Effect of exogenous and endogenous insulin on the secretory response of the pancreas to the octapeptide of cholecystokinin (CCK8) in normal rats

The author studied the effect of insulin on CCK8-stimulated secretion by the pancreas. CCK8 (0.6 nmol.kg-1) was administered to normal anaesthetized rats 30 min after the intravenous injection of insulin (10 U.kg-1), glucose (2 g.kg-1) or NaCl (controls). Pancreatic juice was collected from the intubated common bile duct. In rats given exogenous insulin, there were no statistically significant differences in total protein, amylase and trypsinogen output after CCK8 compared with the controls. In rats in which endogenous insulin secretion was stimulated with glucose, the amylase response to CCK8 was not significantly different from the control animals, but the trypsinogen response was significantly lower. The results show that insulin, in some still unknown manner, inhibits the trypsinogen secretory response to CCK8. In addition, they confirm data claiming that the synthesis and secretion of pancreatic amylase require a given critical ratio of insulin to glucose, or of insulin to the factor stimulating pancreatic secretion.     

吗啡成瘾大鼠胰腺外分泌的变化

本实验采用急性吗啡成瘾法,观察了吗啡成瘾大鼠在整体胰导管引流和离体胰片灌流条件下,胰腺对ＣＣＫ８刺激的反应。结果如下：（１）吗啡成瘾大鼠对ＣＣＫ８诱导的淀粉酶分泌反应降低;（２）吗啡成瘾大鼠胰腺组织中淀粉酶含量降低。提示吗啡成瘾大鼠胰淀粉酶合成受到抑制。     

Glucocorticoids effects on exocrine pancreatic secretion in caerulein-induced acute pancreatitis in the rat.

The present work reports on exocrine pancreatic secretion in control rats, adrenalectomized rats and hydrocortisone-treated (10 mg/Kg/d) rats during 7 days, under normal conditions and after induction of acute pancreatitis with caerulein (20 micrograms/Kg) by 4 subcutaneous injections at hourly intervals. Pancreatic secretion was seen to be affected by the procedure of adrenalectomy, which led to a marked reduction in the secretion of proteins and amylase with respect to control values. This was probably due to the decrease occurring in the zymogen granules in the acinar cells of the exocrine pancreas, a phenomenon which also led to a decrease in pancreatic weight observed in these animals. Treatment with hydrocortisone induced a decrease in the secretion of proteins and amylase, as well as an increase in pancreatic weight. This agrees with the accepted hypothesis that large amounts glucocorticoids stimulate the synthesis and storage of proteins in the exocrine pancreas, reducing the secretory phase. The administration of high doses of caerulein under these conditions led to acute pancreatitis in the three groups of animals. This was paralleled by a dramatic decrease in protein and amylase secretion and by severe interstitial edema of the pancreas and by increases in serum amylase values. In the case of the animals treated previously with hydrocortisone, the latter were tripled with respect to the control animals. The conclusion is offered that since the storage of enzyme proteins is governed by glucocorticoids, which furthermore increase the sensitivity of the acinar cells to stimulation by secretagogues, the administration of these substances during the development of pancreatic lesions such as acute pancreatitis is highly compromising to the organism.     

Changes in parotid acinar cells accompanying salivary secretion in rats on sympathetic or parasympathetic nerve stimulation

Morphological and secretory effects of stimulating autonomic nerves have been studied in parotid glands of rats. Sympathetic stimulation evoked a slow flow of saliva which had a high concentration of amylase. After long term sympathetic stimulation secretory granules were heavily depleted from the parotid acinar cells. Parasympathetic stimulation evoked a copious flow of saliva with a low concentration of amylase. However, at high frequency stimulation the total amount of amylase secreted on parasympathetic stimulation was as great or even greater than on symphatetic stimulation, nevertheless, any loss of secretory granules from the acinar cells was very small. It is concluded that secretion of parotid acinar granules in the rat is prinicipally a sympathetic function. Secretion of fluid is more effectively produced by parasympathetic stimulation and much of the amylase in such saliva appears to have arisen from sources other than the secretory granules.     

