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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Increased intramyocellular fat content and fatty acid metabolites have a pivotal role in the development of skeletal muscle insulin resistance.
“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]
Dysregulation of fatty acid metabolism has a central role in the development of insulin resistance in skeletal muscle.
“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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BackgroundIRS1-Independent Defects Define Major Nodes of Insulin Resistance
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“A major feature of type 2 diabetes mellitus (T2DM) is impairment of both basal and insulin-stimulated glucose metabolism in insulin-responsive, peripheral tissues, including skeletal muscle (SM) and liver (2, 37, 41).”
BackgroundIntracellular Trafficking and Secretion of VLDL
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Nutritional Interventions to Alleviate the Negative Consequences of Heat Stress
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“Insulin resistance, a major abnormality underlying type 2 diabetes mellitus, is defined as the pathophysiological condition reducing insulin responsiveness in liver, muscle, and adipose tissue [8,9].”
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“These lipids induce insulin resistance in skeletal muscle by causing defects in insulin signaling (36).”
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“Its most common cause is overfeeding, when the caloric intake exceeds energy expenditure (Petersen and Shulman, 2006).”
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“Insulin resistance is characterized by the accumulation of intrahepatic lipids due to the imbalances in the input, oxidation, synthesis and output of free-fatty acids by the hepatocytes [4,23,34].”
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Shanbhogue, V. V., Mitchell, D. M., Rosen, C. J., & Bouxsein, M. (2015) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00283-1 · Cited by 237 · see citing works
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“All conditions of increased lipid availability are thought to cause insulin resistance by the production of intracellular lipid metabolites (long-chain fatty acyl-CoA, diacylglycerol, and ceramides), which are known to stimulate inflammatory pathways that interfere with insulin signaling [11].”
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“The gradual accumulation of ectopic fat in obese subjects interferes with local insulin signaling, and plays a key role in the development of type 2 diabetes, which is becoming a major public health threat (7).”
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“Nonetheless, some still contend that lipid accumulation in skeletal muscle causes insulin resistance (77).”
BackgroundUncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB
Purkayastha, S., Zhang, G., & Cai, D. (2011) · Nature Medicine · doi:10.1038/nm.2372 · Cited by 220 · see citing works
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“DOI: 10.1002/jcp.21936 Insulin resistance plays a central role in the development of obesity, type 2 diabetes mellitus, and metabolic syndrome (Petersen and Shulman, 2006; Hirabara et al., 2007).”
BackgroundInfluentialCatecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity
Jocken, J. W. E., & Blaak, E. E. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2008.01.002 · Cited by 211 · see citing works
“fatty acyl CoA, ceramides, diacylglycerol (DAG)) in skeletal muscle may inhibit insulin signal transduction, leading to insulin resistance [2].”
BackgroundAdipose tissue and adipocyte dysregulation
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“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.”
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“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
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“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
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“part for the age-related increase in insulin resistance (32,33).”
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BackgroundExosomes as Mediators of the Systemic Adaptations to Endurance Exercise
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“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).”
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“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].”
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Development of a Type 2 Diabetes Risk Model From a Panel of Serum Biomarkers From the Inter99 Cohort
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“The dysregulation of many biological pathways precedes the development of overt type 2 diabetes (12).”
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“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].”
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“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).”
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The Phosphotyrosine Interactome of the Insulin Receptor Family and Its Substrates IRS-1 and IRS-2
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Background
- 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 › Epidemiology › 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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