Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans

J Clin Endocrinol Metab. 1995 May;80(5):1584-90. doi: 10.1210/jcem.80.5.7745004.

Abstract

We previously demonstrated in the rat that long term exposure to fatty acids inhibits B-cell function in vivo and in vitro. To further assess the clinical significance of these findings, we tested in human islets the effects of fatty acids on glucose-induced insulin release and biosynthesis and on pyruvate dehydrogenase (PDH) activity. Human islets were obtained from the beta-Cell Transplant Unit (Brussels, Belgium). Exposure to 0.125 mmol/L palmitate or oleate for 48 h during tissue culture (RPMI-1640 and 5.5 mmol/L glucose) inhibited the postculture insulin response to 27 mmol/L glucose by 40% and 42% (P < 0.01 for difference). Inhibition was partly prevented by coculture with 1 mumol/L etomoxir, a carnitine-palmitoyl-transferase-I inhibitor (P < 0.05 for effect of etomoxir). Inhibitory effects on glucose-induced insulin secretion by previous palmitate were additive to the inhibitory effects exerted by previous high glucose (11 and 27 mmol/L). Palmitate-induced inhibition of insulin secretion was evident after exposure to 25 mumol/L added fatty acid. The insulin content of islets exposed to fatty acids was significantly reduced, and glucose-induced proinsulin biosynthesis was inhibited by 59% after palmitate addition and by 51% after oleate exposure (P < 0.01). These effects were partly prevented by etomoxir (P < 0.05). The activity of PDH in mitochondrial extracts of islets preexposed for 48 h to palmitate was decreased by 35% (P < 0.05) vs. that in control islets, whereas the activity of PDH kinase (which inactivates PDH) was significantly increased in the same preparations (P < 0.05). The effects of ketones were tested by 48-h exposure to beta-hydroxybutyrate (beta-D-OHB). Ten millimoles of D-beta-OHB per L inhibited the subsequently tested insulin response to 27 mmol/L glucose by 56% (P < 0.001). Half-maximal inhibitory effects of D-beta-OHB on insulin secretion and insulin content were seen at concentrations between 0.5-2.5 mmol/L. Inhibition by D-beta-OHB was partially reversed by etomoxir, whereas exposure to D-beta-OHB failed to affect PDH and PDH kinase activities. We conclude that fatty acids as well as ketone bodies diminish B-cell responsiveness to glucose in human islets by way of a glucose-fatty acid cycle. Increased plasma concentrations of fatty acids and ketones are likely to be important factors behind the negative influences on B-cell function exerted by a diabetic state in both type 1 and type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid
  • Adolescent
  • Adult
  • Child
  • Dose-Response Relationship, Drug
  • Epoxy Compounds / pharmacology
  • Fatty Acids / pharmacology*
  • Glucose / pharmacology
  • Humans
  • Hydroxybutyrates / pharmacology
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism*
  • Ketones / pharmacology*
  • Middle Aged
  • Palmitates / pharmacology
  • Proinsulin / biosynthesis
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex / metabolism
  • Time Factors

Substances

  • Epoxy Compounds
  • Fatty Acids
  • Hydroxybutyrates
  • Hypoglycemic Agents
  • Insulin
  • Ketones
  • Palmitates
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex
  • Proinsulin
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Glucose
  • etomoxir
  • 3-Hydroxybutyric Acid