Intestinal phase of pancreatic polypeptide release: the effect of segmental perfusion of the small intestine with various secretagogues

The purpose of this study was to examine the effect of various nutrients perfused selectively into isolated sections of the small intestine on the release of pancreatic polypeptide (PP). Six dogs were prepared with chronic gastric, duodenal, and three permanent intestinal fistulas (one distal to the ligament of Treitz, one in the terminal ileum, and one halfway between). After a 24-h fast, the duodenum was perfused for 45 min (200 ml/h) via the duodenal limb with HCl (30 mM), an amino acid solution (50 mM), or sodium oleate (NaO, 40 mM). In separate studies, the jejunal and ileal segments were isolated by inflating two balloon catheters via the intestinal fistula, and these segments were perfused as described earlier. Plasma PP, cholecystokinin (CCK)-33, and secretin levels were measured. Results of this study showed that the perfusion of all segments of the small intestine with amino acid caused a significant elevation of plasma PP levels. Perfusion of the duodenum and jejunum but not the ileum with a fatty acid resulted in a significant elevation of plasma levels of PP. Perfusion of HCl into any segment did not affect plasma levels of PP. This study shows that PP is released by the presence of nutrients in all segments of the small intestine, and that a PP elevation was always accompanied with a rise in plasma levels of CCK-33.     

Studies on the localization of secretin release from canine intestine

In conscious dogs with chronic pancreatic fistulas, duodenal perfusion with HCl (16 mmol/h) stimulated pancreatic HCO-3 secretion to a similar degree as exogenous secretin (2 U/kg X h), while meat feeding (500 g) and duodenal perfusion with oleate (16 mmol/h) increased this secretion to about 58 and 43% of the highest response to secretin. Plasma secretin increments with duodenal HCl, feeding and duodenal oleate amounted to about 45, 13 and 8% of that achieved with secretin, producing the highest HCO-3 response. Perfusion of the in situ intestine with HCl at gradually increasing rates produced HCO-3 responses similar to those induced by exogenous secretin in graded doses, but the increments in plasma secretin with duodenal HCl were only about half those obtained with exogenous secretin, producing an equal rate of HCO-3 secretion. HCl perfusion of isolated Thiry loops made of the duodenojejunal portion also stimulated the HCO-3 secretion in a dose-dependent way, but raised plasma secretin only to about half that attained with secretin, producing a similar secretory rate. HCl in the proximal duodenal and distal jejunal loop slightly stimulated the HCO-3 secretion without affecting plasma secretin, and that in the ileal loop was without any effect on the pancreatic or plasma secretin. This study provides evidence that (a) endogenous secretin is released by feeding and duodenal perfusion with HCl and oleate, but only HCl appears to release sufficient amounts of secretin to drive the HCO-3 secretion, and (b) the release of secretin is confined mainly to the distal duodenum and proximal jejunum.     

Jejunal brake

Optimal absorption of fat requires adequate time of contact with the absorptive sites of the small intestine. In order to prevent steatorrhea, intestinal transit must be slowed in response to the fat that has emptied into the small intestine. Intestinal transit is known to be inhibited by fat in the ileum via the ileal brake. This response has suggested that the regulation of intestinal transit is a function of the distal small intestine. However, clinical observations suggest that the ileal brake is not the only control mechanism for intestinal transit. In short bowel patients with resection of the ileum, the proportion of fecal fat recovery remained constant even after the fat intake was increased threefold. In these patients, optimal fat absorption based on the slowing of intestinal transit must have been triggered by an inhibitory mechanism located outside of the distal small intestine. To test the hypothesis that fat in the proximal small intestine inhibited intestinal transit, we compared intestinal transit during perfusion of the proximal half of the small intestine with 0 (buffer only), 15, 30, or 60 mM oleate in dogs equipped with duodenal and mid-intestinal fistula. Intestinal transit across a 150-cm test segment (between fistulas) was measured by counting for the recovery of a radioactive marker in the output of the mid-intestinal fistula during the last 30 min of a 90-min perfusion. We found that oleate inhibited intestinal transit in a load-dependent fashion (P<0.005). Specifically, while the mean cumulative recovery of the transit marker was 95.5% during buffer perfusion, the recovery decreased when 15 mM (64.3%), 30 mM (54.7%), or 60 mM oleate (38.7%) was perfused into the proximal half of the small intestine. We conclude that fat in the proximal small intestine inhibits intestinal transit as the jejunal brake.     

