The role of the exocrine pancreas in the stimulation of insulin secretion by intestinal hormones

Summary The effect of the intestinal hormones secretin, pancreozymin, gastrin-pentapeptide and of glucagon upon insulin secretion of rat isolated pancreatic islets were studied. Only pancreozymin and glucagon were found to stimulate insulin release from the isolated islets, pancreozymin without and glucagon only in presence of glucose in the medium. The effect of pancreozymin was repeatedly shown by using the same islets in a dynamic perifusion system. The studies imply classification of the insulin stimulating actions of the intestinal hormones according to dependence upon and independence of the presence of intact exocrine pancreatic tissue. Supported by Deutsche Forschungsgemeinschaft, Bad Godesberg (Pf 38/24).     

The role of the exocrine pancreas in the stimulation of insulin secretion by intestinal hormones

Summary A comparison was made of the effects of the intestinal hormones secretin and pancreozymin on insulin secretion in non-diabetic rats with experimentically induced exocrine pancreatic insufficiency and in control animals. The rats with exocrine pancreatic insufficiency exhibited normal disappearence of glucose and secretion of insulin. In rats with exocrine pancreatic insufficiency secretin did not lead to any increase in insulin secretion in contrast to its effect in the controls. In rats with exocrine pancreatic insufficiency pancreozymin evoked secretion of insulin to the same extent as in the normal animals. — From these results it is inferred that the effect of secretion upon the -cells of the rat is dependent upon the presence of intact exocrine pancreatic tissue. However, pancreozymin and glucose exert their effects upon the -cells directly without the involvement of the exocrine portion of the pancreas. All of these findings made under conditions in vivo are in perfect accord with studies made on isolated islets of rats subjected to the same stimuli in the preparation in vitro.Supported by Deutsche Forschungsgemeinschaft, Bad Godesberg, Germany, (Pf 38/24).     

Effect of diabetes mellitus on pancreatic exocrine secretion from isolated perfused pancreas in rats

We studied pancreatic exocrine function in response to cerulein and carbamylcholine in isolated perfused pancreas obtained from control, streptozotocin-induced diabetic, and insulin-treated diabetic rats. The time course of pancreatic juice, protein, amylase, and trypsinogen secretion in response to cerulein or carbamylcholine in diabetic rats was similar to that in control rats. Basal as well as cerulein- or carbamylcholine-stimulated output of amylase from diabetic rat pancreas was significantly reduced, whereas that of trypsinogen was similar to the control. Amylase and trypsinogen outputs in response to 620 pM (1.0 ng/ml) cerulein from insulin-treated diabetic rat pancreas were significantly lower than those from control rat pancreas, although the pancreatic contents of these enzymes were similar to or greater than those in control rats. The dose-response curves of pancreatic juice, protein, amylase, and trypsinogen for cerulein and carbamylcholine were biphasic in both control and diabetic rats. The minimal and the maximal release in response to cerulein occurred with higher concentrations in diabetic rats compared with control rats. In contrast, the maximal responses were obtained with 1 M carbamyl-choline in control rats and with 0.1–1 M carbamylcholine in diabetic rats. The present study demonstrates that the concentration of cerulein required to elicit maximal response was increased, whereas that to carbamylcholine was reduced in diabetic rat pancreas, and that the protein and enzyme outputs in response to cerulein were significantly reduced in insulin-treated diabetic rat pancreas despite restoration of the pancreatic enzyme contents to control levels.     

Duodenum preservation in pancreatic head resection to maintain pancreatic exocrine function (determined by pancreatic function diagnostant test and cholecystokinin secretion)

Background/Purpose

Organ-preserving surgery, such as pylorus-preserving pancreatoduodenectomy (PPPD), duodenum-preserving pancreatic head resection (DPPHR), or medial pancreatectomy (MP), is one of the recent advances in pancreatic surgery. There was a previous report that preservation of the duodenum maintained pancreatic function. However, concerning the resected pancreas, patients were divided into two groups; one group included pancreatic head resections such as Whipple, PPPD, and complete DPPHR, and the other group included MP that removed only the pancreatic neck and preserved the pancreatic head and distal pancreas. The present study was designed to clarify the significance of duodenum preservation, in comparison with duodenum removal, in patients with pancreatic head resection, in terms of pancreatic function, determined by a pancreatic function diagnostant (PFD) test and cholecystokinin (CCK) secretion.

