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Effects of Free Fatty Acids (FFA) on Glucose Metabolism: Significance for Insulin Resistance and Type 2 Diabetes
Abstract
Most obese individuals have elevated plasma levels of free fatty acids (FFA) which are known to cause peripheral (muscle) insulin resistance. They do this by inhibiting insulin-stimulated glucose uptake and glycogen synthesis. The mechanism involves intramyocellular accumulation of diacylglycerol and activation of protein kinase C. FFAs also cause hepatic insulin resistance. They do this by inhibiting insulin-mediated suppression of glycogenolysis. On the other hand, FFAs support between 30 and 50 % of basal insulin secretion and potentiate glucose-stimulated insulin secretion. The insulin stimulatory action of FFAs is responsible for the fact that the vast majority ( approximately 80 %) of obese insulin resistant people do not develop type 2 diabetes. They are able to compensate for their FFA mediated insulin resistance with increased FFA mediated insulin secretion. Individuals who are unable to do this (probably for genetic reasons) eventually develop type 2 diabetes. FFAs have recently been shown to activate the IkappaB/NFkappaB pathway which is involved in many inflammatory processes. Thus, elevated plasma levels of FFAs are not only a major cause of insulin resistance in skeletal muscle and liver but may, in addition, play a role in the pathogenesis of coronary artery disease.
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“Obesity-related type 2 diabetes patients often have elevated plasma FFAs, because of either increased amounts of FFAs released from large amounts of adipose tissue or impaired FFA clearance [258].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [258]
In the citing paper
“Alterations in non-esterified (i.e. free) fatty acid (NEFA) levels play a central role in the pathogenesis of insulin resistance and the development of metabolic diseases [8, 9].”
From Sleep restriction increases free fatty acids in healthy men (2015) · cites this paper as [9]
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TLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690
Huynh, K., Bernardo, B. C., McMullen, J. R., & Ritchie, R. H. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.01.003 · Cited by 556
Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs
Artasensi, A., Pedretti, A., Vistoli, G., & Fumagalli, L. (2020) · Molecules · doi:10.3390/molecules25081987 · Cited by 540
“Elevated plasma FFA concentrations are associated with increased liver production and secretion of glucose [17].”
BackgroundTarnopolsky, M. A., Rennie, C. D., Robertshaw, H. A., Fedak-Tarnopolsky, S. N., Devries, M. C., & Hamadeh, M. J. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00472.2006 · Cited by 457
Redox Control of the Cell Cycle in Health and Disease
Sarsour, E. H., Kumar, M. G., Chaudhuri, L., Kalen, A. L., & Goswami, P. C. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2513 · Cited by 393
“FFA produced during the process of lipolysis has been shown to be higher in obese and diabetic individuals (26).”
Metadata
- Authors
- Boden, G.
- Affiliations
- Temple University (US)
- Corresponding author
- Boden, G.
- Venue
- Experimental and Clinical Endocrinology & Diabetes
- Publisher
- Georg Thieme Verlag KG
- Published
- 2003-06-04
- Volume
- 111
- Issue
- 03
- Pages
- 121-124
- ISSN
- 0947-7349 (ISSN-L)
- 1439-3646
- OpenAlex
- W121967333
- Cited by
- 348
- References
- 0
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 20 · 2023: 17 · 2022: 26 · 2021: 30 · 2020: 17 · 2019: 17 · 2018: 15 · 2017: 16 · 2016: 9 · 2015: 12 · 2014: 14 · 2013: 13 · 2012: 18
- FWCI
- 14.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental and Clinical Endocrinology & Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag007988-10, 5r01ag015363-05)
- National Institute on Aging (AG15363, R01-AG07988)
- National Center for Research Resources (2 M01-RR-349)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- free fatty acids, insulin resistance, type 2 diabetes, glucose metabolism, skeletal muscle insulin signaling, hepatic insulin resistance, insulin secretion, diacylglycerol, protein kinase C, glycogen synthesis, glycogenolysis, obesity, NF-κB signaling, inflammation, coronary artery disease
- MeSH terms
- Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Glucose, Humans, Insulin Resistance, Liver, Obesity
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