Intestinal Transit Is More Potently Inhibited by Fat in the Distal (Ileal Brake) than in the Proximal (Jejunal Brake) Gut

Fat in the proximal and distal gut inhibitsintestinal transit as the jejunal brake and the ilealbrake. It is unknown, however, whether the intestinaltransit response to fat in the proximal vs distal gut is different. Since surgical removal of thedistal small intestine induced faster transit andgreater steatorrhea than removal of the proximal smallintestine, we hypothesized that the ileal brakeinhibited intestinal transit more potently than thejejunal brake. In six dogs equipped with duodenal (10 cmfrom pylorus) and midintestinal (160 cm from pylorus)fistulas, we compared intestinal transit across an isolated 150-cm test segment (betweenfistulas), while 0 (buffer), 15, 30, or 60 mM oleate wasdelivered into either the proximal (between fistulas) orthe distal (beyond the midintestinal fistula) half of the gut. The half of the gut not receivingoleate was perfused with buffer. Buffer perfused intoboth the proximal and the distal half of the gut servedas the control. A meal was administered and diverted completely out of the duodenal fistula so thatthe studies were all done in the fed state. Intestinaltransit was measured by counting for the recovery of aradioactive marker from the temporarily diverted output of the midintestinal fistula. We foundthat (1) intestinal transit was inhibited more potentlyby oleate in the distal than in the proximal half of thegut (region effect; P < 0.01), (2) oleate inhibited intestinal transit in a load-dependent fashion(dose effect; P < 0.05), and (3) load-dependentinhibition of intestinal transit by oleate depended onthe region of exposure (interaction between load and region; P < 0.01). We conclude that intestinaltransit is more potently inhibited by fat-induced ilealthan jejunal brake.     

Hormonal control of pancreatic secretion by intrajejunal HCl: studies in dogs with an autotransplanted entire jejunoileum.

To elucidate the role of hormones in the control of pancreatic secretion, we developed, in seven dogs, a model of total extrinsic denervation of the jejunoileum by autotransplanting this segment of bowel. A Thomas-like cannula was placed into the stomach, the duodenum (to collect pure pancreatic juice), and the proximal part of the jejunum. Thus, intestinal stimulants could only stimulate the pancreas via release of humoral (= hormonal) mediators. Seven control dogs received only the three fistulas. After recovery, dose-response curves of pancreatic bicarbonate and protein response to perfusion of the extrinsically denervated or innervated jejunoileum with HCl (1.5 to 48 mmol h-1) were performed with and without atropine (14 nmol kg-1 h-1 i.v.). Plasma levels of secretin were determined by radioimmunoassay. The maximal bicarbonate output occurred in response to 24 mmol h-1 of HCl and was significantly (p less than 0.05) higher in intact as compared to denervated animals. Atropine only significantly depressed the bicarbonate response to HCl in dogs with a denervated jejunoileum. HCl caused a dose-dependent increase in plasma levels of secretin, which was not altered by denervation and/or atropine. Irrespective of the innervation of the small bowel, pancreatic protein output was only significantly stimulated above basal when high loads (12-48 mmol h-1) of HCl were given. Atropine significantly reduced these responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma Gastrin and Gastric Secretory Response to Duodenal Perfusion with Liver Extract in Healthy Human Subjects