Methods

The subjects were 61 patients (10 with Whipple, 41 with PPPD, and 10 with complete DPPHR). PFD tests and postprandial plasma CCK secretion were used for evaluation.

Results

There was a significant difference between pre- and postoperative PFD values in the patients who received Whipple or PPPD; however, there was no difference in those who had complete DPPHR. Concerning the postoperative PFD value, complete DPPHR was superior to Whipple and PPPD. Regarding postprandial CCK secretion, the pre- and postoperative values were significantly different in the patients with Whipple or PPPD, but there was no difference in those with complete DPPHR. Comparing the three kinds of operations, complete DPPHR was superior to the other two procedures in its maintenance of pancreatic function. There was the significant correlation between CCK and PFD in our patients in the Spearman Rank Correlation (P < 0.0029) and Fisher’s r to z (P < 0.0058).

Conclusions

When pre- and postoperative pancreatic exocrine function and postprandial CCK secretion were measured in patients with pancreatic head resection, it was found that preservation of the entire duodenum was an important factor for maintaining pancreatic function.     

Comparison of two enteric coated microsphere preparations in the treatment of pancreatic exocrine insufficiency caused by cystic fibrosis

BACKGROUND: Pancreatic exocrine insufficiency is a common condition in patients with cystic fibrosis. Large amounts of pancreatic enzyme supplements are required to reduce malabsorption but patient compliance is not always optimal. AIMS: To compare patients' preference and the efficacy of two enteric coated microsphere preparations in patients with cystic fibrosis. PATIENTS: Patients with pancreatic exocrine insufficiency due to cystic fibrosis. METHODS: Patients were assigned to the crossover treatment with Creon or Pancrease for 1 week and then to the alternative treatment. Patients had to follow a fixed diet (at least 2 g fat/kg) and had to assume 1000 units lipase/g fat. The evaluation parameters were: patients' preference, acceptance of therapy, stool fat excretion, stool weight, gastrointestinal symptoms, and tolerance. RESULTS AND CONCLUSIONS: Of the 33/60 patients who expressed a preference for one of the two treatments, 30 preferred Creon while only 3 patients preferred Pancrease (p<0.001). No difference between the two treatments was observed regarding stool characteristics, gastrointestinal symptoms and tolerance. The mean number of capsules taken daily was reduced by 35% with Creon. The results of this study showed a preference in favour of Creon probably due to the reduction of daily capsule intake of 35%, supporting digestion as well as Pancrease.     

The influence of cutting the pancreatic nerve plexus on exocrine function in the pancreas of rats

This study was performed to clarify changes in protein synthesis and exocrine enzymes of the pancreas after cutting the pancreatic nerve plexus of Wistar rats. The rats were divided into two groups, consisting of a group that underwent cutting of the pancreatic nerve plexus (neurotomy group) and a group that underwent a sham operation (control group).³H-leucine uptake in the pancreatic protein fraction of the neurotomy group at 3, 5 and 7 days after the operation was significantly lower than that of the control group (P<0.05-0.01), and this low uptake returned to the normal range at 14 days. Amylase, lipase and trypsin values in pancreatic tissue of the neurotomy group decreased during the period of from 1 to 7 days, and there were significant differences in the values of the respective enzymes at 5 or 7 days between the neurotomy and the control group (P<0.05). Thereafter, all enzyme values increased to within the normal range. Upon examination of pancreatic blood flow using a microsphere, the neurotomy group showed a significant reduction at 7 days compared with the control group (P<0.05), and thereafter exhibited recovery of blood flow. These results indicate that after cutting the pancreatic nerve plexus, exocrine function in the pancreas is reduced immediately but recovers within a short period of time, and that these changes in exocrine function are affected by blood flow in the pancreas. Supported partially by the grants from the Japanese Ministry of Health & Welfare.     

