Peter Colin Gregory

Effects of intraduodenal administration of tarazepide on pancreatic secretion and duodenal EMG in neonatal calves

The influence of CCK-A receptor antagonism on pancreatic exocrine secretion and duodenal EMG, and the mechanism(s) involved in CCK-induced pancreatic secretion were studied in conscious calves. Seven 1-week-old calves were fitted with a pancreatic duct catheter, duodenal cannula and duodenal electrodes. Pancreatic exocrine secretion and duodenal EMG were studied following intraduodenal CCK-A receptor antagonist (Tarazepide), intravenous atropine, and intravenous or intraduodenal CCK-8 administrations. Tarazepide decreased duodenal electric activity, reduced interdigestive pancreatic secretion, especially protein; reduced cephalic and early postprandial (milk) induced secretion of bicarbonate and protein. Pancreatic protein secretion to intravenous CCK-8 was little affected by atropine, but was significantly reduced by Tarazepide+/-atropine; in contrast, protein secretion to intraduodenal CCK-8 was abolished by Tarazepide or atropine. We conclude that pre- and especially early postprandial pancreatic secretion are partly controlled via CCK-A (mainly mucosal) mediated mechanisms.

The enzyme levels in blood are not affected by oral administration of a pancreatic enzyme preparation (Creon 10,000) in pancreas-insufficient pigs.

After oral intake, small amounts of intact protein may be absorbed into the blood circulation. The current study investigated whether orally administered pancreatic enzymes were absorbed from the intestine. The study included 28 pigs; 3 control pigs with intact pancreatic function and 25 pigs that were made exocrine pancreas insufficient by duct ligation (20 pigs) or total pancreatectomy (5 pigs).The pigs received a pancreatic enzyme preparation (0, 2, 4, or 8 g of Creon 10,000) together with the feed. The blood plasma was analyzed for pancreatic lipase activity with a [3H]-triolein substrate assay, while (pro)colipase and cationic trypsin(ogen) levels were measured with enzyme-linked immunosorbent assay (ELISA). Administration of Creon (0–8 g) caused no significant changes in plasma (pro)colipase or cationic trypsin(ogen) levels. Lipase activity peaks in plasma samples were found, but they did not correspond to the administration of Creon. The potential source of these plasma lipase activity peaks is discussed. The results showed no absorption into blood of pancreatic enzymes after oral administration (0, 2, 4, or 8 g of Creon mixed with 100 g of feed) to pancreas-insufficient pigs.

CHOLECYSTOKININ-8 AND VASOACTIVE INTESTINAL POLYPEPTIDE STIMULATE EXOCRINE PANCREATIC SECRETION VIA DUODENALLY MEDIATED MECHANISMS IN THE CONSCIOUS PIG

The effects of local and peripheral administration of cholecystokinin‐8 (CCK‐8) and vasoactive intestinal polypeptide (VIP) on basal pancreatic secretion were investigated in conscious pigs. Five pigs (20 +/− 2 kg, mean +/− S.E.M.) were chronically fitted with a T‐shaped cannula in the duodenum, and catheters in the pancreatic duct, jugular vein, and right gastroepiploic artery. The arterial catheter was inserted against the bloodstream with its tip opposite the duodenal branch(es) of the right gastroepiploic artery, so that all injected peptides would reach the duodenal arterial circulation excluding the pancreas. Pancreatic secretion during basal conditions (i.e. after an overnight fast) exhibited a characteristic cyclic pattern (cycle duration, 70 +/− 4.2 min). Secretion volume oscillated between 0.2 +/− 0.04 and 4.0 +/− 0.9 ml kg‐1 h‐1 (P < 0.001), trypsin output between 9.6 +/− 1.9 and 29.1 +/− 4.1 U kg‐1 h‐1 (P < 0.001) and protein output between 0.36 +/− 0.08 and 9.2 +/Ȓ 1.7 mg kg‐1 h‐1 (P < 0.001). Infusion into the jugular vein for 1 min, during the trough of pancreatic secretion, of either CCK‐8 (15 pmol kg‐1 min‐1) or VIP (7 pmol kg‐1 min‐1) did not stimulate pancreatic secretion. However, local infusion of an identical dose of CCK‐8 or VIP into the duodenal arterial circulation increased the volume, protein output and trypsin output of the pancreatic juice (P < 0.05 to < 0.001). These results indicate that CCK‐8 and VIP can stimulate the exocrine pancreas by a duodenally mediated mechanism.

