Pancreatic Polypeptide Cells Research Articles

Pancreatic polypeptide: a unique model for vagal control of endocrine systems.

Pancreatic polypeptide (PP) is a hormone synthesized only in the duodenal pancreas where the PP cell is the dominating endocrine cell type. The secretion of PP is regulated by food-intake and by plasma glucose--in both cases through vagal cholinergic mechanisms. In vitro cholinergic stimulation is 4-10 times as potent as any other stimulatory mechanism, e.g. beta-adrenergic stimulation. Although other agents such as gastrointestinal hormones and neuropeptides are potent stimulators of PP secretion in vivo, their action is totally eliminated by blockade of the muscarinic receptor and in several cases also abolished by vagotomy. Furthermore, these peptides have no or only a weak effect in vitro. The stimulation of PP secretion by hypoglycemia and inhibition by hyperglycemia is mediated also through an efferent vagal mechanism. Under extreme hypoglycemia the stimulation of PP release becomes partially atropine resistant, although still totally dependent on the vagus; conceivably the release of other transmitters, like e.g. VIP, is activated under these circumstances. In the basal state, PP secretion is under oscillating cholinergic tone. Thus, the secretion of PP is unique in the way that the cholinergic, vagal stimulation is not only the most powerful stimulatory mechanism, but also the key through which other mechanisms act. PP secretion can be used, e.g. as a sensitive indicator of autonomic disorders in patients with diabetes.

Quantitative morphology of endocrine cells in human fetal pancreas.

Sections of pancreas from human fetuses, 6-20 weeks gestation, were stained with immunoperoxidase for insulin (B cells), glucagon (A cells), pancreatic polypeptide or somatostatin (D cells). Morphometric analyses were performed on sections from head and tail regions of each fetus. No stained cells were found at 7 weeks. A, B, pancreatic polypeptide and D cells were found at 9 weeks in primitive islets or as isolated cells adjacent to duct cells. There was no relationship between the density of each endocrine cell type and fetal age, but there was a significant increase in the relative density (percentage total endocrine cells) of D cells from 10-20 weeks (p less than 0.01). The tail contained significantly more A cells (p less than 0.05) and less pancreatic polypeptide cells (p less than 0.01) than the head but similar densities of B and D cells. Lobules containing a high density of pancreatic polypeptide cells and few A cells were found in the posterior part of the head in six fetuses, aged 10-20 weeks.

Cellular composition of the human diabetic pancreas.

Insulin, glucagon, somatostatin and pancreatic polypeptide cells were stained by immunoperoxidase techniques and quantitated morphometrically in sections of pancreases obtained from eight control subjects, four Type 1 (insulin-dependent) and eight Type 2 (non-insulin-dependent) diabetic patients. The whole pancreas was studied to take into consideration the heterogeneous distribution of the different cell types. From the volume density of each cell type, and the weight of each lobe of the pancreas, the total mass of endocrine tissue was calculated. It averaged 1395 mg in control subjects, 413 mg in Type 1 and 1449 mg in Type 2 diabetic patients. The loss of endocrine tissue observed in the Type 1 patients was almost restricted to the lobe poor in pancreatic polypeptide cells. In these patients, B cells were practically absent (at the most seven per section), but the 'atrophic islets' still contained numerous A, D, or pancreatic polypeptide cells. The mass of A, D and pancreatic polypeptide cells and the ratio of D to A cells were not different from those measured in the control subjects. This shows that the disappearance of B cells in Type 1 diabetes has no preferential effect on any other endocrine cell of the pancreas. In Type 2 diabetes, the mass of A cells was increased, whereas that of B, D and pancreatic polypeptide cells was not changed. This hyperplasia of A cells leads to a decrease in the ratio of B to A and of D to A cells. These alterations may enlighten certain aspects of the physiopathology of Type 2 diabetes.

The duct-ligated pancreas transplant and its effect on the islet cellular composition of the host pancreas. A morphometric analysis.

