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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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“At the cellular level, the development of insulin resistance is caused in part by abnormal accumulation and metabolism of lipids, as well as by mitochondrial dysfunction [2,3].”
BackgroundGlycemic load and risk of Alzheimer's disease.
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“Insulin resistance results in increased β-cell insulin production, which leads to weight gain, perpetuating a cycle of insulin resistance [13,14].”
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“Type 2 diabetesmellitus is one of themain causes ofmorbidity and mortality in the world, and its prevalence has increased dramatically in the past ten years [7].”
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“For example, insulin signaling regulates invertebrate and vertebrate lifespan, and drugs that target this pathway are central diabetes therapies [7,13,57].”
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“Chronic hyperglycemia or diabetes mellitus often precipitates complications such as neuropathy, retinopathy, nephropathy, cardiomyopathy, etc. (Stumvoll et al., 2002; Scheen, 2003a,b; Petersen and Shulman, 2006; Association, 2014).”
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“The etiology of INS resistance has been intensely studied in nonruminants (Petersen and Shulman, 2006; Glass and Olefsky, 2012), and it is now recognized that ER stress is an essential cause of INS resistance in liver and adipose tissue (Ozcan et al.”
BackgroundDing, X., Beier, J. I., Baldauf, K. J., Jokinen, J. D., Zhong, H., & Arteel, G. E. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00085.2013 · Cited by 27
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“Skeletal muscle insulin resistance plays a central role in the development of type 2 diabetes (1) and precedes overt type 2 diabetes, often by decades.”
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“Two potential mechanisms explain the development of metabolic complications resulting from obesity, including 1) lipotoxicity, where excess lipids overflow from an incompetent and dysfunctional adipose tissue (4), and 2) specific patterns of adipokines and proinflammatory cytokines released from dysfunctional adipose…”
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Hippocampal insulin resistance and altered food decision-making as players on obesity risk
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“If the latter occurs, blood glucose levels increase, creating a vicious cycle of insulin secretion, lipoprotein hypersecretion, adiposity and chronic inflammation [8].”
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“The resulting metabolic phenotype, decreased fatty acid and carbohydrate (CHO) uptake and a decrease in oxygen consumption, is similar to that observed in Type 2 diabetes, where oversupply of a single substrate leads to impaired metabolic function (13, 23).”
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Proteomic analysis to identify candidate biomarkers associated with type 1 diabetes
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“It is a metabolic and endocrine condition more common in childhood development and is preceded by the dysregulation of many biological pathways.(2) At present, no therapy exists to halt the immune-mediated destruction of β-cells,(3) and DM1 has a substantial long-term impact on the quality of life, particularly in chi…”
The assembly of lipid droplets and its relation to cellular insulin sensitivity
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“In particular, glycogen and TG levels in liver tissue strongly correlate with IR [55].”
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Inhibition of Renin-Angiotensin System: Implications for Diabetes Control and Prevention
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“Skeletal muscle insulin resistance is a hallmark decrement in T2D (3, 4).”
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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