Pancreatic digestive enzyme secretion in the rabbit: rapid cyclic variations in enzyme composition.

Abstract

The role and mechanism of nonparallel pancreatic secretion of digestive enzymes, in which enzyme proportions change in rapidly regulated fashion, remain controversial. Secretion was collected from male 2.2-kg New Zealand rabbits in 5-min The pancreas is a major organ of digestion, producing gram quantities of digestive enzymes daily in the human. The enzyme mixture is composed of -24 species that hydrolyze a diverse mixture of polymeric substrates. The basic question of whether the relative proportions of the specific enzyme species in the mixture can be rapidly adjusted to reflect the immediate requirements for intraluminal intestinal hydrolysis dates back to the work of Pavlov who demonstrated "nonparallel" changes in the enzyme mixture after administration of different digestive substrates. Nearly a century later, the subject is still disputed (1).Recently, the debate has been reformulated in terms of cell biological secretory mechanisms, especially the vectorial secretion of cellular products by exocytosis. On the one hand, a substantial number of observations have been made, usually in the intact pancreas, of rapid nonparallel secretion of enzymes after administration of digestive substrates, end products, gastrointestinal hormones, and hormone-like factors (2). These observations have led to a dispute concerning the basic concept that the prepackaged digestive enzymes are secreted en masse by exocytosis of the mixed contents of the secretory (zymogen) granules, since this would necessarily result in parallel secretion.Others (3-7), citing the requirement of the exocytosis mechanism for parallel discharge of granule contents, have disputed the very existence of nonparallel secretion, claiming it to be due to experimental artifact. Both schools have assumed that the exocrine pancreas is a homogeneous organ in which the mixed enzymes are distributed in secretion granules throughout the gland. Recently, a way has been found that may resolve the apparent paradox: this laboratory has shown (8, 9) that digestive enzymes can be secreted in a regulated but nonparallel fashion consistent with exocytosis from heterogeneous sources in the pancreas, and differential secretion from these sources would accommodate both exocytosis and nonparallel secretion. Others (10) have shown that individual zymogen granules may contain differing proportions of enzymes. We show here that nonparallel secretion is a primary characteristic of pancreatic function and, surprisingly, that under constant conditions, digestive enzymes are secreted in a cyclic neurosecretory-like fashion. MATERIALS AND METHODSCollection of Pancreatic Juice. Male albino New Zealand rabbits (2.2 kg), fed chow (Purina), were fasted overnight but allowed water before cannulation of the pancreas as described (9). The rabbits were anesthetized by i.p. administration of xylazine (12.5 mg/kg) and inhaled methoxyflurane and 02-Ringer's lactate solution and secretagogues dissolved in Ringer's lactate were infused at 15 ml/h via the femoral vein. A 1-h constant...

Temporal Analysis of Amylase Expression in Control, Autoantibody-Positive, and Type 1 Diabetes Pancreatic Tissues

“…The exocrine pancreas has historically been thought to be homogeneous in function, supported by the relatively uniform structural organization of acini throughout the organ alongside the capacity for a single cell type to produce all four digestive enzymes (i.e., trypsin, chymotrypsin, amylase, and lipase) (13). This notion was, however, challenged in the 1980s-1990s by studies establishing that acinar cells or whole acini may differ in terms of their enzyme production and secretory response to immediate digestive requirements (14,15), potentially depending on innervation or gut hormones (16,17). Moreover, acinar cells differ in their response to certain secretagogues (18,19), which is particularly relevant to the exocrine-endocrine cell interactions occurring within the islet-acinar axis (20,21).…”

Fundamental cellular heterogeneity of the exocrine pancreas.

“…However, several physiological studies have recently introduced the possibility of functional heterogeneity or specialization of either individual acinar cells or acini. It has now been shown that newly synthesized digestive enzymes are sequestered in heterogeneous pools, from which they are secreted in a cyclic neurosecretory-like and secretagogue-specific fashion (1)(2)(3)(4)(5)(6). A few previous reports have deduced the existence of morphological differences among acinar cells, but until now none has actually visualized distinct differences such as we have reported here.…”

“…Further studies in the conscious rat showed that the nonparallel enzyme secretory patterns in rat were highly cyclic ( 5 ) . Extensive study of the nonparallel secretory phenomenon in the rabbit, using a mass assay of the enzymes (electrophoretic separation with quantitative densitometry) to avoid potential difficulties with quantitative enzyme assays, showed the secretion to be rapidly cyclic and highly nonparallel, consistent with secretion of enzyme mixtures from heterogeneous sources within the gland (6). Despite predictions of pancreatic heterogeneity based on physiological work, little is known about the morphological or cellular basis for heterogeneity within the gland.…”

“…In recent years, however, evidence has accumulated at the functional level that the pancreas stores newly synthesized digestive enzymes in heterogeneous pools and releases them from these pools in a cyclic and secretagoguespecific fashion (1)(2)(3)(4)(5)(6). Digestive enzyme mixtures of distinct and rapidly variable composition have been shown to be secreted in nonparallel fashion by the pancreas of the rabbit after different physiological stimuli, whereas correlation and regression analysis of the enzyme secretory patterns showed that distinct digestive enzyme species were secreted together in tightly linked groups, as expected of the exocytotic secretory mechanism (2).…”

Quantal Basis of Secretory Granule Biogenesis and Inventory Maintenance: the Surreptitious Nano-machine Behind It

“…The next group of cells down the size ladder (rosette size K between 12 and 25) is represented by the adaptive immune system (e.g., mast cells, eosinophils) and the acinar cells of the gastro-intestinal system (GIT, e.g., pancreatic and parotid acinar cells). These cells, which vary in their evoked secretion frequency, respond to demand dictated by the environment, whether it is exposure to an antigen (immune system) 38,39 or to food (GIT) 44,45 . Basal secretion is minimal in the immune system to prevent tissue destruction, whereas in GIT it is about 10 times faster due to its food processing role.…”