Rats rendered diabetic by streptozotocin were subjected to pancreas transplantation. After twenty weeks, the duct-ligated pancreas transplant was studied morphometrically to determine the effect of duct occlusion on the various cell populations of the islets. Concomitantly, the streptozotocin-treated host pancreas was examined for a possible influence of the graft on the diabetic pattern of islet cell population. Twenty weeks after pancreas transplantation, the volume fractions of insulin, glucagon, somatostatin and pancreatic polypeptide cells in the graft islets did not differ from those of the normal control pancreas. In the pancreas of nontransplanted diabetic rats, insulin-positive B cells were reduced from 60-65% to less than 10% of the islet volume, whereas non-B cells were significantly increased in volume density. The changes in fractional volume of the various islet cells correlated fairly well with changes in plasma concentration of the corresponding pancreas hormones. In the recipient's own pancreas, the relative volumes of glucagon and somatostatin cells were unaffected by the pancreas transplant. However, the insulin cell mass was significantly increased, and comprised about 20% of the islet volume, while cells containing pancreatic polypeptide were found only sporadically.

Recent advances in pancreatic hormone research.

Summary The pancreas secretes 4 major polypeptide hormones: insulin from the beta cells; pancreatic glucagon from the alpha cells; somatostatin from the D cells in the islets of Langerhans, and pancreatic polypeptide (PP) from the PP cells which are spread more diffusely through pancreatic exocrine and endocrine tissue. Some or all of these 4 hormones may also have paracrine effects; this means that the peptide is secreted locally and has metabolic effects on neighbouring cells. Gastrin is synthesized in G cells in the foetal pancreas, but these cells disappear postnatally. Certain other polypeptides such as vasoactive intestinal polypeptide (VIP) have also been demonstrated in human pancreas, but appear predominantly localized to nerves; these substances, which were initially classified as ‘gut hormones’, are now thought to be neurotransmitters or neuromodulators of the non-adrenergic, non-cholinergic branch of the autonomic nervous system. In view of the multiple modes of actions of these peptides, the descriptive term ‘regulatory peptides’ is now often used. Basic information about the peptides to be discussed is listed in Table 1, but it should be emphasized that many of them exist in multiple molecular forms. The purpose of this review is to discuss some primarily non-diabetic aspects of the physiology and pathophysiology of pancreatic polypeptides which have recently received attention.

The pancreatic polypeptide cells in the human pancreas: the effects of age and diabetes.

Pancreases from insulin-dependent diabetics (IDDM), noninsulin-dependent diabetics (NIDDM), and nondiabetic subjects were analyzed by stereological and morphometrical methods in order to determine the weight of the lobe rich in pancreatic polypeptide (PP) cells in relation to the total weight of the pancreas and the volume density of PP cells in both parts of the gland, those rich and poor in PP cells. In control subjects, neither the relative weight of the lobe rich in PP cells, nor the volume density of PP cells varied significantly with aging. In IDDM and NIDDM, the volume density of PP cells was similar to that observed in control subjects. The total weight of the pancreas was markedly decreased in IDD because of an almost selective atrophy of the lobe poor in PP cells; the relative weight of the lobe rich in PP cells was thus much higher than that in control subjects. A less marked atrophy, restricted to the lobe poor in PP cells, was also observed in NIDDM. It is suggested that PP may exert a local trophic role which protects the lobe of the pancreas rich in PP cells from atrophy in diabetic patients. The results further show that the elevated levels of PP in the plasma of elderly or diabetic subjects cannot be ascribed to a hyperplasia of PP cells.

Pancreatic polypeptide (PP) cells in the PP-rich lobe of the human pancreas are identified ultrastructurally and immunocytochemically as F cells.

