Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle

J Clin Invest. 1994 Feb;93(2):870-6. doi: 10.1172/JCI117042.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caprylates / pharmacology
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Cells, Cultured
  • Epoxy Compounds / pharmacology
  • Ethanol / pharmacology
  • Fatty Acids, Nonesterified / metabolism
  • Fatty Acids, Nonesterified / pharmacology*
  • Glucose / metabolism*
  • Glucose / pharmacology*
  • Hypoglycemic Agents / pharmacology
  • Insulin / biosynthesis*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiology*
  • Keto Acids / pharmacology
  • Kinetics
  • Male
  • Oleic Acid
  • Oleic Acids / pharmacology
  • Palmitic Acid
  • Palmitic Acids / pharmacology
  • Proinsulin / biosynthesis
  • Protein Biosynthesis
  • Proteins / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors

Substances

  • Caprylates
  • Epoxy Compounds
  • Fatty Acids, Nonesterified
  • Hypoglycemic Agents
  • Insulin
  • Keto Acids
  • Oleic Acids
  • Palmitic Acids
  • Proteins
  • Oleic Acid
  • Palmitic Acid
  • Ethanol
  • alpha-ketoisocaproic acid
  • Proinsulin
  • Carnitine O-Palmitoyltransferase
  • Glucose
  • etomoxir
  • octanoic acid