Lowering of pancreatic amylase activity induced by cold exposure, fasting and adrenalectomy in rats.

1. Alteration of amylase activity in the pancreas was studied in rats under different stressful situations. 2. Cold-exposed rats had reduced amylase activity, hypertrophy of adrenal glands, and lowered plasma insulin and glucose. 3. In fasted rats, amylase activity decreased and plasma insulin and glucose lowered. 4. Immobilized animals failed to produce the reduced amylase activity, despite existence of higher plasma corticosterone. 5. Adrenalectomy caused reduction of amylase activity accompanied by decreases in plasma insulin and glucose. 6. Glucocorticoid hormone is not correlated with suppression of amylase synthesis. The lowered amylase activity might involve changes in glycolytic flux and/or suppression of amylase synthesis by insulin deficiency.     

Parasympathetic non-adrenergic, non-cholinergic transmission in rat parotid glands: effects of cholecystokinin-A and -B receptor antagonists on the secretory response

Recent studies show i.v. administered pentagastrin and cholecystokinin to evoke protein/amylase secretion from the rat parotid gland and to stimulate gland protein synthesis, the two phenomena being abolished by cholecystokinin receptor antagonists. In the rat parotid gland, non-adrenergic, non-cholinergic transmission mechanisms contribute to secretion of fluid and protein/amylase. Since cholecystokinin may act as a neurotransmitter, activation of cholecystokinin receptors of the gland might contribute to the parasympathetic nerve-evoked secretion. In this study, the parasympathetic innervation was stimulated in non-atropinized (in periods of 2 min) or atropinized (in periods of 3 min) pentobarbitone-anaesthetized rats before and after administration of the cholecystokinin-A receptor antagonist lorglumide (48 mg/kg, i.v.) and the cholecystokinin-B receptor antagonist itriglumide (5.5 mg/kg, i.v.). The non-adrenergic, non-cholinergic transmission fatigues rapidly resulting in declining responses. Therefore, atropinized rats, not receiving the cholecystokinin receptor antagonists, had to serve as controls. Neither at a stimulation frequency of 10 Hz nor of 40 Hz were the secretory responses of the atropinized rats affected by the receptor antagonists. After lorglumide, the saliva volume and the amylase output were (expressed as percentage of the response to the stimulation period before the administration of the antagonist) 98.0+/-3.8% (vs. control 91.1+/-4.0%) and 91.9+/-4.9% (vs. 87.7+/-3.7%) at 10 Hz, respectively, and 79.8+/-4.5% (vs. 77.3+/-2.1%) and 73.6+/-5.3% (vs. 71.7+/-2.3%) at 40 Hz, respectively. After itriglumide, the corresponding percentage figures for saliva volume and amylase output were, at 10 Hz, 99.5+/-8.9% (vs. 92.0+/-2.8%) and 95.8+/-11.8% (vs. 89.2+/-6.4%), respectively, and, at 40 Hz, 74.0+/-3.1% (vs. 79.6+/-2.2%) and 66.6+/-3.3% (vs. 63.9+/-6.0%), respectively. Similarly, the antagonists were without effect on the parotid secretory responses of non-atropinized rats subjected to stimulation at 10 Hz. Thus, under physiological conditions, the cholecystokinin receptors of the parotid gland are likely to be stimulated by circulating hormones rather than by nervous activity.     

