Pancreatic Growth Factors Research Articles

Group II p21-activated kinase, PAK4, is needed for activation of focal adhesion kinases, MAPK, GSK3, and β-catenin in rat pancreatic acinar cells.

PAK4 is the only member of the Group II p21-activated kinases (PAKs) present in rat pancreatic acinar cells and is activated by gastrointestinal hormones/neurotransmitters stimulating PLC/cAMP and by various pancreatic growth factors. However, little is known of the role of PAK4 activation in cellular signaling cascades in pancreatic acinar cells. In the present study, we examined the role of PAK4's participation in five different cholecystokinin-8 (CCK-8)-stimulated signaling pathways (PI3K/Akt, MAPK, focal adhesion kinase, GSK3, and β-catenin), which mediate many of its physiological acinar-cell effects, as well as effects in pathophysiological conditions. To define PAK4's role, the effect of two different PAK4 inhibitors, PF-3758309 and LCH-7749944, was examined under experimental conditions that only inhibited PAK4 activation and not activation of the other pancreatic PAK, Group I PAK2. The inhibitors' effects on activation of these five signaling cascades by both physiological and pathophysiological concentrations of CCK, as well as by 12-O-tetradecanoylphobol-13-acetate (TPA), a PKC-activator, were examined. CCK/TPA activation of focal adhesion kinases(PYK2/p125FAK) and the accompanying adapter proteins (paxillin/p130CAS), Mek1/2, and p44/42, but not c-Raf or other MAPKs (JNK/p38), were mediated by PAK4. Activation of PI3K/Akt/p70s6K was independent of PAK4, whereas GSK3 and β-catenin stimulation was PAK4-dependent. These results, coupled with recent studies showing PAK4 is important in pancreatic fluid/electrolyte/enzyme secretion and acinar cell growth, show that PAK4 plays an important role in different cellular signaling cascades, which have been shown to mediate numerous physiological and pathophysiological processes in pancreatic acinar cells.NEW & NOTEWORTHY In pancreatic acinar cells, cholecystokinin (CCK) or 12-O-tetradecanoylphobol-13-acetate (TPA) activation of focal adhesion kinases (p125FAK,PYK2) and its accompanying adapter proteins, p130CAS/paxillin; Mek1/2, p44/42, GSK3, and β-catenin are mediated by PAK4. PI3K/Akt/p70s6K, c-Raf, JNK, or p38 pathways are independent of PAK4 activation.

Pleiotropic roles of the insulin-like growth factor axis in type 1 diabetes.

We review studies demonstrating lowered levels of insulin-like growth factors (IGFs) in patients with recent-onset type 1 diabetes (T1D) and discuss their potential roles in the disorder's pathogenesis. IGFs have long been recognized as a class of hormones that promote growth, development, and cellular metabolism throughout the human body. More recently, studies have noted an association between reduced pancreatic weight/volume and T1D. Thus, we believe it is important to understand pancreatic regulation of IGF expression and bioavailability, as well as the impact of IGFs on pancreatic growth and islet health. Additional studies of IGFs have been extended to their influence on the inflammatory/regulatory balance of monocytes, B cells, and T cells; features which have been previously established to show dysregulation in settings of T1D. These data suggest that IGFs may prevent known impairments in the pancreas and immune system in T1D and underscore the need to extend these studies, some of which were performed in health or other autoimmune diseases, toward T1D specifically. Collectively, the work emphasized here support the potential therapeutic use of IGFs in T1D prevention efforts as pancreatic growth factors and/or immunoregulatory agents.