Effect of natural peptide YY on blood flow and exocrine secretion of pancreas in dogs

Little is known regarding the mechanism by which peptide YY exerts an inhibitory effect on exocrine pancreatic secretion. The purpose of this study is to determine if peptide YY affects pancreatic blood flow with simultaneous measurement of exocrine pancreatic secretion in dogs. Pancreatic blood flow was measured by a laser Doppler flowmeter which allows continuous measurement of tissue blood flow. Natural peptide YY (0.1, 0.5, 1g/kg) was infused intravenously as a bolus under background infusion of secretin (1 unit/kg/hr) in combination with cholecystokinin-octapeptide (0.1g/kg/hr). Peptide YY caused a reduction of pancreatic blood flow in a dose-dependent manner as well as inhibition of pancreatic protein output, attaining the maximal reduction (28±4%) and inhibition (45±9%) at a dose of 1 g/kg, respectively. Simultaneous and continuous observation on tissue blood flow and exocrine secretion of the pancreas revealed that there was a highly significant correlation between the percent reduction of pancreatic blood flow and that of volume of pancreatic juice in response to peptide YY (r=0.849, P < 0.001). This study provides evidence that the mechanism of peptide YY-induced inhibition of exocrine pancreatic secretion is mediated, at least partly, through the decreased pancreatic blood flow.This study was supported by a grant from the Ministry of Education, Japan (A,61440060).A portion of this work was presented at the American Gastroenterological Association Meeting in New York in May 1985.     

Evaluation of insulin resistance during inhibition of endogenous insulin and glucagon secretion by somatostatin in non-obese subjects with impaired glucose tolerance

Summary Insulin resistance was studied in seven non-obese male subjects with impaired glucose tolerance and four healthy, age and body-weight matched male control subjects by means of a continuous intravenous infusion of somatostatin, glucose and insulin over 150 min. Glucose tolerance was evaluated by means of a 2-h glucose infusion test. Endogenous insulin (C-peptide), growth hormone, and glucagon secretion were suppressed by somatostatin in both groups. Steady-state plasma insulin and glucose levels were achieved between 90–135 min. Since similar steady-state levels of exogenous insulin were achieved, the resulting steady-state plasma glucose level provided a direct estimate of the ability of insulin to dispose of the infused glucose. The glucose levels were higher in subjects with impaired glucose tolerance with values of 14.6 ± 1.8 mmol/1 compared with 5.1 ± 1.2 mmol/1 in control subjects (p < 0.01), thus indicating insulin resistance. There was a direct correlation between the steady-state plasma glucose level and glucose tolerance suggesting that the degree of glucose intolerance is proportional to the degree of insulin resistance. These results revealed that decreased insulin sensitivity is found in non-obese subjects with impaired glucose tolerance.     

Inhibitory effects of pirenzepine on cholecystokinin and secretin stimulation on exocrine and endocrine rat pancreas

Effects of pirenzepine, a newly developed anticholinergic drug, on exocrine and endocrine pancreatic functions stimulated by cholecystokinin octapeptide and secretin were studied in both isolated pancreatic acini and the isolated perfused pancreas of rats. In the isolated acini, pirenzepine did not have any significant effect on cholecystokinin-inducec amylase release but caused an inhibition of amylase secretion initiated by secretin and shifted the dose-response curve for amylase secretion to the right. In the isolated perfused pancreas stimulated with 100 pM cholecystokinin octapeptide, addition of 10 M pirenzepine before as well as after 20 min of perfusion significantly inhibited pancreatic juice flow but not enzyme output. In contrast, pirenzepine caused an inhibition of secretin-stimulated enzyme secretion, but not pancreatic juice flow. The stimulatory effect of both cholecystokinin octapeptide and secretin on insulin secretion was also inhibited by pirenzepine. The present data indicate that pirenzepine may have an influence on pancreatic exocrine and endocrine function by inhibiting endogenous cholinergic activity of the pancreas when a large dose is given.     