Hormonal stimulation in the exocrine pancreas results in coordinate and anticoordinate regulation of protein synthesis

24-h intravenous caerulein infusion studies in the rat were combined with in vitro amino acid incorporation studies followed by high-resolution separation of proteins by two-dimensional isoelectric focusing and SDS gel electrophoresis to study the extent to which persistent changes in the biosynthesis of exocrine pancreatic proteins are regulated by cholecystokinin-like peptides. Beginning in the third hour of optimal hormone infusion at 0.25 microgram kg-1 h-1, changes were observed in the synthetic rates of 12 proteins, which progressed over the course of the 24-h study. Based on coordinate response patterns, exocrine proteins could be classified into four distinct groups. Group I (trypsinogen forms 1 and 2) showed progressive increases in synthetic rates reaching a combined 4.3-fold increase over control levels. Group II (amylase forms 1 and 2) showed progressive decreases in synthesis to levels 7.1- and 14.3-fold lower than control levels, respectively. Group III proteins (ribonuclease, chymotrypsinogen forms 1 and 2, procarboxypeptidase forms A and B, and proelastase 1) showed moderate increases in synthesis, 1.4-2.8-fold, and group IV proteins (trypsinogen 3, lipase, proelastase 2, and unidentified proteins 1-4) did not show changes in synthesis with hormone stimulation. Regulation of protein synthesis in response to caerulein infusion was specific for individual isoenzymic forms in the case of both trypsinogen and proelastase. The ratio of biosynthetic rates of trypsinogen forms 1 + 2 to amylase forms 1 + 2 increased from a control value of 0.56 to 24.4 after 24 h of hormonal stimulation (43.5-fold increase). Biosynthetic rates for an unidentified protein (P23) with an Mr = 23,000 and isoelectric point of 6.2 increased 14.2-fold, and the ratio of synthesis of P23 to amylase 2 increased 200-fold during caerulein infusion. During hormone stimulation the anticoordinate response in the synthesis of pancreatic glycosidases (decreased synthesis) and serine protease zymogens (increased synthesis) explain previous observations that showed little change in rates of total protein synthesis under similar conditions.     

Effects of inverse changes in dietary lipid and carbohydrate on the synthesis of some pancreatic secretory proteins

The effect of ingesting isocaloric and isonitrogenous diets with increasing amounts of lipid (0-30%) and consequently decreasing amounts of carbohydrates (68.7-1.25%) on the exocrine pancreas was studied in adult male Wistar rats. Pancreatic contents of chymotrypsin, lipase and colipase activity, as well as synthesis of amylase, lipase, procarboxypeptidases and individual serine proteases were examined. Lipid-free diets and diets containing 1% lipid were found to have little effect on pancreatic proteins as compared with lipid-rich diets where two distinct patterns of response were observed. Ingestion of diets containing 3-20% lipid resulted in a progressive increase in the activity of lipase, colipase and chymotrypsin up to 2-fold in the first case and 1.6-fold in the two other cases when animals were fed the 20% fat diet. Under the latter conditions, the relative synthesis of secretory proteins, as expressed as percentage of the radioactivity incorporated into individual proteins compared to that incorporated into the total mixture of exocrine proteins, was unchanged for procarboxypeptidases, whereas it was stimulated for lipase (2-fold) and serine proteases (1.6-fold). Amylase relative synthesis progressively decreased as the lipid content of diets increased. Consumption of hyperlipidic diets containing 25% and 30% fat resulted in a further enhancement in the activity of lipase and colipase in the gland in contrast with chymotrypsin activity which was unchanged as compared to the control diet (3% lipid). As far as biosynthesis was concerned, a plateau in the relative synthesis of lipase and serine protease was reached. Amylase relative synthesis further decreased down to 2.2-fold when rats were fed the 30% fat-rich diet whereas that of procarboxypeptidases was markedly increased (about 1.7-fold). Absolute rates of synthesis of total pancreatic secretory proteins, as expressed with regard to the DNA content of the tissue, indicated that biosynthesis of all secretory pancreatic proteins was stimulated by hyperlipidic diets (at least 2-fold with the 30% lipid diet). Consequently, when such an increase was taken into consideration, the absolute synthesis of amylase was found to be unchanged throughout the dietary manipulations, whereas that of lipase, procarboxypeptidases and serine proteases were stimulated by 4.0-fold, 3.4-fold and 3.2-fold, respectively.     