P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades.

p21-activated kinases (PAKs) are highly conserved serine/threonine protein kinases, which are divided into two groups: group-I (PAKs1-3) and group-II (PAKs4-6). In various tissues, Group-II PAKs play important roles in cytoskeletal dynamics and cell growth as well as neoplastic development/progression. However, little is known about Group-II PAK's role in a number of physiological events, including their ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth factors (GFs). We used rat pancreatic acini to explore the ability of GI hormones/neurotransmitters/GFs to activate Group-II-PAKs and the signaling cascades involved. Only PAK4 was detected in pancreatic acini. PAK4 was activated by endothelin, secretagogues-stimulating phospholipase C (bombesin, CCK-8, and carbachol), by pancreatic GFs (insulin, insulin-like growth factor 1, hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor), and by postreceptor stimulants (12-O-tetradecanoylphobol-13-acetate and A23187 ). CCK-8 activation of PAK4 required both high- and low-affinity CCK1-receptor state activation. It was reduced by PKC-, Src-, p44/42-, or p38-inhibition but not with phosphatidylinositol 3-kinase-inhibitors and only minimally by thapsigargin. A protein kinase D (PKD)-inhibitor completely inhibited CCK-8-stimulated PKD-activation; however, stimulated PAK4 phosphorylation was only inhibited by 60%, demonstrating that it is both PKD-dependent and PKD-independent. PF-3758309 and LCH-7749944, inhibitors of PAK4, decreased CCK-8-stimulated PAK4 activation but not PAK2 activation. Each inhibited ERK1/2 activation and amylase release induced by CCK-8 or bombesin. These results show that PAK4 has an important role in modulating signal cascades activated by a number of GI hormones/neurotransmitters/GFs that have been shown to mediate both physiological/pathological responses in acinar cells. Therefore, in addition to the extensive studies on PAK4 in pancreatic cancer, PAK4 should also be considered an important signaling molecule for pancreatic acinar physiological responses and, in the future, should be investigated for a possible role in pancreatic acinar pathophysiological responses, such as in pancreatitis. NEW & NOTEWORTHY This study demonstrates that the only Group-II p21-activated kinase (PAK) in rat pancreatic acinar cells is PAK4, and thus differs from islets/pancreatic cancer. Both gastrointestinal hormones/neurotransmitters stimulating PLC and pancreatic growth factors activate PAK4. With cholecystokinin (CCK), activation is PKC-dependent/-independent, requires both CCK1-R affinity states, Src, p42/44, and p38 activation. PAK4 activation is required for CCK-mediated p42/44 activation/amylase release. These results show PAK4 plays an important role in mediating CCK physiological signal cascades and suggest it may be a target in pancreatic acinar diseases besides cancer.

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

P-21-activated kinases (PAKs) are serine/threonine kinases comprising six isoforms divided in two groups, group-I (PAK1–3)/group-II (PAK4–6) which play important roles in cell cytoskeletal dynamics, survival, secretion and proliferation and are activated by diverse stimuli. However, little is known about PAKs ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth-factors. We used rat pancreatic acini to explore the ability of GI-hormones/neurotransmitters/growth-factors to activate Group-I-PAKs and the signaling cascades involved. Only PAK2 was present in acini. PAK2 was activated by some pancreatic growth-factors [EGF, PDGF, bFGF], by secretagogues activating phospholipase-C (PLC) [CCK, carbachol, bombesin] and by post-receptor stimulants activating PKC [TPA], but not agents only mobilizing cellular calcium or increasing cyclic AMP. CCK-activation of PAK2 required both high- and low-affinity-CCK1-receptor-state activation. It was partially reduced by PKC- or Src-inhibition, but not with PI3K-inhibitors (wortmannin, LY294002) or thapsigargin. IPA-3, which prevents PAK2 binding to small-GTPases partially inhibited PAK2-activation, as well as reduced CCK-induced ERK1/2 activation and amylase release induced by CCK or bombesin. This study demonstrates pancreatic acini, possess only one Group-I-PAK, PAK2. CCK and other GI-hormones/neurotransmitters/growth-factors activate PAK2 via small GTPases (CDC42/Rac1), PKC and SFK but not cytosolic calcium or PI3K. CCK-activation of PAK2 showed several novel features being dependent on both receptor-activation states, having PLC- and PKC-dependent/independent components and small-GTPase-dependent/independent components. These results show that PAK2 is important in signaling cascades activated by numerous pancreatic stimuli which mediate their various physiological/pathophysiological responses and thus could be a promising target for the development of therapies in some pancreatic disorders such as pancreatitis.