The stomachs of 8 healthy volunteers were intubated with a Levine tube under radiological control. In addition, a thin polyethylene tube was placed in the proximal duodenum. After a 1-hour period with no perfusion, the duodenum was perfused for two hours with 15% liver extract (LE) (pH 4.5-5.5; 1027 mosm/kg water) at a rate of 100 ml/hour either alone or in combination with intravenous infusion of different doses of exogenous pentagastrin. All subjects were also tested with the tubes in place for 3 hours, but with no perfusion or pentagastrin. Reflux to the stomach was monitored by addition of radio-activeB₁₂ to the perfusates. Plasma gastrin, gastric acid, and pepsin were measured in 15-minute periods. During perfusion of the proximal duodenum, where reflux of the perfusates was less than 4%, only a slight and inconstant change in plasma gastrin was seen. Gastric acid and pepsin outputs were increased to approx. 18% and 25% of the maximal pentagastrin stimulation respectively. Whereas 15% LE was shown to release gastrin by antral perfusion however, such release was not found by duodenal perfusion, except where reflux to the antrum was seen. The results suggest that intestinal stimulation of gastric secretion exists, but has not been found to be gastrin dependent in the present investigation.     

Pancreatic bicarbonate response to food-bound hydrogen ion along the gut

Recent reports suggest most solid food enters the duodenum as small particles. Our studies showed that small particles of liver were capable of binding hydrogen ions (H+), but there was slow equilibration of H+ between particulate and aqueous phases. We wondered whether titratable acid as H+ bound to meat particles could effectively stimulate pancreatic bicarbonate secretion despite slow diffusion. We studied mongrel dogs with chronic pancreatic fistulas; the intestinal lumen was washed free of endogenous pancreatic enzymes. Pancreatic bicarbonate and protein responses were measured during duodenal perfusion with pH 2 or pH 3 gels that delivered 1, 2, or 4 mEq/15 min of titratable acid (endpoint pH 4.5). Gels consisted of acidified, 0.1-0.7-mm particles of beef liver or bovine serum albumin or lactic acid suspended with 2% starch in 0.15 M NaCl. The liver, bovine serum albumin, and lactate had similar titration curves. At pH 2 or pH 3, liver particles were about as effective as bovine serum albumin in stimulating pancreatic bicarbonate secretion. Likewise, pH 3 liver particles were equipotent with pH 3 lactate on pancreatic bicarbonate secretion when both perfusates were allowed access to the whole intestine. However, when confined to the first 45 cm of proximal intestine, much less H+ was dissipated from the liver versus the lactate; and, correspondingly, there was a much greater decrement in pancreatic bicarbonate secretion from whole gut responses with liver versus lactate. We conclude that titratable acid bound to solid food particles is a potent stimulus of pancreatic bicarbonate secretion despite its slow diffusion. Our studies suggest that H+ slowly diffusing from particles excites pancreatic bicarbonate secretion by triggering H+ receptors along more distal intestine.     

Induction and maintenance of mucosal enterokinase activity in proximal small intestine by a genetically determined response to mediated sodium transport

Mucosal enterokinase activity was established at intervals throughout the small intestine in guinea-pigs; maximum activity was present in the duodenum and proximal jejunum in new born as well as adult animals. Transposition of 5 cm lengths of small gut from the high enterokinase containing proximal region to the distal intestine and vice versa showed that mucosal enterokinase activity in the transposed segments was little changed after several weeks of healthy life. Isolation of proximal jejunal loops from luminal continuity resulted in the fall of mucosal enterokinase activity to minimal levels within 16 hours. Low levels of mucosal enterokinase activity were identified in loops of both proximal and distal jejunum 12 weeks after isolation. Luminal perfusion studies in vivo in proximal jejunal loops 24 hours after isolation showed that mucosal enterokinase activity could be restored to near normal levels within four to six hours by luminal sodium in the presence of active pancreatic endopeptidases, oligopeptides, L-amino acids, or D-glucose but not D-amino acids or D-fructose. Near normal mucosal enterokinase activity persisted in the loops for as long as luminal perfusion with 144 mM sodium and L-lysine or trypsin was maintained (24 hours). The time course of the restoration of mucosal enterokinase activity was compatible with an initial precursor activation as well as biosynthesis. The requirement for luminal sodium appeared to be absolute regardless of the co-substrate and supports the conclusion that mucosal enterokinase activity is dependent on mediated sodium transport. The ability of proximal intestinal enterocytes to respond to sodium flux with an increase in enterokinase activity is a property determined in intrauterine life: distal intestinal enterocytes may have functioning structural genes for enterokinase but appear to be unable to respond.     