Folate deficiency and pancreatic acinar cell function

The present study was designed to determine the effect of folate deficiency on pancreatic acinar cell function. In the first series of experiments, three groups of rats were fed ad libitum regular rat feed, folate-deficient diet, or an equivalent amount of folate-sufficient diet. In the second series of experiments, rats were either fed ad libitum or rendered folate deficient by a purified folate-deficient diet; half of the folate-deficient group was replenished with oral folate. Body weight, pancreatic weight, DNA [methyl-14C]thymidine incorporation into DNA, RNA, [8-14C]adenine incorporation into RNA, protein content, synthesis of proteins, amylase content, and basal and bethanechol-stimulated amylase secretion were determined. The parameters were the same in the rats fed a folate-sufficient diet as in those fed a regular rat feed. Feeding a folate-deficient diet resulted in impaired DNA synthesis as evidenced by diminished incorporation of [methyl-14C]thymidine into DNA. There was no change in secretion of amylase. Similar results were obtained in the second series of experiments. These studies indicate that folate deficiency (rather than antibiotic content of the diet) impaired pancreatic function. Folate deficiency may therefore contribute to pancreatic injury in malnutrition and alcoholism.     

Newly raised anti‐VAChT and anti‐ChAT antibodies detect cholinergic cells in chicken embryos

The autonomic nervous system consists of sympathetic and parasympathetic nerves, which functionally antagonize each other to control physiology and homeostasis of organs. However, it is largely unexplored how the autonomic nervous system is established during development. In particular, early formation of parasympathetic network remains elusive because of its complex anatomical structure. To distinguish between parasympathetic (cholinergic) and sympathetic (adrenergic) ganglia, vesicular acetylcholine transporter (VAChT) and choline O‐acetyltransferase (ChAT), proteins associated with acetylcholine synthesis, are known to be useful markers. Whereas commercially available antibodies against these proteins are widely used for mammalian specimens including mice and rats, these antibodies do not work satisfactorily in chickens, although chicken is an excellent model for the study of autonomic nervous system. Here, we newly raised antibodies against chicken VAChT and ChAT proteins. One monoclonal and three polyclonal antibodies for VAChT, and one polyclonal antibody for ChAT were obtained, which were available for Western blotting analyses and immunohistochemistry. Using these verified antibodies, we detected cholinergic cells in Remak ganglia of autonomic nervous system, which form in the dorsal aspect of the digestive tract of chicken E13 embryos. The antibodies obtained in this study are useful for visualization of cholinergic neurons including parasympathetic ganglia.     

Cholecystokinin- and gastrin-induced protein and amylase secretion from the parotid gland of the anaesthetized rat

I.V. infusion of pentagastrin (20 microg/kg/h) or cholecystokinin (CCK)-8 (1 microg/kg/h) for 10 min caused secretion of salivary proteins from the parotid gland in the anaesthetized rat without any accompanying overt fluid secretion. This "occult" response was revealed by a subsequent wash-out injection of methacholine (5 microg/kg, I.V.) 10 min after the end of the infusion period (aiming at avoiding synergistic interactions). While the fluid response to methacholine was unaffected by the preceding infusion of pentagastrin and CCK-8, the output of protein increased by 147% (pentagastrin) and 74% (CCK-8) and that of amylase by 45% (CCK-8) compared to the responses to methacholine upon saline infusion. Those increases were abolished by the CCK-A receptor blocker (lorglumide), but not by the CCK-B receptor blocker (itriglumide). Evisceration, combined sympathetic and parasympathetic denervation of the glands and assay under adrenoceptor blockade excluded contribution from the gastro-intestinal tract, central or ganglionic mechanisms and circulating catecholamines to the increase in protein/amylase. Furthermore, Western blot demonstrated CCK receptors for both A and B subtypes in normal and chronically denervated glands. In the submandibular gland, both pentagastrin and CCK-8 evoked a trace secretion of saliva but, under the present experimental set-up, no statistically significant increase in protein output. Thus, in addition to the autonomic nervous system, gastrointestinal hormones may, in some types of glands, be involved in the secretion of salivary gland proteins.     

