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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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“fatty acyl CoA, ceramides, diacylglycerol (DAG)) in skeletal muscle may inhibit insulin signal transduction, leading to insulin resistance [2].”
BackgroundAdipose tissue and adipocyte dysregulation
Lafontan, M. (2013) · Diabetes & Metabolism · doi:10.1016/j.diabet.2013.08.002 · Cited by 218
“They also serve as potent second messengers, are mplicated in hepatic and skeletal muscle FA-induced insulin esistance [30], signal nutrient mediation to the central nervous ystem (CNS) and have central effects on insulin action.”
BackgroundSkov, V., Glintborg, D., Knudsen, S., Jensen, T. E., Kruse, T. A., Tan, Q., Brusgaard, K., Beck‐Nielsen, H., & Højlund, K. (2007) · Diabetes · doi:10.2337/db07-0275 · Cited by 204
“Although similar abnormalities in proximal insulin signaling have been reported in obesity and type 2 diabetes (7,8), it has been hypothesized that the molecular mechanisms underlying insulin resistance in PCOS differ from those seen in these conditions (12).”
BackgroundInfluentialDPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats
Pintana, H., Apaijai, N., Chattipakorn, N., & Chattipakorn, S. C. (2013) · Journal of Endocrinology · doi:10.1530/joe-12-0521 · Cited by 211
“Insulin resistance is a pathological condition in which tissues do not respond to normal physiological insulin concentrations resulting in increased insulin concentration required to maintain glucose homeostasis (Kahn & Flier 2000, Petersen & Shulman 2006).”
BackgroundThe Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations
Lee, P., & Halter, J. B. (2017) · Diabetes Care · doi:10.2337/dc16-1732 · Cited by 226
“part for the age-related increase in insulin resistance (32,33).”
BackgroundThe Molecular Mechanisms by Which Vitamin D Prevents Insulin Resistance and Associated Disorders
Szymczak-Pajor, I., Drzewoski, J., & Śliwińska, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186644 · Cited by 214
“Several studies demonstrated that vitamin D decreases monocyte chemotaxis, secretion of cytokines and chemokines playing an important role in reducing the extent of inflammation [70,76,80,81].”
BackgroundExosomes as Mediators of the Systemic Adaptations to Endurance Exercise
Safdar, A., & Tarnopolsky, M. A. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a029827 · Cited by 203
Mulvihill, E. E., Assini, J. M., Lee, J. K., Allister, E. M., Sutherland, B. G., Koppes, J. B., Sawyez, C. G., Edwards, J. Y., Telford, D. E., Charbonneau, A., et al. (2011) · Diabetes · doi:10.2337/db10-0589 · Cited by 202
Sprecher, D. L., Massien, C., Pearce, G., Billin, A. N., Perlstein, I., Willson, T. M., Hassall, D. G., Ancellin, N., Patterson, S. D., Lobe, D. C., et al. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000252790.70572.0c · Cited by 207
Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner
Fischer-Posovszky, P., Kukulus, V., Tews, D., Unterkircher, T., Debatin, K.-M., Fulda, S., & Wabitsch, M. (2010) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28435 · Cited by 195
“However, our data also revealed a down-regulation of PPARc and Glut-4, which is not preferable because these molecules are important regulators of insulin sensitivity (63, 64).”
BackgroundVial, G., Chauvin, M., Bendridi, N., Durand, A., Meugnier, E., Madec, A., Bernoud‐Hubac, N., de Barros, J.-P. P., Fontaine, E. M., Acquaviva, C., et al. (2014) · Diabetes · doi:10.2337/db14-1220 · Cited by 194
“of PKC and ROS-mediated activation of JNK are well-described contributors to hepatic insulin resistance (22-27).”
BackgroundInflammatory cause of metabolic syndrome via brain stress and NF-κB
Cai, D., & Liu, T. (2012) · Aging · doi:10.18632/aging.100431 · Cited by 192
“In addition to TLRs, cytokine receptors can also participate in the central induction of metabolic syndrome and related diseases, given that a prominent pathologic feature of these diseases, especially in the late stage, is the prevalent presence of cytokines in the circulation and various tissues of the body [20-30].”
