Short- and long-term effects of hyperlipidemia with elevated FFA on insulin secretion were investigated. Male Sprague-Dawley rats were fed ad libitum and additionally infused with Intralipid 10%, 1.0 ml/h. After 3 h of Intralipid the response to 27 mM glucose in isolated perfused pancreas was enhanced by 86%, P < 0.02. After 6 h of Intralipid enhancement had subsided. After 48 h of Intralipid glucose-induced insulin release was inhibited by 49%, from 1950 ± 177 μU/min after saline to 1003 ± 232 μU/min after Intralipid, P < 0.02. Inhibition was glucoseselective since responses to other secretagogues (1 mM 3-isobutyl- 1 methylxanthine, 10 mM octanoate, or 5 mM a-ketoisocaproic acid) were unaffected as were pancreatic contents of insulin (2284 ± 111 mU/pancreas after saline, 2566 ± 131 mU/pancreas after Intralipid).

In isolated islets from 48 h lipid infused rats production of [14-C]CO₂ from D[U-14-C]glucose was decreased (P < 0.02) in parallel with the insulin response to 27 mM glucose. Glucoseinduced secretion was partially normalized by in vitro exposure to a carnithine palmitoyl-transferase I inhibitor (Etomoxir).

Effects of a 48 h lipid infusion were also tested during hyperglycemia. Rats were infused with glucose, and hyperglycemia was enhanced by dexamethasone (25 Mg/24 h). Hyperglycemia depressed glucose-induced secretion from perfused pancreas from 2072 ± 22 /uU/min after saline + dexamethasone to 1185 ± 155 μU/min after glucose + dexamethasone, P < 0.01). Intralipid, added to the latter protocol, further inhibited glucoseinduced secretion to 437 ± 87 /ttU/min, P < 0.005.

Hyperlipidemia is concluded to be associated with short term stimulation but long term inhibition of glucose-induced insulin secretion. Evidence indicates that inhibition depends on fatty acid oxidation, is coupled to decreased glucose oxidation and operates both during normo- and hyperglycemia. (Endocrinology127: 1580–1589, 1990)