title: Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans.
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.
authors.affiliation: Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: Y P
authors.initials: YP
authors.lastname: Zhou
authors.forename: V
authors.initials: V
authors.lastname: Grill
mesh_terms: D020155:3-Hydroxybutyric Acid; D000293:Adolescent; D000328:Adult; D002648:Child; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology*; D008875:Middle Aged; D010168:Palmitates / Q000494:pharmacology; D011384:Proinsulin / Q000096:biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D013997:Time Factors
chemical_list: D004852:Epoxy Compounds; D005227:Fatty Acids; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents; D007328:Insulin; D007659:Ketones; D010168:Palmitates; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D011384:Proinsulin; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; C054207:etomoxir; D020155:3-Hydroxybutyric Acid