Paradoxical effects of endogenous and exogenous insulin on amino acid transport activity in the isolated rat pancreas: somatostatin-14 inhibits insulin action

Summary Regulatory effects of insulin, somatostatin and cholecystokinin on amino acid transport in the isolated perfused rat pancreas have been studied using a rapid dual isotope dilution technique. Uni-directional L-serine transport (15 s) was quantified relative to an extracellular tracer D-mannitol over a wide range of substrate concentrations. In pancreata perfused with 2.5 mmol/l D-glucose, a weighted nonlinear regression analysis of overall transport indicated an apparent K_m=14.4±1.6 mmol/l and V_max=25.9±1.4 mol ·min^–1·g^–1 (n=6). Although L-serine transport was stimulated during perfusion with 100 U/ml bovine insulin, endogenous insulin (7–25 ng·min^–1·g^–1) released during continuous perfusion with either 8.8 mmol/l or 16.8 mmol/l D-glucose had no such effect. Exogenous somatostatin-14 (250 pg/ml) or cholecystokinin octapeptide (CCK-8, 3 × 10^–11mol/l) appeared to increase only the K_m for transport. Only CCK-8 evoked a notable protein output (2.9±0.3 mg·30min^–1·g^–1) and juice flow (68±10l·30min^–1·g ^–1, n=3) from the exocrine pancreas. When pancreata were perfused with bovine insulin (100 U/ml) and somatostatin-14 (250 pg/ml), the stimulatory action of exogenous insulin on L-serine transport was abolished. If endogenous insulin and somatostatin, released concurrently in response to 16.8 mmol/l D-glucose, were conveyed to the exocrine epithelium via an islet-acinar portalaxis, it is conceivable that somatostatin modulates the stimulatory action of insulin on basolateral amino acid transport in the exocrine pancreas.     

The effect of chronic intraperitoneal infusion of bacterial endotoxin on exocrine pancreas function in rats

Summary Conclusion This study demonstrated that LPS infusion can induce tissue lesions and impair the exocrine protein secretion of the pancreas in rats. Background The effect of chronic ip infusion of lipopolysaccharide (LPS) on the exocrine pancreas function was studied in rats. Methods Four milligrams per kilogram per day ofSalmonella typhi LPS were infused intraperitoneally by means of surgically implanted osmotic pumps. Rats were studied after 7-d LPS infusion. Results Plasma fibrinogen and amylase activity increased significantly in LPS-treated rats when compared with control rats. Histological examination of the pancreas showed congestion, infiltration, and focal necrosis in LPS-treated rats. The pancreas wet weight, as well as DNA and total soluble protein contents were significantly increased in LPS-treated animals when compared with controls. The pancreas protein output was significantly decreased in pure pancreatic juice, whereas the pancreatic juice flow rate was significantly increased in LPS-treated animals, when compared with controls. Electrophoretic patterns showed a marked decrease in digestive enzyme contents, whereas there was an increased content of 15 kDa protein.     

The role of glucose and insulin in the metabolic regulation of growth hormone secretion

The exact physiological basis for the suppression of growth hormone secretion by oral glucose intake remains unknown, despite the widespread use of the oral glucose tolerance test in endocrinology. Lack of growth hormone suppression by glucose occurs in about a third of patients with acromegaly, as well as in other disorders. It is currently known that the secretion of growth hormone is affected by various factors, such as age, gender, body mass index, and the redistribution of adipose tissue. There is also evidence of the impact of overeating as well as being overweight on the secretion of growth hormone. It is known that both of these conditions are associated with hyperinsulinemia, which determines the possibility of its predominant role in suppressing the secretion of growth hormone. The purpose of this review is to discuss the accumulated data on the isolated effects of hyperglycemia and hyperinsulinemia on growth hormone secretion, as well as other metabolic regulators and conditions affecting its signaling. Understanding of the pathophysiological basis of these mechanisms is essential for further research of the role of glucose and insulin in the metabolic regulation of growth hormone secretion. However, the studies in animal models are complicated by interspecific differences in the response of growth hormone to glucose loading, and the only possible available model in healthy people may be the hyperinsulinemic euglycemic clamp.     

