Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.
Open accessAbstract
UNLABELLED: We tested effects of long-term exposure of pancreatic islets to free fatty acids (FFA) in vitro on B cell function. Islets isolated from male Sprague-Dawley rats were exposed to palmitate (0.125 or 0.25 mM), oleate (0.125 mM), or octanoate (2.0 mM) during culture. Insulin responses were subsequently tested in the absence of FFA. After a 48-h exposure to FFA, insulin secretion during basal glucose (3.3 mM) was several-fold increased. However, during stimulation with 27 mM glucose, secretion was inhibited by 30-50% and proinsulin biosynthesis by 30-40%. Total protein synthesis was similarly affected. Conversely, previous palmitate did not impair alpha-ketoisocaproic acid (5 mM)-induced insulin release. Induction and reversibility of the inhibitory effect on glucose-induced insulin secretion required between 6 and 24 h. Addition of the carnitine palmitoyltransferase I inhibitor etomoxir (1 microM) partially reversed (by > 50%) FFA-associated decrease in secretory as well as proinsulin biosynthetic responses to 27 mM glucose. The inhibitory effect of previous palmitate was similar when co-culture was performed with 5.5, 11, or 27 mM glucose. Exposure to palmitate or oleate reduced the production of 14CO2 from D-[U-14C]glucose, and of 14CO2 from D-[3,4-14C]-glucose, both effects being reversed by etomoxir. CONCLUSIONS: long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid cycle.
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Exposure to NEFA in vitro decreased insulin-mediated glucose uptake and glycogen synthesis and reduced beta-cell function, including reduced insulin release and impaired proinsulin to insulin processing.
“Exposure to NEFA in vitro decreased insulin-mediated glucose uptake and glycogen synthesis [146] as well as reduced beta-cell function [147, 148], encompassing both reduced insulin release and impaired proinsulin to insulin processing.”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [147]
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- Authors
- Zhou, Y. P., & Grill, V. E.
- Affiliations
- Karolinska University Hospital (SE)
- ORCID
- Zhou, Y P
- Venue
- Journal of Clinical Investigation
- Published
- 1994-02-01
- Volume
- 93
- Issue
- 2
- Pages
- 870-876
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC293952
- OpenAlex
- W2108709856
- Cited by
- 677
- References
- 28
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 8 · 2021: 16 · 2020: 15 · 2019: 12 · 2018: 7 · 2017: 19 · 2016: 12 · 2015: 30 · 2014: 19 · 2013: 28 · 2012: 29
- FWCI
- 18.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Karolinska Institutet
- Medical Research Council
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- free fatty acids, pancreatic islets, beta-cell function, insulin secretion, proinsulin biosynthesis, glucose-fatty acid cycle, palmitate, oleate, octanoate, alpha-ketoisocaproate, etomoxir, carnitine palmitoyltransferase 1, glucose metabolism
- MeSH terms
- Insulin Secretion, Ethanol, Animals, Caprylates, Carnitine O-Palmitoyltransferase, Cells, Cultured, Epoxy Compounds, Fatty Acids, Nonesterified, Glucose, Hypoglycemic Agents, Insulin, Islets of Langerhans, Keto Acids, Kinetics, Male, Oleic Acids, Palmitic Acids, Proinsulin, Proteins, Time Factors, Protein Biosynthesis, Rats, Sprague-Dawley, Oleic Acid, Palmitic Acid, Rats
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