Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.
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.
Zhou
Y P
YP
Department of Endocrinology, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
Grill
V E
VE
D000818:Animals; D002210:Caprylates / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004852:Epoxy Compounds / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007651:Keto Acids / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000494:pharmacology; D011384:Proinsulin / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002210:Caprylates; D004852:Epoxy Compounds; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D007651:Keto Acids; D009829:Oleic Acids; D010169:Palmitic Acids; D011506:Proteins; D019301:Oleic Acid; D019308:Palmitic Acid; D000431:Ethanol; C013082:alpha-ketoisocaproic acid; D011384:Proinsulin; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; C054207:etomoxir; C031492:octanoic acid