Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM
Abstract
Evidence is reviewed that free fatty acids (FFAs) are one important link between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations in plasma FFA concentrations inhibit insulin stimulated peripheral glucose uptake in a dose-dependent manner in normal controls and in patients with NIDDM. Two possible mechanisms are identified: 1) a fat-related inhibition of glucose transport or phosphorylation, which appears after 3–4 h of fat infusion, and 2) a decrease in muscle glycogen synthase activity, which appears after 4–6 h of fat infusion. Third, FFAs stimulate insulin secretion in nondiabetic individuals. Some of this insulin is transmitted in the peripheral circulation and is able to compensate for FFA-mediated peripheral insulin resistance. FFA-mediated portal hyperinsulinemia counteracts the stimulation of FFAs on hepatic glucose production (HGP) and thus prevents hepatic glucose overproduction. We speculate that, in obese individuals who are genetically predisposed to develop NIDDM, FFAs will eventually fail to promote insulin secretion. The stimulatory effect of FFAs on HGP would then become unchecked, resulting in hyperglycemia. Hence, continuously elevated levels of plasma FFAs may play a key role in the pathogenesis of NIDDM in predisposed individuals by impairing peripheral glucose utilization and by promoting hepatic glucose overproduction.
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In vivo, infusion of lipid emulsions and heparin in healthy subjects increased plasma NEFA concentrations above the physiological range and was associated with development of insulin resistance mediated by changes in post-receptor insulin signalling.
“In vivo, infusion of lipid emulsions and heparin in healthy subjects increased plasma NEFA concentrations to above the physiological range and were associated with the development of insulin resistance, an effect mediated by changes in post-receptor insulin signalling [149, 150, 151].”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [149]
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- Authors
- Boden, G.
- Affiliations
- Temple University (US)
- Corresponding author
- Boden, Guenther
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1997-01-01
- Volume
- 46
- Issue
- 1
- Pages
- 3-10
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2146845495
- Cited by
- 1,728
- References
- 0
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 20 · 2023: 22 · 2022: 29 · 2021: 35 · 2020: 37 · 2019: 35 · 2018: 63 · 2017: 50 · 2016: 55 · 2015: 66 · 2014: 64 · 2013: 73 · 2012: 67
- FWCI
- 38.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag007988-10, 5r01aa010221-03)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA-10221)
- National Institute on Aging (R01-AG07988)
- National Center for Research Resources (RR-349)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- free fatty acids, insulin resistance, type 2 diabetes, obesity, peripheral glucose uptake, glucose transport, glycogen synthase, insulin secretion, hyperinsulinemia, hepatic glucose production, hyperglycemia, type 2 diabetes pathogenesis
- MeSH terms
- Insulin Secretion, Animals, Diabetes Mellitus, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Glucose, Humans, Insulin, Insulin Resistance, Models, Biological, Obesity, Tumor Necrosis Factor-alpha, Muscle, Skeletal
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