Adrenergic pathway in the inhibition of pancreatic secretion by peptide YY in dogs

Peptide YY (PYY) is released by perfusion of an ileocolonic segment with oleate and inhibits exocrine pancreatic secretion. This study was designed to determine the role of the adrenergic pathway in the PYY-induced inhibition of pancreatic secretion. After intravenous administration of PYY, there was a dose-dependent inhibition of pancreatic HCO3 and protein responses to secretin, cholecystokinin, and feeding in conscious dogs and a reduction in pancreatic blood flow in anesthetized animals. These inhibitory effects of PYY on pancreatic secretion and blood flow were abolished in the presence of combined phentolamine and propranolol. Ileal perfusion with oleate caused a rise in plasma PYY levels similar to that observed after intravenous infusion of exogenous PYY. Combined alpha- and beta-adrenergic blockade also antagonized the effects of ileal perfusion with oleate on hormonal and postprandial pancreatic secretion. We conclude that exogenous PYY or endogenous PYY released by ileal oleate inhibits pancreatic secretory responses to exogenous secretin, cholecystokinin, or a meal and causes pancreatic vasoconstriction. Both these effects are mediated, at least in part, by the adrenergic pathway.     

Effect of duodenal fat on plasma levels of gastrin and secretin and on gastric acid responses to gastric and intestinal meals in dogs.

The effects of duodenal instillation of sodium oleate (10 mmoles per hr) on plasma levels of gastrin and secretin and on gastric acid secretion in response to gastric and intestinal meals were determined. Four dogs prepared with a septum between stomach and duodenum were provided with a special cannula that allowed separate access to the stomach or duodenum. Each dog received a 10% liver extract meal introduced either into the stomach (gastric phase) or into the duodenum (intestinal phase). Sodium oleate administered during the gastric phase caused approximately a 30% reduction in plasma gastrin level and a 25% inhibition of gastric acid secretion. Sodium oleate given during the intestinal phase completely abolished the plasma gastrin response and resulted in a 75% inhibition of gastric acid secretion. Plasma secretin levels were not changed during the gastric phase or the intestinal phase by instillation of sodium oleate. These results show that fat in the duodenum is a potent inhibitor of gastrin release and gastric acid secretion; the intestinal mechanism involved does not appear to affect plasma secretin concentrations.     

In vivo absorption of medium-chain fatty acids by the rat colon exceeds that of short-chain fatty acids

BACKGROUND AND AIMS: Short-chain fatty acids (SCFAs) are main fuels of the colonic epithelium, and are avidly absorbed by the colon of animal and man. The current knowledge on colonic metabolism and absorption of medium-chain fatty acids (MCFAs) is limited. In some clinical situations, colonic absorption of high-energy substances could compensate for reduced absorptive capacity because of a shortened or malfunctioning small bowel. We evaluated and compared colonic absorption and metabolism of MCFAs (octanoate, decanoate, and dodecanoate), SCFAs (acetate and butyrate), and long-chain fatty acids (LCFAs) (oleate). METHODS: Rats were surgically operated on to cannulate a 7-cm segment of proximal colon, isolate the vasculature, and cannulate the right colic vein draining this segment. The lumen was perfused with (14)C-labeled substrates for 100 minutes. Right colic vein blood was analyzed for total (14)C, (14)CO(2), and metabolites by scintillation counting and high-performance liquid chromatography. RESULTS: The transport from the colonic lumen to mesenteric blood of substrate carbon from MCFAs exceeded by 2-13-fold that of SCFAs and LCFAs. The CO(2) production from the oxidation of MCFAs was as high as or higher than that from SCFAs. CO(2) produced from the LCFA, oleate, was lower than from SCFAs or MCFAs. In addition to CO(2), ketone bodies were major metabolites of SCFAs and MCFAs. Ketogenesis from butyrate and the MCFAs was significantly higher than from acetate and oleate. A substantial proportion (50%-90%) of all substrates was absorbed without being metabolized. CONCLUSIONS: The colonic epithelium serves to absorb and partially metabolize MCFAs. For patients with a compromised small-bowel function, colonic absorption of MCFAs could represent an important way of receiving calories.     