The ageing pancreas: a systematic review of the evidence and analysis of the consequences

Senior people constitute the fastest growing segment of the population. The elderly are at risk for malnutrition, thought to be caused by reduced food intake or involution of the physiological capacity of the GI tract. Age‐related changes are well known in other secretory organs such as liver, kidney and intestine. The pancreas, representing a metabolically active organ with uptake and breakdown of essential nutritional components, changes its morphology and function with age. During childhood, the volume of the pancreas increases, reaching a plateau between 20 and 60 years, and declines thereafter. This decline involves the pancreatic parenchyma and is associated with decreased perfusion, fibrosis and atrophy. As a consequence of these changes, pancreatic exocrine function is impaired in healthy older individuals without any gastrointestinal disease. Five per cent of people older than 70 years and ten per cent older than 80 years have pancreatic exocrine insufficiency (PEI ) with a faecal elastase‐1 below 200 μg g^?1 stool, and 5% have severe PEI with faecal elastase‐1 below 100 μg g^?1 stool. This may lead to maldigestion and malnutrition. Patients may have few symptoms, for example steatorrhoea, diarrhoea, abdominal pain and weight loss. Malnutrition consists of deficits of fat‐soluble vitamins and is affecting both patients with PEI and the elderly. Secondary consequences may include decreased bone mineral density and results from impaired absorption of fat‐soluble vitamin D due to impaired pancreatic exocrine function. The unanswered question is whether this age‐related decrease in pancreatic function warrants therapy. Therapeutic intervention, which may consist of supplementation of pancreatic enzymes and/or vitamins in aged individuals with proven exocrine pancreas insufficiency, could contribute to healthy ageing.     

The role of skeletal muscle sphingolipids in the development of insulin resistance

Insulin resistance is an important risk factor for type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and other diseases. The most important stage in the development of insulin resistance is impairment of insulin-stimulated skeletal muscle glucose uptake. There is evidence that intramyocellular lipids might be responsible for this process through inhibition of insulin signaling. One of the important intracellular lipid pools is associated with the sphingomyelin signaling pathway. The second messenger in this pathway is ceramide. In vitro data indicate that ceramide inhibits insulin signaling, mainly through inactivation of protein kinase B. In vivo data suggest that ceramide accumulation within muscle cells might be associated with the development of insulin resistance. In this review, we discuss both in vitro and in vivo evidence for the role of muscle ceramide in the impairment of insulin action with particular focus on the question whether findings from animal studies are applicable to humans. We describe problems that are unresolved so far and topics of potential interest for future research.     

Effects of free fatty acids on insulin secretion in obesity

The prevalence of obesity in Western society has reached epidemic proportions and its aetiological role in the development of type 2 diabetes has made finding an effective treatment for the condition of crucial importance. Of the many consequences of obesity, derangements in glucose metabolism present one of the greatest problems to health. While the role of obesity in causing insulin resistance has received much attention, the effect of obesity on β‐cell failure and the consequent development of type 2 diabetes requires re‐emphasis. In this review, the current understanding of the effects of elevated free‐fatty acids on β‐cell function will be examined, including a discussion of potential mechanisms. In particular, dysregulation of biochemical pathways and alterations in key enzymes, proteins and hormones will be considered as grounds for the progression to a diabetic phenotype.     