The ultrastructure of immunohistochemically identified PP cells has been investigated by applying the serial semithin/thin section technique to the human pancreas, with special reference to the posterior part of the head, reputed to originate from the ventral primordium. PP cells of this area differ from those already identified in the rest of the pancreas and correspond to a cell, not yet described in the human pancreas, characterized by larger granules of very variable shape and structure. Such granules resemble those of so-called "F cells", i.e. the PP cells of dog uncinate process and cat duodenal lobe, also coming from the ventral primordium. Thus, human "ventral lobe" PP cells have peculiar potentialities which are expressed in distinctive structural patterns of presently unknown functional meaning.

Sex difference in the sensitivity of the human pancreatic polypeptide cell to autonomic nervous stimulation in man.

We have examined the plasma human pancreatic polypeptide (hPP) response to beta-adrenergic (infusion of epinephrine-phentolamine), vagal cholinergic, (insulin-hypoglycemia), and extravagal cholinergic (secretion infusion) stimulation in healthy, nonobese, age-matched males and females. beta-Adrenergic stimulation caused a rise in plasma hPP concentration in males that was 6 times that of females, whereas there were no differences between the sexes in the mean responses of pulse rate, systolic and diastolic blood pressure, or in plasma concentrations of glucose, insulin, and glucagon. Extravagal cholinergic stimulation caused increases of hPP secretion that were similar in males and females. Insulin-induced hypoglycemia was the most efficacious stimulus, and caused a similar rise in hPP response in males and females. Thus, in males there is greater sensitivity of the hPP cell to beta-adrenergic stimulation than females. The plasma hPP responses appear to be a more sensitive, discriminating index of adrenergic autonomic function than cardiovascular and other pancreatic hormonal responses.

Mechanism of elevated serum pancreatic polypeptide concentrations in chronic renal failure.

Basal serum concentrations of pancreatic polypeptide (PP) in five patients with chronic renal failure (CRF; 165-2100 pmol/liter) were significantly (P less than 0.01) higher than those in six age-matched normal control subjects (18-54 pmol/liter). Ingestion of a mixed meal resulted in significantly (P less than 0.01) larger increases in serum PP in patients with CRF (245-1740 pmol/liter) than in the normal subjects (72-196 pmol/liter). The iv administration of somatostatin (125 micrograms as a bolus injection, followed by infusion of 125 micrograms/h) to two patients with CRF and two normal subjects completely abolished postprandial PP release. By administering the same dose of somatostatin 60 min after ingestion of the meal, the disappearance rate of endogenously released PP could be estimated. The half-life of disappearance for PP in patients with CRF (t1/2 = 13.2 +/- 1.8 min) was significantly (P less than 0.01) increased compared to that in the normal subjects (t1/2 = 5.6 +/- 0.8 min). Sephadex G-50 column chromatography of basal sera from three patients with CRF revealed three major peaks of PP: one eluting in the void volume, one coeluting with the 4200 molecular weight human PP standard, and one in between. The PP peak coeluting with standard PP comprised 64 +/- 3% of total PP immunoreactivity. Ingestion of food, followed by subsequent infusion of somatostatin, resulted in marked changes in the PP peak coeluting with standard PP, while the two larger molecular forms remained relatively unchanged. At least three findings may be related to the mechanism of elevated serum PP concentrations in patients with CRF: 1) the presence of large molecular forms of PP, 2) a slower disappearance rate for postprandially released PP, and 3) increased postprandial secretion of PP indicating hyperresponsiveness of PP cells to physiological stimuli.

Regional distribution of pancreatic polypeptide cells in the 21-day fetal rat pancreas.

21-day fetal rat pancreata were stained with the unlabeled antibody peroxidase-antiperoxidase technique using bovine pancreatic polypeptide as the primary antibody. Total counts of pancreatic polypeptide cells were made over the entire pancreas. It was found that the head region contained the greatest number of pancreatic polypeptide cells with the body next and the tail having the smallest number. The pancreatic polypeptide cells of the body were concentrated in the portion closest to the distal duodenum. This distribution pattern seems to support the suggested role of pancreatic polypeptide on the physiological function of the digestive tract.

Islet cell surface antibodies from insulin-dependent diabetics bind specifically to pancreatic B cells.