Human iPS cell-derived insulin producing cells form vascularized organoids under the kidney capsules of diabetic mice.

Type 1 diabetes (T1D) is caused by autoimmune disease that leads to the destruction of pancreatic β-cells. Transplantation of cadaveric pancreatic organs or pancreatic islets can restore normal physiology. However, there is a chronic shortage of cadaveric organs, limiting the treatment of the majority of patients on the pancreas transplantation waiting list. Here, we hypothesized that human iPS cells can be directly differentiated into insulin producing cells (IPCs) capable of secreting insulin. Using a series of pancreatic growth factors, we successfully generated iPS cells derived IPCs. Furthermore, to investigate the capability of these cells to secrete insulin in vivo, the differentiated cells were transplanted under the kidney capsules of diabetic immunodeficient mice. Serum glucose levels gradually declined to either normal or near normal levels over 150 days, suggesting that the IPCs were secreting insulin. In addition, using MRI, a 3D organoid appeared as a white patch on the transplanted kidneys but not on the control kidneys. These organoids showed neo-vascularization and stained positive for insulin and glucagon. All together, these data show that a pancreatic organ can be created in vivo providing evidence that iPS cells might be a novel option for the treatment of T1D.

Human iPS Cell-Derived Insulin Producing Cells Form Organoids In Vivo That Are Glucose Responsive in Diabetic Mice.

Type I diabetes (T1D) is a condition caused by autoimmune destruction of pancreatic β-cells. The consequences of T1D are dysregulation of metabolism with severe consequences for the cardiovascular system, nervous system and kidney function. Islet and whole pancreatic organ transplantation are the most effective ways to treat T1D. Unfortunately, the shortage of cadaveric organs is a major obstacle to the management of T1D patients. Thus, an alternative source of insulin producing cells (IPCs) could significantly improve patient treatment. Here, we seek to establish induced pluripotent stem (iPS) cells as a novel source of IPCs that are patient tailored, obviating the need for immunosuppression. If successful, such an alternative could provide for a novel unlimited source of IPCs. For the generation of IPCs, we hypothesized that 3D differentiation of iPS cells into IPCs enhances the efficiency of pancreatic endocrine differentiation due to the increased cell-cell contact and scaffold-embedded signaling, giving rise to superior organoids that more efficiently secrete insulin and are glucose responsive. Thus, we developed a novel matrigel culture platform for generating IPCs from human iPS cells. This process follows a few simple steps: first we drive iPS cells to form the endoderm through signaling with Activin A. These cells are then exposed to specific pancreatic growth factors that induce the expression of the pancreatic master regulator Pdx1, among other transcription factors. Subsequently the Pdx1+ pancreatic precursor cells are exposed to nicotinamide and IGF-1 for another 6-10 days. Subsequently, the cell clusters develop into large spheroids that appear solid or hollow. On staining for pancreatic hormones, the solid spheroids, but not the hollow vacuoles, were strongly positive for insulin. These IPCs partially secrete insulin in vitro after stimulation with high glucose. Remarkably, when placed under the kidney capsule of diabetic mice, they form organoids that display neovascularization and regulate hyperglycemia. Thus, our data show that dermal fibroblasts can be reprogrammed into iPS cells, which when assembled into high density cell clusters with access to matrigel signaling and pancreatic growth factors, can generate IPCs that are glucose responsive. This strategy provides an alternative source of IPCs with the potential for clinical management of T1D.