Comparison of gastric secretory response in man to duodenal and jejunal liver extract perfusion.

The stomachs of six healthy volunteers were intubated with a Levine tube. In addition, a thin polyethylene tube was placed in the proximal jejunum or in the proximal duodenum. After a 1-h period with no perfusion the intestine was perfused for 2 h with 7% liver extract (LE) (pH 5.5; 380 MOsm/kg water) at a rate of 100 ml/h. In control tests 200 ml of 0.9% physiologic saline solution were used as perfusate. Reflux to the stomach was determined by addition of radioactive B12 to the perfusates. Plasma gastrin, gastric acid, and pepsin levels were measured in 15-min periods. During perfusion of the proximal jejunum only pepsin outputs were increased significantly. During duodenal perfusion of LE, gastric acid and pepsin outputs were increased to 31% and 73% of maximal pentagastrin stimulation, respectively. Controls showed no changes in gastric secretion. Plasma gastrin levels were not elevated after jejunal or duodenal perfusion. These results confirm that the intestinal phase of gastric secretory stimulation does exist in humans. Furthermore, it appears that the major portion of this stimulation originates from the duodenum and is not gastrin-dependent.     

Increased canine jejunal absorption of water,glucose, and sodium with intestinal pacing

Our aim was to determine if pacing a segment of jejunum backwards with electrical stimuli could increase absorption from it. In four dogs, 75-cm loops of jejunum were isolated from the intestinal stream. After recovery, fluid was infused into the proximal stoma of the loop and effluent collected from the distal stoma for three consecutive 30-min periods. In the second period electrical stimuli were applied to the distal end of the loop to drive the pacesetter potentials of the loop, hence its contractions, backwards. The output of water, glucose, and sodium from the loop was decreased, and the transit of content through the loop was slowed during backward pacing. We conclude that pacing a segment of jejunum backwards with electrical stimuli enhances absorption of water, glucose, and sodium from that segment.An abstract of this work has been published in Surgical Forum 28:428–430, 1977.Research support: USPHS Grants AM 18278, AM 6908; and Wellcome Foundation.     

Gastrointestinal function in obesity: motility, secretion, and absorption following a liquid test meal.

Digestive responses to a 300-mL liquid fat-rich meal (432 kcal) in a group of massively obese patients were compared with those observed in a group of healthy lean subjects of variable body weight. Gastric and intestinal propulsion, digestive secretions, and absorption in the proximal 70 cm of intestine were measured using a multiple-marker dilution method. The average gastric emptying of energy, acid, volumes, and meal marker were similar in the two groups 80 minutes after intake, justifying a comparison of intestinal processing of the meal. Compared with lean subjects, the obese subjects responded with less pancreatic secretion (P less than .05) and gallbladder emptying, but absorbed a larger proportion of the emptied energy in the test segment (P less than .01) during a similar or shorter transit time. In addition, when the entire meals were compared, the obese group generally absorbed the test meal more effectively and rapidly in the upper part of the intestine. As a consequence, the flow volumes at the exit of the test segment were lower (P less than .05), and less of the test meal was propulsed to distal parts of the intestine. In the lean subjects, the body weight or height correlated positively with the gastric emptying rate, peak gastric acid output, and pancreatic responses, and negatively with (P less than .05) the segment transit time. The taller the subject, the greater the proportion of the meal which was rapidly propulsed unabsorbed to lower parts of the intestine, indicating that a large intestinal area was exposed for rapid energy uptake. No such correlations were observed in the obese group.     