Viable rat islet cells were used to detect islet cell surface antibodies (ICSA) in the sera of diabetic and control patients. ICSA were present in almost all recent-onset insulin-dependent diabetics younger than 30 yr (15/16); their incidence in other diabetics (6/22) was also higher than in normal controls (1/18) or in patients with autoimmune thyroiditis (1/12). The varying specificity of the ICSA for the different islet cell types led to the recognition of class I sera, whose ICSA bind exclusively to B cells, class II sera, binding only to A and pancreatic polypeptide (PP) cells and class III sera, reacting with the three islet cell types but not with D cells. Most recent-onset insulin-dependent diabetics younger than 30 contained class I-ICSA, which is consistent with an autoimmune basis of their disease and with an involvement of surface antibodies in the B cell destruction. The presence of class II ICSA in three older diabetics and in one normal control raises the question whether autoimmune reactions against A and PP cells exist and are associated with a distinct entity in islet disease. It is concluded that the autoimmune form of diabetes mellitus represents a heterogeneous group, in which ICSA-positive patients can be distinguished on the basis of their ICSA-binding to one or more islet cell types. Three techniques can be used for the further identification of circulating ICSA, namely binding experiments with purified A or B cells, electron microscopical analysis of ICSA-binding islet cells purified by fluorescence-activated cell sorting, and the immunocytochemical characterization of ICSA-positive cells.

Glicentin precedes glucagon in the developing human pancreas.

A quantitative evaluation of immunofluorescence elicited by anti-insulin, anti-glucagon, anti-glicentin, anti-somatostatin and anti-pancreatic polypeptide antisera has been carried out in the pancreas of 5 human fetuses from 3.0 to 9.6 cm C.R. The data obtained indicate that while insulin and somatostatin-containing cells are approximately in similar proportions with respect to the other endocrine cell types in the five fetuses studied, the glucagon and glicentin immunoreactive cells and the pancreatic polypeptide cells are not : a) pancreatic polypeptide-containing cells increase in proportion as fetuses grow older; b) the youngest fetuses (3.0 to 4.3 cm C.R.) contain a high proportion of cells reacting to anti-glicentin antiserum only (GLI-cells) and a small proportion of cells stained both with the anti-glicentin and anti-glucagon antisera (GLI/GLU-cells). However, the latter cell type which stains similarly as the postnatal and adult pancreatic A-cell (GLI-cells are not detectable in the postnatal and adult pancreas) increases iin proportion in older fetuses, while the proportion of GLI-cells decrease. The data suggest that the definitive adult-type A-cell matures from a GLI-cell type which is not able to convert glucagon precursors GLI(s) into glucagon.

Isolation and biogenesis of a new peptide from pancreatic islets.

Pancreatic polypeptide (PP) was discovered as a major peptide contaminant of insulin preparations1,2. The peptide is stored in a distinct endocrine cell type3 that is the predominating islet cell in the duodenal part of the pancreas4 and it is released in response to physiological events, including food intake5 and decrease in blood glucose6,7. Furthermore, infusions of PP mimicking physiological fluctuations in plasma concentrations of the peptide affect gastrointestinal functions, by inhibiting exocrine pancreatic secretion8–10 and relaxing the gallbladder10,11. Although the PP cell is more sensitive to small reductions in blood glucose than is the glucagon cell6, many studies have failed to demonstrate any metabolic effect of PP12,13. it is recognized that the biogenesis of secretory peptides by conversion of larger precursors results in multiple peptide fragments of which more than one might be bioactive14–16. Recently we identified a precursor of PP with a molecular weight (Mr) of 8,000–10,000 and showed, by pulse-chase experiments and peptide mapping, that this biosynthetically labelled precursor was converted into a low molecular weight peptide in addition to PP17. We report here the isolation and primary structure of this icosapeptide and show how it arises through an intermediate form by post-translational modification of the COOH-terminal part of the PP precursor. This second product of pro-pancreatic polypeptide conversion might fulfill the physiological potential of the major endocrine cell type of the duodenal pancreas.

