Cited by 825Diabetes, Cardiovascular Risks, and LipoproteinsMetabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic Diseases

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Etiology of Insulin Resistance

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Petersen, Kitt Falk, Shulman, Gerald I.·2006·The American Journal of Medicine

DOI 10.1016/j.amjmed.2006.01.009PMC PMC2995525

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Abstract

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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Parathyroid Hormone-Related Protein, Human Adipose-Derived Stem Cells Adipogenic Capacity and Healthy Obesity
Roca-Rodríguez, M. D. M., Bekay, R. E., Garrido‐Sánchez, L., Gómez‐Serrano, M., Coín‐Aragüez, L., Oliva‐Olivera, W., Lhamyani, S., Clemente‐Postigo, M., García‐Santos, E., Díaz, R. D. L., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-4132 · Cited by 16
“PTHrP levels were measured by enzyme immunoassay (ELISA) kits (PTHrP [1–34], Phoenix Pharma-”
Method
INSR gene variation is associated with decreased insulin sensitivity in Iraqi women with PCOs.
Mutib, M. T., Hamdan, F. B., & Al-Salihi, A. R. (2014) · Europe PMC (PubMed Central) · Cited by 16
Electrochemical Glucose Sensors and Their Application in Diabetes Management
Heller, A., & Feldman, B. (2013) · Modern aspects of electrochemistry · doi:10.1007/978-1-4614-6148-7_5 · Cited by 16
Knockdown of JNK rescues 3T3-L1 adipocytes from insulin resistance induced by mitochondrial dysfunction
Kim, T., Leitner, J. W., Adochio, R., & Draznin, B. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.11.121 · Cited by 17
Plant Foods, Healthy Plant-Based Diets, and Type 2 Diabetes: A Review of the Evidence
del Carmen Fernández-Fígares Jiménez, M. (2024) · Nutrition Reviews · doi:10.1093/nutrit/nuad099 · Cited by 20
Insulin sensitivity is related to glycemic control in type 2 diabetes and diabetes remission after Roux-en Y gastric bypass
Gavin, T. P., Ernst, J. M., Caudill, S. E., Dohm, G. L., Pories, W. J., Dar, M. S., & Reed, M. A. (2014) · Surgery · doi:10.1016/j.surg.2014.02.005 · Cited by 15
Mechanisms Linking the Metabolic Syndrome and Cardiovascular Disease: Role of Hepatic Insulin Resistance
Meshkani, R., & Adeli, K. (2009) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 15
Glabridin attenuates antiadipogenic activity induced by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin in murine 3T3‐L1 adipocytes
Choi, E. M., Suh, K. S., Jung, W., Park, S. Y., Chin, S. O., Rhee, S. Y., Pak, Y. K., & Chon, S. (2018) · Journal of Applied Toxicology · doi:10.1002/jat.3664 · Cited by 15
Akt activation by insulin treatment attenuates cachexia in Walker‐256 tumor‐bearing rats
Silva, F. D. F., de Morais, H., Silva, M. O., da Silva, F. G., Croffi, R. V., Serrano‐Nascimento, C., Graciano, M. F. R., Carpinelli, Â. R., Bazotte, R. B., & de Souza, H. M. (2020) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29682 · Cited by 15
A novel metformin derivative showed improvement of lipid metabolism in obese rats with type 2 diabetes
Chen, D., Jia, D. T., Wu, X., Shi, K., Ren, C., Dou, Y., Guo, M., Wang, J., Ma, M., Wu, Z., et al. (2020) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13302 · Cited by 15
Extracts of Adlay, Barley and Rice Bran have Antioxidant Activity and Modulate Fatty Acid Metabolism in Adipocytes
Park, T., Lee, S., Kim, H., Kim, K., Kim, Y. J., Jeong, I., Do, W.-N., & Lee, H.-J. (2009) · The Korean Journal of Food And Nutrition · Cited by 15