Effects of varying frequency of sympathetic stimulation on chloride and amylase levels of saliva elicited from rat parotid gland with electrical stimulation of both autonomic nerves.

Simultaneous stimulation of the parasympathetic and sympathetic nerves to the parotid gland of rats elicited saliva at a rate dependent on the frequency of sympathetic stimulation when parasympathetic frequency was maintained at 16 Hz. The flow rate was lowest at 2 Hz (sympathetic), moderate at 5 Hz, and highest at 16 Hz. Cl concentration of the saliva evoked with stimulation of both nerves was highest at the highest frequency and flow rate (maintained at the level of 102 mEq/liter, for 35 min) and lowest at 2 Hz (declining from 40 mEq/liter initially to 28 mEq/liter). With sympathetic nerve stimulation alone, Cl concentration ranged from 27 to 58 mEq/liter when frequency was varied from 2 to 16 Hz, and with parasympathetic stimulation alone (16 Hz), it ranged from 132 to 124 mEq/liter. Amylase concentration of sympathetically elicited saliva was, in contrast, highest at 2 Hz (1.5 times the level at 5 Hz, and twice the level at 16 Hz), and nearly 18-38 times that seen with parasympathetic stimulation alone. The same pattern was found when both nerves were stimulated, and at 2 Hz (sympathetic), amylase concentration was 1.6 times the level at 5 Hz and 2.6 times the level at 16 Hz. When the two nerves were simultaneously stimulated, the total amount of amylase secreted over 35 min was twice as high as that observed with sympathetic nerve stimulation alone, at any frequency. The relation of frequency to norepinephrine concentration was examined. There was no consistent difference in norepinephrine concentration related to variation in frequency of sympathetic stimulation. Only when both nerves were stimulated at 16 Hz was there a statistically significant reduction in norepinephrine concentration of 46%. A relation between frequency of sympathetic stimulation, flow rate, amylase concentration, and Cl concentration was established, but these changes could not be directly correlated with quantitative differences in norepinephrine concentration.     

Interstrain Variation in Amylase Gene Copy Number and mRNA Abundance in Three Mouse Tissues

Amylase expression in strain YBR differs in several respects from the standard mouse phenotype. The synthesis of salivary amylase is elevated twofold in YBR mice and the synthesis of pancreatic amylase is reduced to one-half the normal rate. We have compared the concentrations of amylase mRNA in the parotid, liver and pancreas of YBR mice with those in strains A/J and C3H. We observed differences in amylase mRNA abundance which can account for the levels of amylase protein synthesis in the parotid and pancreas of these strains. Unexpectedly, the concentration of amylase mRNA in the liver of YBR mice was also higher than in the other strains. Since liver amylase is transcribed from the same gene as parotid amylase, duplication of the Amy-1 locus could account for the elevated mRNA concentration in both tissues. Quantitative analysis of genomic DNA by Southern blotting provided direct evidence for duplication of Amy-1 in strain YBR.     

Effect of hypophysectomy on the rates of protein synthesis and degradation in rat liver.

The effect of hypophysectomy on the protein metabolism of the liver in vivo was studied. Fractional rates of protein synthesis and degradation were determined in the livers of normal and hypophysectomized rats. Synthesis was measured after the injection of massive amounts of radioactive leucine. Degradation was estimated either as the balance between synthesis and accumulation of stable liver proteins or from the disappearance of radioactivity from the proteins previously labelled by the injection of NaH14CO3. The results indicate that: (1) hypophysectomy diminishes the capacity of the liver to synthesize proteins in vivo, mainly of those that are exported as plasma proteins; (2) livers of both normal and hypophysectomized rats show identical protein-degradation rates, whereas plasma proteins are degraded slowly after hypophysectomy.     

