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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]
In the citing paper
“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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Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes
Tsuchiya, Y., Hatakeyama, H., Emoto, N., Wagatsuma, F., Matsushita, S., & Kanzaki, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.128520 · Cited by 91
Protein and energy metabolism in type 1 diabetes
Hebert, S. L., & Nair, K. S. (2009) · Clinical Nutrition · doi:10.1016/j.clnu.2009.09.001 · Cited by 91
Altered Insulin Receptor Signalling and β-Cell Cycle Dynamics in Type 2 Diabetes Mellitus
Folli, F. B., Okada, T., Perego, C., Gunton, J. E., Liew, C. W., Akiyama, M., D’Amico, A. M., Rosa, S. L., Placidi, C., Lupi, R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028050 · Cited by 94
“toxicity and amyloid deposition [1,2,3,4,5,6,7,8,9,10].”
Paul, C. I., Laganà, A. S., Maniglio, P., Triolo, O., & Brady, D. M. (2016) · Gynecological Endocrinology · doi:10.3109/09513590.2016.1144741 · Cited by 88
“FFAs cause impairment of intracellular insulin signaling and support increased triglycerides synthesis [4,11,12].”
BackgroundMembrane lipid alterations in the metabolic syndrome and the role of dietary oils
Perona, J. S. (2017) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2017.04.015 · Cited by 91
Direct and macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells
Bilan, P. J., Samokhvalov, V., Koshkina, A., Schertzer, J. D., Samaan, M. C., & Klip, A. (2009) · Archives of Physiology and Biochemistry · doi:10.1080/13813450903079314 · Cited by 88
“Muscle glucose uptake through GLUT4 is rate-limiting for glucose utilization, and glucose uptake is the defective step in insulin resistance associated with type 2 diabetes (Petersen and Shulman, 2006).”
BackgroundSerum Resistin Concentrations and Risk of New Onset Heart Failure in Older Persons
Butler, J., Kalogeropoulos, A. P., Georgiopoulou, V. V., de Rekeneire, N., Rodondi, N., Smith, A. L., Hoffmann, U., Kanaya, A. M., Newman, A. B., Kritchevsky, S. B., et al. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.186783 · Cited by 88
Frequency of the metabolic syndrome in obese Spanish pediatric population
López-Capapé, M., Alonso, M., Colino, E., Mustieles, C., Corbatón, J., & Barrio, R. (2006) · European Journal of Endocrinology · doi:10.1530/eje.1.02206 · Cited by 83
“Obesity leads to fat accumulation not only in adipocytes but also in muscle and liver cells, resulting in IR in these organs ( 46 ).”
BackgroundBravo, S., Lowndes, J., Sinnett, S., Yu, Z., & Rippe, J. (2013) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2012-0322 · Cited by 86
“Type 2 diabetes (Korenblat et al. 2008; Petersen and Shulman 2006; Milikovic-Gacic et al. 2008; Goodpaster et al. 2003; Berglund 2005; Shulman 2000) is a major cause of morbidity and mortality worldwide, and a predisposing condition for high blood pressure, some dyslipidemias, and coronary heart disease (Shulman 2000;…”
BackgroundInfluentialKim, H.-K., & Kim, C.-H. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.1348 · Cited by 89
“The mechanisms linking the accumulation of fat within skeletal muscle with insulin resistance and type 2 diabetes are still unclear, but some have proposed that the accumulation of IMCL may impair the insulin receptor substrate 1/phosphatidylinositol 3-kinase pathway and the growth-factor-regulated protein kinase B pa…”
BackgroundParsanathan, R., Sathish, S., Srinivasan, C., Jayaraman, S., & Balasubramanian, K. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24399 · Cited by 86
IGF-I treatment of insulin resistance
McDonald, A. L., Williams, R. M., Regan, F. M., Semple, R. K., & Dunger, D. B. (2007) · European Journal of Endocrinology · doi:10.1530/eje-07-0271 · Cited by 87
Nediani, C., Raimondi, L., Borchi, E., & Cerbai, E. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3198 · Cited by 83
“In fact, on one hand, insulin resistance can be induced by a well-known pattern of inflammatory neurohumoral factors (409); on the other, by substrate excess as an increased availability of cardiac fatty acids (298), a condition that also induces the typical electrophysiological alterations observed in diabetic cardio…”
InfluentialAbu-Elheiga, L. A., Wu, H., Gu, Z., BRESSLER, R. C., & Wakil, S. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.309559 · Cited by 85
“Fat accumulation in animal tissues, including the liver, is associated with insulin resistance (24).”
BackgroundDiabetes mellitus: new challenges and innovative therapies
Sena, C. M., Bento, C. F., Pereira, P., & Seiça, R. M. F. (2010) · The EPMA Journal · doi:10.1007/s13167-010-0010-9 · Cited by 92
“Insulin secretion is affected by multiple factors, including the baseline secretion capacity, incretin effect, nutrient excess of glucose and free fatty acids (FFAs), and amyloid deposition [73, 74].”
BackgroundThe α-Amylase and α-Glucosidase Inhibition Capacity of Grape Pomace: A Review
Cisneros‐Yupanqui, M., Lante, A., Mihaylova, D. S., Krastanov, A. I., & Rizzi, C. (2022) · Food and Bioprocess Technology · doi:10.1007/s11947-022-02895-0 · Cited by 82
“The insulin resistance is described to be the result of intracellular lipid-induced inhibition of insulin-stimulated insulin-receptor substrate (IRS)-1 tyrosine phosphorylation that determines a reduced IRS-1-associated phosphatidyl inositol 3 kinase activity (Petersen & Shulman, 2006).”
