A B S T R A C T A continuous-flow centrifuge was used to infuse sodium salts of oleic, linoleic, lauric, or palmitic acid into the pancreatic artery of anesthetized dogs. In these regional perfusion studies there was no increase in FFA levels in the general circulation. Elevation of pancreatic FFA levels produced an immediate increase in pancreatic venous immunoreactive insulin (IRI). After 10 min of FFA infusion, IRI levels declined somewhat from the initial peak response but soon rose again to high levels which were then sustained until the infusion was terminated. All four long-chain FFA tested produced a similar biphasic IRI response. Clearcut increases in IRI were associated with absolute FFA levels (measured in pancreaticoduodenal venous plasma) as low as 0.6-0.8 Aeq/ml and with increments over basal levels of as little as 0.4-0.5 geq/ml. At higher levels of FFA, absolute IRI levels in the pancreatic venous effluent exceeded 1,000 AU/ml in some experiments and 5-to 10-fold increases over basal values were observed.These studies indicate that long-chain FFA, in physiological concentrations, can markedly stimulate insulin secretion by a direct effect on the pancreas. The results lend support to the concept of insulin as a hormone that is importantly involved in regulating the metabolism of all three principal classes of metabolic substrates and whose release is in turn regulated by all of them. The relative importance and precise nature of its physiologic role in the regulation of lipolysis, lipid deposition, and ketone body formation remains to be established. INTRODUCTIONWe have previously reported that the acute elevation of plasma free fatty acid (FFA) levels by systemic infusion of sodium oleate into conscious dogs was accompanied by a marked increase in immunoreactive insulin (IRI) and a fall in glucose levels in plasma (1). Seyffert and Madison reported similar effects accompanying the elevation of FFA levels produced by infusion of a triglyceride emulsion and injection of heparin into anesthetized dogs with chronic portacaval shunts (2). Sanbar, Evans, Lin, and Hetenyi demonstrated a hypoglycemic effect of octanoate in dogs with increase in plasma insulin levels (3). These studies do not establish whether the elevated FFA levels stimulate insulin release in vivo by a direct effect on the pancreas or whether the effect is indirect (e.g., secondary to metabolic effects in the periphery, effects via other endocrine systems or effects on the nervous system). There is some evidence that FFA may stimulate insulin secretion directly in vitro (4, 5) but other investigators have reported negative results (6, 7). In any case in order to establish physiologic significance it is still necessary to demonstrate effectiveness of FFA in vivo. In the present study, we have examined the nature of the insulin response accompanying infusion of long-chain FFA directly into the pancreatic artery of anesthetized dogs. These infusions raised intrapancreatic FFA levels without significantly increasing plasma FFA concentrati...

A B S T R A C r The acute elevation of plasma free fatty acid (FFA) levels by direct infusion of sodium oleate into the plasma of conscious dogs was accompanied by the rapid onset of a 2-to 12-fold increase in plasma immunoreactive insulin, and, subsequently, a marked fall in plasma glucose, even in dogs receiving intravenous glucose throughout the infusion. The magnitude of both the insulin and glucose responses correlated with the mean FFA level during infusion. A large increase in plasma insulin and fall in glucose also occurred when glycerol was infused with oleate in order to simulate endogenous lipolysis more closely. Insulin levels in pancreaticoduodenal vein blood rose markedly during oleate infusion, while plasma ketone levels rose only slightly.In contrast to the effects of oleate infusion, elevation of plasma FFA to correspondingly high levels by triolein ingestion and intravenous heparin produced only small increases in plasma insulin, which did not correlate well with the FFA level reached, and small increases in plasma glucose.The results indicate that under certain conditions elevated FFA levels may be a potent stimulus of insulin secretion. This response is modified under other conditions such as during chylomicron removal under the influence of heparin. This effect may play a role in the regulation of lipolysis and ketone formation, but determination of the exact mechanism of FFA stimulation of the pancreas and its physiological significance will require further investigation.

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A B S T R A C T We have developed a method for the rapid infusion into plasma of large amounts of longchain free fatty acids (FFA). Unanesthetized dogs were connected by a peripheral artery to a closed, continuousflow centrifuge from which cells and plasma emerged in separate lines. Sodium oleate was infused directly into the plasma line before cells and plasma were recombined and returned to the animal through a peripheral vein.The centrifugation procedure itself produced only small changes in circulating levels of glucose, FFA, and electrolytes. Plasma flow rates as high as 100 ml/min could be maintained, and centrifugations of 12 hr were accomplished without complications.During

By using a continuous-flow centrifuge to separate carotid artery blood into cells and plasma, sodium linoleate was infused into the jugular vein of five conscious dogs at a mean rate of 41.9 μEq. · kg.−1 · min−1 for ninety minutes without adverse side effects. Linoleate infusion quickly elevated plasma free fatty acid (FFA) levels to approximately 1.50 μEq./ml. and was accompanied by a rapid four- to sixfold increase in plasma immunoreactive insulin (IRI) which was sustained throughout the infusion. After thirty minutes of infusion, plasma glucose began to fall, ultimately declining 35 per cent from control levels. Plasma ketone levels rose to twice their control levels during linoleate infusion but were always less than 20 per cent of the ketone levels shown to be insulinogenic in dogs. Upon termination of the infusion, plasma FFA, IRI, and ketones fell quickly to control levels, while plasma glucose rose toward normal. The half-life of plasma linoleate, estimated from the infusion rate and the increment in plasma FFA during steady-state infusion, was 0.76 minute. This result, based on net flux, validates estimates based on tracer experiments. The similarity between the metabolic responses to linoleate infusion and those previously found to oleate suggests that these effects may be common to most physiologic long-chain FFA. Stimulation of insulin secretion by high levels of FFA could thus play a role in modulating lipolytic responses and changes in glucose metabolism accompanying such responses.

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The metabolism of lipoprotein-apoprotein was examined in four subjects with normal lipid metabolism and in one subject with type II hyperlipemia by means of isotopic tracer methodology. Studies were performed after intravenous injection of a radioactive amino acid precursor for apoprotein synthesis (75Se-selenomethionine), in both the basal state and following the acute injection of intravenous heparin. Computer technics were used to evaluate a series of multicompartmental models, and a general model is proposed that yields optimum fitting of experimental data for serum free amino acid precursor, very-low-density lipoprotein-apoprotein (VLD-apoprotein), and low-density lipoprotein-apoprotein (LDL-apoprotein) in man. The analysis demonstrates that approximately half of the transport of 75Se-apoVLDL from the plasma VLDL pool is converted to 75Se-apoLDL. The acute injection of heparin in two normal subjects results in a two-and-a-half-fold increase in this rate of conversion of 75Se-apoVLDL to 75Se-apoLDL. 75Se-apoLDL is metabolized by rapid transport into a recycling extravascular pool and by irreversible catabolism. The fractional rate of recycling is large relative to the fractional rate of catabolism of apoLDL (3.7:1.0), suggesting extravascular recycling as a potential site of regulation of the plasma concentration of apoLDL. In a patient with type II hyperlipemia, the extravascular recycling pathway is reduced and is not corrected with D-thyroxine therapy. However, this therapy did reduce conversion of apoVLDL to apoLDL in this type II patient. The kinetic data support the validity of the compartmental model in simulating both normal and pathologic apoprotein metabolism and that perturbation of physiology seen with heparin injection and D-thyroxine therapy. These data support a quantitative role of apoVLDL as a precursor of apoLDL and identify an important recycling pathway of apoLDL metabolism in addition to that of catabolism.