Immunohistochemical evidence of peptide hormones in endocrine tumors of the rectum.

Twenty-five endocrine tumors of the rectum (rectal carcinoids) were examined immunohistochemically for various pancreatic and gut neurohormonal polypeptides. Twenty-one of the tumors were found to contain cells displaying pancreatic polypeptide (PP), glucagon, somatostatin, insulin, substance P, enkephalin or beta-endorphin immunoreactivity. At least 11 of the tumors contained more than one peptide hormone. In some of the tumors PP cells made up the major cell population, in others the glucagon cells constituted the majority. Only four of the tumors contained 5-hydroxytryptamine. Rectal endocrine tumors seem unique among gut endocrine tumors in that they may store immunoreactive enkephalin, beta-endorphin and even insulin. None of the patients displayed the carcinoid syndrome; symptoms were usually vague and uncharacteristic. In many cases the tumor was found at routine examination.

Four pancreatic endocrine cells in the bullfrog ( Rana catesbeiana)

The pancreas of the bullfrog was studied by the immunoperoxidase method and electron microscopy for hormone-storing cells and radioimmunoassay for content of four pancreatic hormones. Immunoperoxidase staining disclosed four cell types, namely insulin, glucagon, somatostatin (SRIF), and pancreatic polypeptide (PP) cells with regional differences of distribution: the hepatic process contained relatively small islets with abundant insulin, glucagon, and PP cells, and a few SRIF cells, whereas the duodenal process contained relatively large islets with abundant insulin cells and scattered glucagon and SRIF cells. There were few PP cells in the duodenal process. The morphology of four distinct secretory granules was confirmed by electron microscopy. The amount of the four hormones was estimated by nonhomologous radioimmunoassay and compared with the levels of immunoreactive hormone measured in human pancreas.

The effect of treatment of type 2 (insulin independent) diabetes mellitus on plasma concentrations of pancreatic polypeptide and glucagon.

The effect of the control of diabetes with diet and insulin upon plasma levels of human pancreatic polypeptide and glucagon was determined in eight patients with Type 2 (insulin independent) diabetes mellitus. The mean +/- SEM fasting plasma glucose was 15.9 +/- 1.3 mmol/l for 5 days of diet treatment and 5.9 +/- 0.4 mmol/l for the last 5 days of treatment with diet plus insulin (p less than 0.0001); corresponding fasting plasma pancreatic polypeptide levels were 328 +/- 97 and 247 +/- 71 pg/ml (p less than 0.05) and immunoreactive glucagon levels were 95 +/- 11 and 62 +/- 6 pg/ml (p less than 0.005). Cooked ground beef was administered on the first day of diet treatment and on the last day of treatment with diet plus insulin; mean maximal rise of pancreatic polypeptide, and total and incremental plasma pancreatic polypeptide response areas were significantly lower following treatment (p less than 0.01), as was total area for immunoreactive glucagon (p less than 0.05). Normalisation of fasting plasma glucose by short-term treatment with diet plus insulin is associated with decreases in basal and stimulated secretory activity of the pancreatic polypeptide cells in insulin independent diabetes mellitus.

Developmental changes in pancreatic endocrine function in the young calf.