Effect of dietary fat on the small intestinal mucosa.

The presence of food within the small intestinal lumen promotes mucosal cell proliferation. To define the trophic role of triglycerides, three groups of eight female Wistar rats were isocalorically fed for four weeks with either Vivonex, or Vivonex with 50% calorie substitution with an essential fatty acid mixture, or Vivonex with 50% calorie substitution with a saturated fatty acid mixture. Although Vivonex caused greater body weight gain, both essential fatty acids and saturated fatty acids increased small intestinal weight, mucosal weight, protein and DNA overall, and in each of three intestinal segments (proximal, middle and distal), compared with Vivonex. Mucosal indices were similar for essential fatty acids and saturated fatty acids. These results show that triglycerides, regardless of essential fatty acid content, are trophic to the rat small intestinal mucosa.     

Selective inhibition of fatty acid oxidation in colonocytes by ibuprofen: a cause of colitis?

Ibuprofen is associated with initiation or exacerbation of ulcerative colitis. As ibuprofen selectively inhibited fatty acid oxidation in the liver or caused mitochondrial damage in intestinal cells, its effect on substrate oxidation by isolated colonocytes of man and rat was examined. Ibuprofen dose dependently (2.0-7.5 mmol/l) and selectively inhibited 14CO2 production from labelled n-butyrate in colonocytes from the proximal and distal human colon (n = 12, p = < 0.001). Glucose oxidation was either unaltered or increased. Because short chain fatty acid oxidation is the main source of acetyl-CoA for long chain fatty acid synthesis, the inhibition of prostaglandin synthesis by ibuprofen in the colonic mucosa could also occur at this level. Because the concentrations of ibuprofen that can be attained in the human colon are not known, conclusions drawn from current dosages are tentative. The inhibition of fatty acid oxidation by ibuprofen may be biochemically implicated in the initiation and exacerbation of ulcerative colitis, manifestation of which would depend on the ibuprofen concentrations reached in the colon.     

Reaction of human small intestine to an intraluminal tube and its importance in jejunal perfusion studies

A double-lumen tube with a mercury weight attached to its distal end was positioned in the small intestine of six subjects who were to undergo an elective laparotomy. The tube and the technique for its localization were exactly similar to those used in previous intestinal perfusion experiments.Marked ;concertinaing', or gathering of the small intestine proximal to the mercury weight, was seen at laparotomy in all six subjects. The ratio between the mean intestinal length from the mercury weight to the ligament of Treitz after removal of the tube to that with the tube in situ was 3.0 (2.5-3.8). Mean total jejuno-ileal length was 421 (320-521) cm. In five of the six subjects the distal end of the tube was more than half way between the ligament of Treitz and the ileo-caecal valve although it was only 100-120 (mean 108) cm from the incisor teeth.Segmental perfusion studies of the human jejunum involve a much longer length of small intestine than is generally assumed-by a factor of approximately 3. Such studies assess absorption rates over a substantial proportion of the small intestine and are not confined to a short segment of proximal jejunum. The nutritional significance of such studies in which amino acids, peptides, and carbohydrates are investigated is increased. Studies designed to measure absorption rates from the ileum should be treated with caution as part or all of the perfusion segment may be past the ileo-caecal valve.     