BackgroundInfluentialToward a unifying hypothesis of metabolic syndrome
Bremer, A. A., Mietus-Snyder, M., & Lustig, R. H. (2012) · PEDIATRICS · doi:10.1542/peds.2011-2912 · Cited by 186
Nair, K. S., Bigelow, M. L., Asmann, Y. W., Chow, L. S., Coenen-Schimke, J. M., Klaus, K. A., Guo, Z.-K., Sreekumar, R., & Irving, B. A. (2008) · Diabetes · doi:10.2337/db07-1556 · Cited by 187
Purkayastha, S., Zhang, H., Zhang, G., Ahmed, Z., Wang, Y., & Cai, D. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006875108 · Cited by 184
Deconvoluting the role of reactive oxygen species and autophagy in human diseases
Wen, X., Wu, J., Wang, F., Liu, B., Huang, C., & Wei, Y. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.013 · Cited by 181
Wei, E., Ali, Y. B., Lyon, J. G., Wang, H., Nelson, R. C., Dolinsky, V. W., Dyck, J. R. B., Mitchell, G. A., Korbutt, G. S., & Lehner, R. S. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.02.005 · Cited by 177
Ectopic fat and cardiometabolic and vascular risk
Lim, S. K., & Meigs, J. B. (2013) · International Journal of Cardiology · doi:10.1016/j.ijcard.2013.08.077 · Cited by 175
“Ectopic fat depots that are particularly large (such as VAT) or that occur in organs that have central functions in metabolism (such as the liver) are considered to be primarily systemically acting fat depots [43,44].”
BackgroundFunctional food relevance of whey protein: A review of recent findings and scopes ahead
Patel, S. V. (2015) · Journal of Functional Foods · doi:10.1016/j.jff.2015.09.040 · Cited by 180
Tan, C. Y., & Vidal‐Puig, A. (2008) · Biochemical Society Transactions · doi:10.1042/bst0360935 · Cited by 169
Obesity and diabetes: from genetics to epigenetics
Burgio, E., Lopomo, A., & Migliore, L. (2014) · Molecular Biology Reports · doi:10.1007/s11033-014-3751-z · Cited by 174
Wang, C., Wang, C., Huang, H., & Wei, Y. (2013) · The FEBS Journal · doi:10.1111/febs.12096 · Cited by 165
Plants and Natural Compounds with Antidiabetic Action
Coman, C., Rugină, D. O., & Socaciu, C. (2012) · Notulae Botanicae Horti Agrobotanici Cluj-Napoca · doi:10.15835/nbha4017205 · Cited by 165
Boutari, C., DeMarsilis, A. J., & Mantzoros, C. S. (2023) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2023.110773 · Cited by 178
Development of a Type 2 Diabetes Risk Model From a Panel of Serum Biomarkers From the Inter99 Cohort
Kolberg, J. A., Jørgensen, T., Gerwien, R. W., Hamren, S., McKenna, M. P., Moler, E. J., Rowe, M. W., Urdea, M. S., Xu, X. M., Hansen, T. F., et al. (2009) · Diabetes Care · doi:10.2337/dc08-1935 · Cited by 164
“The dysregulation of many biological pathways precedes the development of overt type 2 diabetes (12).”
BackgroundStearoyl-CoA desaturase and its relation to high-carbohydrate diets and obesity
Flowers, M. T., & Ntambi, J. M. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2008.12.011 · Cited by 165
“These events contribute to both local and systemic insulin resistance resulting in hyperinsulinemia, increased hepatic glucose production, reduced peripheral glucose uptake and dyslipidemia [2,5,6].”
Elo, B., Villano, C. M., Govorko, D., & White, L. A. (2007) · Journal of Molecular Endocrinology · doi:10.1677/jme-06-0037 · Cited by 162
“Hyperglycemia in type II diabetes has a complex etiology resulting fromdefects in insulin production and signaling, changes in insulin sensitivity of target tissues, as well as from increased hepatic gluconeogenesis (see Petersen & Shulman 2006 for review).”
Hypothalamic inflammation: a double‐edged sword to nutritional diseases
Cai, D., & Liu, T. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06388.x · Cited by 162
The Phosphotyrosine Interactome of the Insulin Receptor Family and Its Substrates IRS-1 and IRS-2
Hanke, S., & Mann, M. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800407-mcp200 · Cited by 165
“resistance like excess lipids (13, 18, 19), inflammatory cyto-”
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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