BackgroundProgressive adaptation of hepatic ketogenesis in mice fed a high-fat diet
Sunny, N. E., Satapati, S., Fu, X., He, T., Mehdibeigi, R., Spring-Robinson, C. L., Duarte, J. A. G., Potthoff, M. J., Browning, J. D., & Burgess, S. C. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00033.2010 · Cited by 85
Kawamoto, R., Ninomiya, D., Kasai, Y., Kusunoki, T., Ohtsuka, N., Kumagi, T., & Abe, M. (2016) · Clinical and Experimental Hypertension · doi:10.3109/10641963.2015.1081232 · Cited by 81
Periodontitis and Insulin Resistance: Casual or Causal Relationship?
Gurav, A. N. (2012) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2012.36.6.404 · Cited by 83
“Table 1 depicts the possible mechanisms by which TNF-α contributes to IR [31-38].”
BackgroundInsulin Resistance and Metabolic Syndrome in the Pediatric Population
Nelson, R. A., & Bremer, A. A. (2009) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2009.0068 · Cited by 81
“53 Many mechanisms of postreceptor serine phosphorylation have been postulated, and the involvement of a serine/threonine kinase extrinsic to the IR is often implicated 53,54 ; however, inhibitors of serine/threonine phosphatases may also be involved.”
d-Pinitol: a cyclitol with versatile biological and pharmacological activities
Sánchéz‐Hidalgo, M., León‐González, A. J., Gálvez‐Peralta, M., González-Mauraza, N. H., & Martı́n-Cordero, C. (2020) · Phytochemistry Reviews · doi:10.1007/s11101-020-09677-6 · Cited by 80
Time‐dependent effects of fatty acids on skeletal muscle metabolism
Hirabara, S. M., Silveira, L. R., Abdulkader, F., Carvalho, C. R. D. O., Procópio, J., & Curi, R. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20811 · Cited by 80
“2006 Wiley-Liss, Inc. Insulin resistance plays a central role in the evolution of several diseases such as obesity, type 2 diabetes mellitus, and metabolic syndrome (Petersen and Shulman, 2006).”
BackgroundGreater adipose tissue infiltration in skeletal muscle among older men of African ancestry
Miljkovic, I., Cauley, J. A., Petit, M. A., Ensrud, K. E., Strotmeyer, E., Sheu, Y., Gordon, C. L., Goodpaster, B. H., Bunker, C. H., Patrick, A. L., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2541 · Cited by 79
Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome
Pant, R., Firmal, P., Shah, V. K., Alam, A., & Chattopadhyay, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.619888 · Cited by 83
ECM roles in the function of metabolic tissues
Huang, G., & Greenspan, D. S. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.09.006 · Cited by 81
Malonyl CoenzymeA Decarboxylase Regulates Lipid and Glucose Metabolism in Human Skeletal Muscle
Bouzakri, K., Austin, R., Rune, A., Lassman, M. E., Garcia-Roves, P. M., Berger, J. P., Krook, A., Chibalin, A. V., Zhang, B. B., & Zierath, J. R. (2008) · Diabetes · doi:10.2337/db07-0583 · Cited by 77
Superoxide and Respiratory Coupling in Mitochondria of Insulin-Deficient Diabetic Rats
Herlein, J. A., Fink, B. D., O'Malley, Y., & Sivitz, W. I. (2009) · Endocrinology · doi:10.1210/en.2008-0404 · Cited by 77
Sharma, A. K., Bharti, S., Goyal, S. N., Arora, S., Nepal, S., Kishore, K., Joshi, S., Kumari, S., & Arya, D. S. (2011) · Phytotherapy Research · doi:10.1002/ptr.3442 · Cited by 77
“In our study, HFD‐STZ treatment caused a significant decrease in SOD activity and an increase in TBARS level in pancreatic tissue indicating increased oxidative stress in diabetes (Zhou et al., 2009).”
BackgroundMethodSharma, A. K., Bharti, S., Kumar, R., Krishnamurthy, B., Bhatia, J., Kumari, S., & Arya, D. S. (2012) · Journal of Pharmacological Sciences · doi:10.1254/jphs.11184fp · Cited by 81
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“Key Words: rat NMR spectroscopy In vivo NMR insulin resistance PCr recovery Skeletal muscle accounts for the great majority of insulin-stimulated glucose uptake (1), and insulin resistance of skeletal muscle tissue is one of the earliest detectable disturbances in the development of type 2 diabetes [reviewed by Peters…”
BackgroundYang, W., Jeong, H.-J., Park, S., & Lee, W. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.09.006 · Cited by 77
“Insulin resistance is defined as an inadequate response of the peripheral tissues to insulin, and is a hallmark of type 2 diabetes mellitus (T2DM) and metabolic syndrome [2,3].”
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Mitochondria and heart failure
Murray, A. J., Edwards, L. M., & Clarke, K. (2007) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e3282f0ecbe · Cited by 76
Emerging Epidemic: Diabetes in Older Adults: Demography, Economic Impact, and Pathophysiology
Gambert, S. R., & Pinkstaff, S. M. (2006) · Diabetes Spectrum · doi:10.2337/diaspect.19.4.221 · Cited by 77
Shao, M., Lu, X., Cong, W., Xiao, X., Tan, Y., Li, Y., Li, X., Jin, L., Wang, X., Juancong, D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092574 · Cited by 75
“These kinases can then impair insulin signaling, finally lead to insulin resistance [14,15].”
Background
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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