Experiments suggesting extra-digestive effects of enteral pancreatic amylase and its peptides on glucose homeostasis in a pig model

The studies presented were designed to highlight the impact of pancreatic enzymes on glycemic control and insulin response. Blood glucose and plasma insulin levels were monitored after intravenous, oral or direct gut glucose tolerance tests (GTT) in 6 pigs with an intact gastrointestinal tract and in 12 pigs following duodenal-jejunal bypass (DJB) surgery. In the intact pigs, pancreatic enzymes (Creon®) given orally 1 h prior to the GTT, lowered the blood glucose levels during the oral and meal GTT and reduced the plasma insulin response during the intravenous and meal GTT. In DJB pigs, blood glucose and plasma insulin levels were higher following glucose loading into the by-passed biliopancreatic limb as compared to that following glucose loading orally or into the common intestinal limb. Infusion of amylase or amylase peptides together with glucose into the biliopancreatic limb lowered blood glucose levels in DJB pigs. These preliminary data suggest new, extra-digestive, actions of enteral pancreatic enzymes – probably amylase or its peptides – on glucose homeostasis, with an reduction in net glucose absorption into the blood and in insulin response. This ability of digestive enzymes (amylase) to reduce post-prandial hyperglycaemia in an insulin-independent manner could aid in preventing the development of obesity and diabetes.

The Pancreatic Duct Ligated (Mini)pig as a Model for Pancreatic Exocrine Insufficiency in Man.

Abstract Modern therapy of pancreatic exocrine insufficiency (PEI) using pancreatic enzyme replacement therapy (PERT) has largely been very effective and has greatly helped in improving the nutritional status of patients with PEI and in increasing the life expectancy in cystic fibrosis. It is believed that the use of predictable large animal models could play an important role in assessing and developing new therapies. This article reviews the pancreatic duct ligated (adult) minipig as a chronic model of total PEI, with a detailed look at the influence of PEI and response to PERT on prececal compared to fecal digestibility, to directly investigate effects on protein and starch digestion and absorption. In addition, the piglet with PEI is reviewed as a model for PEI in young patients with the aim of further improving the therapy and nutritional status of young patients with cystic fibrosis.

Specificity of the 3H-triolein assay for pancreatic lipase in blood plasma.

Abstract The aim of this study was to investigate the specificity of the 3H-triolein assay and to investigate the recovery of highly purified pancreatic lipase and pancreatic lipase in the form of pure non-activated pig pancreatic juice. Blood plasma from pigs was analysed for pancreatic lipase activity using the 3H-triolein substrate assay, with a method specific for lipoprotein lipase and with a method specific for hepatic lipase. The recovery of pancreatic lipase from pancreatic juice was approximately 100%, while the recovery of highly purified pancreatic lipase in plasma or whole blood was found to be approximately 1%. Preparations of highly concentrated, purified lipoprotein lipase showed activity in the 3H-triolein assay designed for pancreatic lipase, but the activity did not exceed 1% of the activity of this enzyme measured in an assay specific for lipoprotein lipase (samples containing physiological levels of lipoprotein lipase did not show any activity in the assay). Hepatic lipase was not measurable under the conditions of the 3H-triolein assay. In conclusion, the 3H-triolein assay showed pronounced specificity for pancreatic lipase compared with lipoprotein lipase or hepatic lipase.

Glucose homeostasis dependency on acini–islet–acinar (AIA) axis communication: a new possible pathophysiological hypothesis regarding diabetes mellitus

Studies have highlighted the existence of two intra-pancreatic axes of communication: one involved in the regulation of enzyme production by insulin—the insular–acinar axis; and another involved in the regulation of insulin release by pancreatic enzymes—the acini–insular axis. Previous studies by our laboratory show that pancreatic enzymes can affect blood glucose homeostasis and insulin secretion independently of their digestive functions, both from the gut lumen and probably from the blood. As a result we would like to introduce here the concept of acini–islet–acinar (AIA) axis communication (feedback), which could play an important role in the development of obesity and diabetes type 2. The AIA feedback links the endocrine and exocrine parts of the pancreas and emphasizes the essential role that the pancreas plays, as a single organ, in the regulation of glucose homeostasis by amylase most probably in gut epithelium and by insulin and glucagon in peripheral blood.