Risk factors for extensive skeletal muscle uptake in oncologic FDG-PET/CT for patients undergoing a 4-h fast
Nakatani, K., Nakamoto, Y., & Togashi, K. (2012) · Nuclear Medicine Communications · doi:10.1097/mnm.0b013e328352290f · Cited by 15
ANTIOXIDANT ENZYME LEVELS AS MARKERS FOR TYPE 2 DIABETES MELLITUS
Verma, S., Sagar, N., Shukla, K., Abbas, M., & Banerjee, M. (2013) · International Journal of Bioassays · doi:10.21746/ijbio.2013.04.0023 · Cited by 15
Postprandial microvascular blood flow in skeletal muscle: Similarities and disparities to the hyperinsulinaemic‐euglycaemic clamp
Roberts‐Thomson, K. M., Betik, A. C., Premilovac, D., Rattigan, S., Richards, S. M., Ross, R. M., Russell, R., Kaur, G., Parker, L., & Keske, M. A. (2019) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13237 · Cited by 17
Shorea roxburghii Leaf Extract Ameliorates Hyperglycemia Induced Abnormalities in High Fat/Fructose and Streptozotocin Induced Diabetic Rats
Zhang, W., Meng, J., Liu, Q., Makinde, E. A., Qing, L., & Olatunji, O. J. (2020) · Chemistry & Biodiversity · doi:10.1002/cbdv.201900661 · Cited by 15
“Type 2 diabetes mellitus (T2DM), which accounts for approximately 90% of the global reported cases of DM, bears the hallmark of insulin resistance (IR) and malfunctioning of the pancreatic β-cell.[4,7,8] In DM, the persistent chronic hyperglycemic state plays a pivotal role in impairment and failure of various organs…”
Background
Functions of Forkhead Box O on Glucose Metabolism in Abalone Haliotis discus hannai and Its Responses to High Levels of Dietary Lipid
Wang, L., Guo, Y., Pan, M., Li, X., Huang, D., Liu, Y., Wu, C., Zhang, W., & Mai, K. (2021) · Genes · doi:10.3390/genes12020297 · Cited by 15
“However, carbohydrate metabolism is not the sole cause of dysglycemia; lipid metabolism is also one of the reasons [43,44].”
Background
Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight gain, hyperlipidemia, and hepatic steatosis in db/db mice
Zhang, X.-D., Yan, J., Yan, G., Sun, X.-Y., Ji, J., Li, Y., Hu, Y., & Wang, H. (2010) · Acta Pharmacologica Sinica · doi:10.1038/aps.2010.104 · Cited by 14
Effect of low calorie diet and controlled fasting on insulin sensitivity and glucose metabolism in obese patients with type 1 diabetes mellitus
MUSIL, F., ŠMAHELOVÁ, A., BLÁHA, V., HYŠPLER, R., TICHÁ, A., LESNÁ, J., ZADÁK, Z., & SOBOTKA, L. (2013) · Physiological Research · doi:10.33549/physiolres.932381 · Cited by 12
“%) were determined before the initiation of every hyperinsulinemic-euglycemic clamp.”
BackgroundMethod
Ursonic acid from Artemisia montana exerts anti-diabetic effects through anti-glycating properties, and by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant C2C12 cells
Ali, M. Y., Park, S. E., Seong, S. H., Zamponi, G. W., Jung, H. A., & Choi, J. S. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110452 · Cited by 14
Role of Quercetin in DNA Repair: Possible Target to Combat Drug Resistance in Diabetes
Hussain, Y., Abdullah, Khan, F., Alam, W., Sardar, H., Khan, M. A., Shen, X., & Khan, H. Z. (2024) · Current Drug Targets · doi:10.2174/0113894501302098240430164446 · Cited by 14
Glycaemic load is associated with insulin resistance in older Australian women
O’Sullivan, T. A., Bremner, A., O'Neill, S., & Lyons‐Wall, P. (2009) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2009.115 · Cited by 14
“Although the precise cellular mechanisms of insulin resistance are not yet clear (Shulman, 2000; Petersen and Shulman, 2006), our finding is supported by the proposed mechanisms to explain how high glycaemic intakes could promote insulin resistance.”