Response of exocrine pancreas to corticosterone and aldosterone after adrenalectomy

The long-term effect of adrenalectomy (Adx) on the exocrine pancreas was examined in female adult rats. Pancreatic amylase concentration decrease to 50% of the control level starting 10 days after Adx, whereas the levels of trypsinogen and lipase remained unchanged. Replacement studies beginning 24 h after surgery with corticosterone (B, 1 mg/100 g body wt) or aldosterone (ALDO, 8 micrograms/100 g body wt) alone did not prevent the decline in amylase after Adx. However, when both hormones were administered together, pancreatic amylase concentration was maintained at a level similar to that of the control group. Serum corticosterone levels in the rats receiving B alone or B + ALDO were not different, and were comparable to levels found in normal rats. Both ALDO and B, given for 5 days starting 10 days after Adx, were required to restore amylase concentrations toward control values. When spironolactone (SPIRO, 3 mg/100 g body wt), a specific mineralocorticoid receptor blocker was administered bid together with ALDO + B, it blocked the increase in pancreatic amylase seen in ALDO + B treated rats but did not affect the serum corticosterone levels. These results suggest that mineralocorticoids are also involved in modulating the level of amylase in the rat exocrine pancreas.     

Effect of garlic oil on the levels of various enzymes in the serum and tissue of streptozotocin diabetic rats

Levels of red cell, serum acid, and alkaline phosphatases, serum amylase, alanine and aspartate transferase and bilirubin were examined in streptozotocin-induced diabetic rats treated with garlic oil and compared with the corresponding levels in diabetic control rats, normal rats and normal rats on garlic oil. Values of tissue amylase and total protein were also assessed from the pancreas, liver, and kidney. Treatment of diabetic rats with garlic oil significantly decreased the red cell phosphatase (p<0.01), serum acid and alkaline phosphatase (p<0.001) when compared to diabetic control rats. Serum alanine and asparate transferases were significantly (p<0.001) decreased as well as serum amylase (p<0.002) in garlic oil treated diabetic rats as compared with diabetic control rats. When treated with garlic oil, however, diabetic and normal rats showed significant increase (p<0.05) in the amylase levels of the pancrease, liver, and kidney.     

The acute-phase response of cultured rat hepatocytes. System characterization and the effect of human cytokines.

Hepatocytes were isolated from adult livers and cultured for periods of up to 5 days as monolayers at an initial density of 10(6) cells/10cm2 in Williams E medium containing insulin, dexamethasone and 5% foetal-calf serum. The daily production of 11 plasma proteins was measured by electroimmunoassay and compared with the concentrations of the same proteins in the plasma of normal rats and of those with experimental inflammation. Hepatocytes from normal rats synthesized proteins in relative amounts which were similar to the relative proportions of the same proteins in the plasma of turpentine-injected animals. The pattern changed only slowly during 5 days in culture, but it did so profoundly either when the medium was devoid of dexamethasone or when human cytokines (from endotoxin-stimulated monocytes or unstimulated human squamous-carcinoma cell line COLO-16) were added. The cytokines consistently increased the synthesis of alpha 2-macroglobulin and fibrinogen and depressed that of albumin; variable increases in the synthesis of alpha 1-acute-phase globulin, alpha 1-acid glycoprotein, haptoglobin and alpha 1-proteinase inhibitor, and variable decreases in transferrin synthesis, were seen, whereas the synthesis of antithrombin III, alpha 1-macroglobulin and prothrombin remained virtually unaffected. The cytokine effects on protein synthesis required the presence of dexamethasone. The hepatocyte-stimulating activity derived from monocytes chromatographed on Sephadex G-100 corresponding to 30 000 Da, as opposed to the lymphocyte-activating factor, which was eluted as a molecule of approx. 15 000 Da. This suggests that both activities probably reside with distinct molecular species in the preparations of human cytokines.     

