, M. V., Bager, C. L., Larsen, A. T., Mohamed, K. E., & Karsdal, M. A. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16379 · Cited by 4
“30 Similar to most other tissues, muscle tissue accumulates fatty acids intracellularly throughout the course of excess energy intake and becomes inflamed as well; they also lose physical capacity and become insulin resistant, which, in some cases, results in a phenomenon called sarcopenic obesity.”
An overview of insulin resistance: from molecular mechanisms to medical interventions
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Metadata
- Authors
- Petersen, K. F., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- The American Journal of Medicine
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 119
- Issue
- 5
- Pages
- S10-S16
- ISSN
- 0002-9343 (ISSN-L)
- PMC
- PMC2995525
- OpenAlex
- W1982488301
- Cited by
- 825
- References
- 56
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 18 · 2023: 26 · 2022: 18 · 2021: 34 · 2020: 31 · 2019: 26 · 2018: 25 · 2017: 27 · 2016: 44 · 2015: 41 · 2014: 55 · 2013: 52 · 2012: 43
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The American Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG023686)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK040936)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin resistance, type 2 diabetes, IRS-1 tyrosine phosphorylation, PI3K signaling, intracellular lipid accumulation, fatty acyl-CoA, diacylglycerol, lipodystrophy, hepatic insulin sensitivity, weight loss, intrahepatic fat, mitochondrial dysfunction, intramyocellular lipid, magnetic resonance spectroscopy, adipokines
- MeSH terms
- Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Insulin Resistance, Mitochondria, Magnetic Resonance Spectroscopy, Obesity, Phosphoproteins, Weight Loss, Thiazolidinediones, Glucose Transporter Type 4, Insulin Receptor Substrate Proteins
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