Background
Pioglitazone improves insulin sensitivity and reduces weight loss in Walker-256 tumor-bearing rats
Silva, F. D. F., Ortiz‐Silva, M., Galia, W. B. D. S., Cassolla, P., Graciano, M. F. R., Zaia, C. T. B. V., Zaia, D. A. M., Carpinelli, Â. R., da Silva, F. G., & de Souza, H. M. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.12.016 · Cited by 14
Rapid Non-Enzymatic Glycation of the Insulin Receptor under Hyperglycemic Conditions Inhibits Insulin Binding In Vitro: Implications for Insulin Resistance
Rhinesmith, T., Turkette, T., & Root-Bernstein, R. S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122602 · Cited by 15
“As in T1DM, increased serum concentrations of fatty acids (FAs), and their subsequent metabolites may trigger inhibitory phosphorylation of insulin signaling pathway elements [4].”
Background
Metabolic remodeling in chronic heart failure
Wang, J., & Guo, T. (2013) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b1300137 · Cited by 14
“Insulin resistance is prevalent in CHF and its potential mechanisms (Petersen and Shulman, 2006; Tuunanen and Knuuti, 2011) contain: chronically increased sympathetic nervous system (SNS) activity which leads to decreased insulin secretion, insulin responsiveness, and skeletal muscle blood flow.”
Background
Beneficial effects of dietary restriction in type 2 diabetic rats: the role of adipokines on inflammation and insulin resistance
Crisóstomo, J., Rodrigues, L., Matafome, P. N., Amaral, C., Nunes, E., Louro, T. M., Monteiro, P. F., & Seiça, R. M. F. (2010) · British Journal Of Nutrition · doi:10.1017/s0007114510000164 · Cited by 14
“Various studies reported that increased circulating plasma levels of TAG and NEFA contribute to insulin resistance in peripheral tissues such as skeletal muscle((2,7,27)).”
Background
The effects of diet and lifestyle interventions on insulin resistance in patients with nonalcoholic fatty liver disease: a systematic review
Paris, T., George, E. S., Roberts, S. K., & Tierney, A. C. (2017) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0000000000000890 · Cited by 15
MG53 and disordered metabolism in striated muscle
Hu, X., & Xiao, R. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.10.013 · Cited by 13
3,5-Diiodo-L-Thyronine Affects Structural and Metabolic Features of Skeletal Muscle Mitochondria in High-Fat-Diet Fed Rats Producing a Co-adaptation to the Glycolytic Fiber Phenotype
Silvestri, E., Cioffi, F., Matteis, R. D., Senese, R., de Lange, P., Coppola, M., Salzano, A. M., Scaloni, A., Ceccarelli, M., Goglia, F., et al. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00194 · Cited by 15
“In skeletal muscle, increased fatty acids uptake and corresponding impaired molecular utilization contribute to the accumulation of lipids leading to lipotoxicity and, thus, to insulin resistance (IR) (Falholt et al., 1988; Levin et al., 2001; Adams et al., 2004; Petersen and Shulman, 2006; Sabin et al., 2007; Koves e…”
Background
Serum Resistin Level in Obese Male Children
Amirhakimi, A., Karamifar, H., Moravej, H., & Amirhakimi, G. (2011) · Journal of Obesity · doi:10.1155/2011/953410 · Cited by 15
Reactive Oxygen Species in the Induction of Toxicity
Lenaz, G., & Strocchi, P. (2009) · Wiley eBooks · doi:10.1002/9780470744307.gat024 · Cited by 15
Molecular Mechanisms of Insulin Resistance
Draznin, B. (2019) · Contemporary Endocrinology · doi:10.1007/978-3-030-25057-7_4 · Cited by 13
Neuroinflammation biomarkers
Пискунов, А. К. (2010) · Neurochemical Journal · doi:10.1134/s1819712410010101 · Cited by 13
Timely Bolus Insulin for Glucose Control during Cardiopulmonary Bypass
Kruger, C., Sidebotham, D. A., Brown, A. J., Singh, H. K., & Merry, A. (2012) · Journal of ExtraCorporeal Technology · doi:10.1051/ject/201244034 · Cited by 13
Soluble insulin receptor as a source of insulin resistance and cognitive impairment in HIV-seropositive women
Gerena, Y., Menéndez‐Delmestre, R., Skolasky, R. L., Hechavarría, R., Pérez, S., Hilera, C., González, C., Nath, A., & Wojna, V. (2015) · Journal of NeuroVirology · doi:10.1007/s13365-014-0310-2 · Cited by 13
“Nevertheless, we previously observed in these patients that increased levels of plasma sIR correlated with a significant decrease in IRS-1 tyrosine phosphorylation in CSF leukocytes, a finding that is consistent with insulin resistance (Gerena et al. 2012; Sesti 2006; Petersen and Shulman 2006).”