Coupled induction of exocrine proteins and intracellular compartments involved in the secretory pathway in AR4-2J cells by glucocorticoids

Treatment of AR4-2J cells with dexamethasone at 10 nM for 96 h inhibited cell replication by 75% and increased cell size (30%), protein content (1.6-fold) and protein synthesis (2-fold). The increase in protein synthesis was largely due to a 5 to 10-fold increase in the synthesis of secretory proteins. Amylase activity increased 20 to 30-fold in cellular homogenates and 10 to 20-fold in culture medium. Both in the presence and absence of dexamethasone AR4-2J cells release their secretory proteins by constitutive secretion. The proportion of newly synthesized amylase retained by the cells over the 14 h labeling period increased from 15 to 30% with hormone treatment. As judged by comigration on polyacrylamide gels and Western blots analyzed by immunospecific sera, AR4-2J cells synthesize and secrete the majority of known pancreatic secretory proteins. Dexamethasone increased the synthesis of trypsinogen 12 to 16-fold, chymotrypsinogen 4.5 to 6-fold, the group of procarboxypeptidases 6-fold, and amylase 7 to 10-fold. Messenger RNA levels for trypsinogen, amylase and lipase were each increased 4 to 5-fold. At the ultrastructural level dexamethasone led to significant increases in rough endoplasmic reticulum (RER) (30-fold) and Golgi elements (1.5-fold) and to the de novo appearance of electron-opaque granules (0.1-0.5 microns) which were shown to contain amylase by immunolocalization techniques employing protein A-gold. Dexamethasone also led to the formation of gap junctions between AR4-2J cells. These findings indicate that AR4-2J cells provide a model for differentiation of pancreatic acinar cells which should also be studied for the differentiation markers for the regulated secretory pathway.     

Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg(-1)·day(-1)) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1β, IL-2, IL-6, MCP-1, IFNγ, and TNFα) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents.     

Variable effect of ghrelin administration on pancreatic development in young rats. Role of insulin-like growth factor-1.

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been primarily isolated from the human and rat stomach. Ghrelin has been shown to stimulate appetite and fat deposition in adult rats and humans. The aim of this study was to investigate the effect of ghrelin administration on pancreatic growth in suckling, weaned and peripubertal seven week old rats. Rats were treated with saline or ghrelin (4, 8 or 16 nmol/kg/dose) intraperitoneally twice a day: suckling rats were treated for 7 or 14 days starting from the first postnatal day, three week old weaned rats and seven weeks old rats were treated for 5 days. Treatment with ghrelin did not affect animal weight in suckling or weaned rats, whereas in young seven week old rats, ghrelin caused a significant increase in body weight. Ghrelin decreased food intake in weaned rats; whereas in seven week old rats, food intake was enhanced. In suckling rats, ghrelin decreased the pancreatic weight, pancreatic amylase content, DNA synthesis and DNA content. In contrast, ghrelin increased pancreatic weight, DNA synthesis, DNA content and amylase content in weaned or young seven week old rats. Pancreatic blood flow was not affected by ghrelin in any group of rats tested. Ghrelin increased serum level of growth hormone in all rats. This effect was weak in suckling rats, higher in weaned and the highest in seven week old animals. Ghrelin did not affect serum level of insulin-like growth factor-1 (IGF-1) in suckling rats. In weaned and in seven week old rats, treatment with ghrelin caused increase in serum level of IGF-1. We conclude that ghrelin reduces pancreatic growth in suckling rats; whereas in weaned and young seven week old animals, treatment with ghrelin increases pancreatic growth. This biphasic effect of ghrelin in young animals on pancreatic growth seems to be related to age-dependent changes of the release of anabolic IGF-1.