Intracolonic fat inhibits gastric acid secretion independent of gastrin release in the dog

The purpose of this study was to examine the effect of perfusion of the colon with a fatty acid (oleic acid) on peptone-stimulated gastric acid secretion and release of gastrin in conscious dogs. Gastric acid secretion was monitored by continuous intragastric titration. Perfusion of the colon with sodium oleate (24 mmol/hr) inhibited gastric acid secretion (14.2±2.6 meq/hr) stimulated by a peptone meal (1%) significantly (P<0.05) when compared to perfusion of the colon with saline alone (20.1±1.6 meq/hr). The serum elevation, in gastrin in response to intragastric instillation of the peptone meal was not affected by the colonic perfusion of oleic acid. Plasma concentrations of peptide YY (PYY) increased significantly in response to perfusion of the colon with saline or sodium oleate, and the integrated release of PYY in response to sodium oleate 16.9±2.8 ng (60–120) min/ml] was significantly greater than the response to saline [3.1±0.7 ng (60–120) min/ml]. The results of this study indicate that inhibition of gastric acid secretion by perfusion of the colon with fat is not due to an inhibition of gastrin release. In addition, because PYY is an inhibitor of gastric acid secretion, it is possible that PYY participates as an inhibitor of gastric acid secretion by the colon.Supported by grants from the National Institutes of Health (5R37 DK 15241, P01 DK 35608) and a NATO collaborative research grant (0014/89).     

Intraluminal calcium binding does not mediate fatty acid-induced pancreatic bicarbonate secretion

Since the chain length dependency of fatty acid-induced pancreatic exocrine secretion parallels that of fatty acid-induced inhibition of gastric emptying, similar mechanisms of action may be involved. An earlier study suggested that binding of calcium might mediate fatty acid-induced inhibition of gastric emptying. This study investigated possible mediation of fatty acid-induced pancreatic secretion by calcium binding. Pancreatic secretory response to intraduodenal administration of dodecanoate and various calcium chelators (sodium EDTA, calcium-saturated EDTA, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, and sodium taurocholate) was studied in three dogs equipped with chronic pancreatic fistulae. Calcium affinity of the various test solutions was quantitated by titrating aliquots of perfusate against a standard CaGl₂ solution. Sodium EDTA was found to be the most potent calcium binder (pK_c 8.3); sodium dodecanoate, sodium dodecyl sulfate, and sodium dioctyl sulfosuccinate were moderate calcium binders (pK_c 7.3, 7.2, 6.9, respectively), whereas sodium taurocholate and calcium-saturated EDTA were poor calcium binders. Sodium dodecanoate evoked brisk bicarbonate output (0.6-1.6 mEq/15 min). Minimal secretory responses were observed in response to all other agents tested. These findings suggest that calcium binding is not involved in mediation of fatty acid-induced pancreatic bicarbonate secretion.     

Unbound rather than total concentration and saturation rather than unsaturation determine the potency of fatty acids on insulin secretion.

Isolated mouse islets were used to compare the effects of three saturated (myristate, palmitate and stearate) and three unsaturated (oleate, linoleate and linolenate) long-chain fatty acids on insulin secretion. By varying the concentrations of fatty acid (250-1250 micromol/l) and albumin simultaneously or independently, we also investigated whether the insulinotropic effect is determined by the unbound or total concentration of the fatty acids. Only palmitate and stearate slightly increased basal insulin secretion (3 mmol/l glucose). All tested fatty acids potentiated glucose-induced insulin secretion (10-15 mmol/l), and the following rank order of potency was obtained when they were compared at the same total concentrations: palmitate approximately = stearate > myristate > or = oleate > or = linoleate approximately = linolenate. The effect of a given fatty acid varied with the fatty acid to albumin molar ratio, in a way which indicated that the unbound fraction is the important one for the stimulation of beta cells. When the potentiation of insulin secretion was expressed as a function of the unbound concentrations, the following rank order emerged: palmitate > myristate > stearate approximately = oleate > linoleate approximately = linolenate. In conclusion, the acute and direct effects of long-chain fatty acids on insulin secretion are due to their unbound fraction. They are observed only at fatty acid/albumin ratios higher than those normally occurring in plasma. Saturated fatty acids are stronger insulin secretagogues than unsaturated fatty acids. Unbound palmitate is by far the most potent of the six common long-chain fatty acids.