Background
Adiponectin is related to intramyocellular lipid content in non-diabetic adults
Godoy‐Matos, A. F., Bahia, L., Domingues, R. C., Sicuro, F. L., Tambascia, M. A., Geloneze, B., Kraemer‐Aguiar, L. G., & Bouskela, E. (2009) · Journal of Endocrinological Investigation · doi:10.1007/bf03346608 · Cited by 13
Diabese youngsters have 3.7 more chances in developing metabolic syndrome compared with the obese
Galli‐Τsinopoulou, A., Grammatikopoulou, M. G., Stylianou, C., Emmanouilidou, E., & Kokka, P. (2010) · Journal of Endocrinological Investigation · doi:10.1007/bf03346646 · Cited by 13
Ghrelin—a new player in glucose homeostasis?
Ahima, R. S. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.04.006 · Cited by 13
Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging
Lewis, L., Valvi, D., Gedaly, R., & Martí, F. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1621759 · Cited by 12
“In conditions like type 2 diabetes and obesity, when DY m is impaired, there is a disruption of the electrochemical gradient necessary for the import of substrates like pyruvate and fatty acids (102 – 104).”
Albumin is an important factor in the control of serum free fatty acid flux in both male and female mice
Tomoo, K., Szramowski, M., Pinal, R., Meyer, J. M., Zhang, Y., Murray‐Kolb, L. E., & Henderson, G. C. (2024) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00894.2023 · Cited by 12
Ectopic Fat Deposition on Insulin Sensitivity: Correlation of Hepatocellular Lipid Content andMValue
Hong, B. S., Li, Y., Lai, S., Liu, J., Guan, H., Ke, W., He, X., & Li, Y. (2016) · Journal of Diabetes Research · doi:10.1155/2016/3684831 · Cited by 12
“Insulin resistance promotes hydrolysis of triglycerides and release of free fatty acids from adipose tissues, reduces glucose uptake inmuscle cells, impairs glycogen synthesis, and increases gluconeogenesis, lipogenesis, and synthesis of CRP in the liver [2, 3].”
Background
BAG6 contributes to glucose uptake by supporting the cell surface translocation of the glucose transporter GLUT4
Minami, S., Yokota, N., & Kawahara, H. (2020) · Biology Open · doi:10.1242/bio.047324 · Cited by 11
“Obesityand type 2 diabetes are characterized by insulin resistance (Zierath et al., 1996; Petersen and Shulman, 2006; Bogan, 2012; Foley and Klip, 2014; Aslamy and Thurmond, 2017).”
Gluconeogenesis is reduced from alanine, lactate and pyruvate, but maintained from glycerol, in liver perfusion of rats with early and late sepsis
Galia, W. B. D. S., Biazi, G. R., Frasson‐Uemura, I. G., Miksza, D. R., Zaia, C. T. B. V., Zaia, D. A. M., de Souza, H. M., & Bertolini, G. L. (2021) · Cell Biochemistry and Function · doi:10.1002/cbf.3637 · Cited by 14
“Increased FFA is another factor that can impair insulin signalling.(32,33) However, FFA was not changed in rats with early (8 hours) sepsis, excluding its”
Background

Authors: Petersen, K. F., & Shulman, G. I.
Affiliations: Howard Hughes Medical Institute (US)
ORCID: Petersen, Kitt Falk
Shulman, Gerald I.
Venue: The American Journal of Medicine
Publisher: Elsevier BV
Published: 2006-05
Volume: 119
Issue: 5
Pages: S10-S16
ISSN: 0002-9343 (ISSN-L)
DOI: 10.1016/j.amjmed.2006.01.009
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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