Nicotine infusion acutely impairs insulin sensitivity in type 2 diabetic patients but not in healthy subjects

OBJECTIVES: The aim of this study was to examine if an acute nicotine infusion alters insulin sensitivity to a similar degree in type 2 diabetic patients as in healthy control subjects. DESIGN: . Double-blind, cross-over, placebo-controlled, randomized experimental study. Nicotine 0.3 microg kg-1 min(-1) or NaCl was infused (2 h) during a euglycaemic hyperinsulinaemic clamp (4 h) to assess insulin sensitivity. SETTING: University research laboratory. SUBJECTS: Six male and female type 2 diabetic patients [DM2; age 54 +/- 10 (mean +/- SD) years; body mass index (BMI) 25.6 +/- 2.9 kg m(-2)] treated with diet or one oral hypoglycaemic agent and six age- and BMI-matched control subjects (Ctr). MAIN OUTCOME MEASURE: Insulin sensitivity (rate of glucose infusion per kg fat free body mass and minute), nicotine and free fatty acid (FFA) levels, pulse rate and blood pressure. RESULTS: The infusions produced similar nicotine levels in both groups. In the absence of nicotine, DM2 were more insulin resistant than Ctr (6.7 +/- 0.4 vs. 10.9 +/- 0.3 mg kg-1 LBM min(-1), respectively; P < 0.0001). This insulin resistance was further aggravated by the nicotine infusion in DM2 but not in Ctr (4.6 +/- 0.3 vs. 10.9 +/- 0.3 mg kg(-1) LBM min(-1); P < 0.0001). Only minor differences were seen in FFA levels, pulse rates and blood pressure. CONCLUSIONS: At this low infusion rate, nicotine aggravated the insulin resistance in DM2 but not in Ctr. This finding may be because of the (dysmetabolic) diabetic state per se or to an increased sensitivity to environmental factors associated with a genetic predisposition for type 2 diabetes. These results show that diabetic subjects are particularly susceptible to the detrimental effects of nicotine.     

Effect of sodium salicylate on oxidative stress and insulin resistance induced by free fatty acids

BACKGROUND:It has been reported that high-dose salicylates improve free fatty acids (FFAs)-induced insulin resistance and β-cell dysfunction in vitro,but the mechanism remains uncertain.In insulin-resistant rats,we found that the supplementation of sodium salicylate is associated with a reduction of plasma malondialdehyde (MDA),a marker of oxidative stress.Few studies have investigated the effects of salicylates on oxidative stress levels in insulin-resistant animal models.This study aimed to assess the eff...     

Three-dimensional remnant pancreatic volume ratio indicates postoperative pancreatic exocrine insufficiency in pancreatic cancer patients after distal pancreatectomy

BackgroundPancreatectomy may cause serious pancreatic exocrine insufficiency (PEI), which can lead to some nutritional problems, including new-onset diabetes mellitus (DM) or non-alcoholic fatty liver disease (NAFLD). Recent studies have reported that remnant pancreatic volume (RPV) significantly influences postoperative PEI. However, the specific correlation between RPV and postoperative PEI remains unclear. Here, we compare various pre-, peri-, and postoperative risk factors in a retrospective cohort to address whether preoperatively measured RPV is a predictor of postoperative PEI in pancreatic cancer patients after distal pancreatectomy (DP).MethodsSixty-one pancreatic cancer patients who underwent DP were retrospectively enrolled. Pancreatic volume was measured using preoperative 3D images, which simulated the actual intraoperative pancreatic parenchymal volume. We obtained the 3D-measured RPV and resected pancreatic volume. We calculated the ratio of the RPV to the total pancreatic volume and then divided the cohort into high- and low-RPV ratio groups based on a cut-off value (>0.35, n = 37 and ≤ 0.35, n = 24). Using multivariate analysis, the RPV ratio as well as pre-, peri- and postoperative PEI risk factors were independently assessed.ResultsThe multivariate analysis revealed that a low RPV ratio (odds ratio [OR], 5.911; p = 0.001), a hard pancreatic texture (OR, 3.313; p = 0.023) and TNM stage III/IV (OR, 3.515; p = 0.031) were strong predictors of the incidence of PEI.ConclusionsThe present study indicates that the RPV ratio is an additional useful predictor of postoperative nutrition status in pancreatic cancer patients.