1. Pancreatic endocrine responses to 2-deoxyglucose (1.2 mmol/kg I.V.) known to be mediated via the autonomic innervation, have been investigated in calves 24 h after birth and the results compared with those obtained previously in older calves (Bloom, Edwards & Hardy, 1978). 2. Neurally mediated insulin release was found to be defective in the calf at 24 h, whereas the capacity to release both pancreatic glucagon and pancreatic polypeptide (PP) in response to 2-deoxyglucose appears to be fully developed at this age. 3. Both the release of glucagon and of PP from the pancreas which occurred under these conditions were suppressed by I.V. infusions of glucose (17 mumol . kg-1 . min-1) which raised the arterial plasma glucose concentration of unsuckled 24-h-old calves to the level normally encountered in suckled calves of the same age. 4. Closely similar changes in the haematocrit and plasma cortisol concentration occurred in both suckled and unsuckled 24-h-old calves in response to 2-deoxyglucose, suggesting that the intensity of the stimulus to the brain was equipotent and that glucose inhibits the release of glucagon and PP by a direct action on the alpha and PP cells respectively. 5. closely similar changes in plasma PP concentration were observed in suckled and unsuckled 24-h-old calves in response to 2-deoxyglucose, in spite of the higher plasma glucose concentration in the former group. It is concluded that the PP response is potentiated by some unidentified factor in suckled calves.

Quantitative morphology of B, A, D, and PP cells in infants of diabetic mothers.

Pancreatic specimens from 34 infants of diabetic mothers (IDM) and 32 control infants of gestational ages 26-44 wk were examined histologically using immunocytochemical stains for insulin, glucagon, somatostatin, and pancreatic polypeptide (PP). Each section was divided into PP-rich and PP-poor regions that are thought to be derived from the ventral and dorsal lobes of the gland, respectively. In some of these, the fractional area (%) occupied by positively stained B, A, and PP cells was determined by automatic image analysis, and the area occupied by D cells was determined by conventional point counting. The B cell fractional area was significantly higher in the IDM in both PP-poor and PP-rich areas (P less than 0.02). the fractional area of A cells in PP-poor areas and of PP cells in PP-rich areas was also significantly greater in IDM (P less than 0.02). The total endocrine cell fractional area was significantly greater in IDM in PP-poor but not in PP-rich regions of the pancreas. These results are not compatible with the hypothesis that maternal hyperglycemia results in specific fetal B cell hyperplasia and raise the possibility that hyperplasia of B, A, and PP cells in IDM may result from a variety of stimuli or that one stimulus acts on a pluripotential stem cell.

Gut-hormone profile in totally pancreatectomised patients.

In eight totally pancreatectomised patients the release of the relevant gut hormones was determined after a standard test meal. Plasma levels of pancreatic glucagon were not significantly different from zero in our series of pancreatectomised patients. Pancreatic polypeptide was undetectable. These findings imply the absence of a significant number of normally functioning alpha cells and pancreatic polypeptide cells in extrapancreatic sites in man. Consistent with the antrectomy, duodenectomy, and resection of the upper jejunum that are performed in conjunction with a total pancreatectomy the gastrin release was significantly impaired. In contrast there was a striking post-prandial rise in enteroglucagon probably induced by the rapid intestinal transit time often seen after partial gastrectomy. In contrast plasma motilin and GIP levels were normal. Pancreatectomised man thus presents an interesting model of total deficiency of endogenous insulin, pancreatic polypeptide, and pancreatic glucagon and, in addition, greatly diminished gastrin. The considerable derangement of metabolic and intestinal function that follows total pancreatectomy may, in part, be explained by this gross disturbance of the normal physiology of gut hormone.

Update on pancreatic polypeptide as a specific marker for endocrine tumours of the pancreas and gut.

Serum levels of pancreatic polypeptide (PP) were determined in 31 patients with endocrine tumours, localized in the pancreas (n = 16), small intestine (n = 13) and respiratory tract (n = 2). Two further patients with laxative abuse were investigated. Elevated serum levels in the peripheral circulation were noted in 56% of the patients with pancreatic tumours, in 60% of those with gut or bronchial tumours and in both patients with laxative abuse. Our study suggests that the elevated PP concentrations found in connection with endocrine gastrointestinal tumours originate from non-tumour pancreatic PP cells and only occasionally from the tumour. PP is a valuable tumour marker for endocrine gastrointestinal tumours, although it is not specific for pancreatic tumours. Certain inflammatory diseases, renal function and consumption of laxatives must be considered when evaluating elevated PP levels. Serum PP seems to be of limited value for evaluating the response to cytotoxic therapy.