The Src kinase Yes is activated in pancreatic acinar cells by gastrointestinal hormones/neurotransmitters, but not pancreatic growth factors, which stimulate its association with numerous other signaling molecules

For growth factors, cytokines, G-protein-coupled receptors and numerous other stimuli, the Src Family of kinases (SFK) play a central signaling role. SFKs also play an important role in pancreatic acinar cell function including metabolism, secretion, endocytosis, growth and cytoskeletal integrity, although the specific SFKs involved are not fully known. In the present study we used specific antibodies for the SFK, Yes, to determine its presence, activation by pancreatic secretagogues or growth factors, and interaction with cellular signaling cascades mediated by CCK in which Yes participates in to cause acinar cell responses. Yes was identified in acini and secretagogues known to activate phospholipase C (PLC) [CCK, carbachol, bombesin] as well as post-receptor stimulants activating PKC [TPA] or mobilizing cellular calcium [thapsigargin/calcium ionophore (A23187)] each activated Yes. Secretin, which activates adenylate cyclase did not stimulate Yes, nor did pancreatic growth factors. CCK activation of Yes required both high- and low-affinity CCK1-receptor states. TPA-/CCK-stimulated Yes activation was completely inhibited by thapsigargin and the PKC inhibitor, GF109203X. CCK/TPA stimulated the association of Yes with focal adhesion kinases (Pyk2, FAK) and its autophosphorylated forms (pY397FAK, pY402Pyk2). Moreover, CCK/TPA stimulated Yes interacted with a number of other signaling proteins, including Shc, PKD, p130Cas, PI3K and PTEN. This study demonstrates that in rat pancreatic acini, the SFK member Yes is expressed and activated by CCK and other gastrointestinal hormones/neurotransmitters. Because its activation results in the direct activation of many cellular signaling cascades that have been shown to mediate CCK's effect in acinar cell function our results suggest that it is one of the important pancreatic SFKs mediating these effects.

Gastrointestinal growth factors and hormones have divergent effects on Akt activation

Akt is a central regulator of apoptosis, cell growth and survival. Growth factors and some G-protein-coupled receptors (GPCR) regulate Akt. Whereas growth-factor activation of Akt has been extensively studied, the regulation of Akt by GPCR's, especially gastrointestinal hormones/neurotransmitters, remains unclear. To address this area, in this study the effects of GI growth factors and hormones/neurotransmitters were investigated in rat pancreatic acinar cells which are high responsive to these agents. Pancreatic acini expressed Akt and 5 of 7 known pancreatic growth-factors stimulate Akt phosphorylation (T308, S473) and translocation. These effects are mediated by p85 phosphorylation and activation of PI3K. GI hormones increasing intracellular cAMP had similar effects. However, GI-hormones/neurotransmitters [CCK, bombesin, carbachol] activating phospholipase C (PLC) inhibited basal and growth-factor-stimulated Akt activation. Detailed studies with CCK, which has both physiological and pathophysiological effects on pancreatic acinar cells at different concentrations, demonstrated CCK has a biphasic effect: at low concentrations (pM) stimulating Akt by a Src-dependent mechanism and at higher concentrations (nM) inhibited basal and stimulated Akt translocation, phosphorylation and activation, by de-phosphorylating p85 resulting in decreasing PI3K activity. This effect required activation of both limbs of the PLC-pathway and a protein tyrosine phosphatase, but was not mediated by p44/42 MAPK, Src or activation of a serine phosphatase. Akt inhibition by CCK was also found in vivo and in Panc-1 cancer cells where it inhibited serum-mediated rescue from apoptosis. These results demonstrate that GI growth factors as well as gastrointestinal hormones/neurotransmitters with different cellular basis of action can all regulate Akt phosphorylation in pancreatic acinar cells. This regulation is complex with phospholipase C agents such as CCK, because both stimulatory and inhibitory effects can be seen, which are mediated by different mechanisms.

The Src family kinase, Lyn, is activated in pancreatic acinar cells by gastrointestinal hormones/neurotransmitters and growth factors which stimulate its association with numerous other signaling molecules

Src family kinases (SFK) play a central signaling role for growth factors, cytokines, G-protein-coupled receptors and other stimuli. SFKs play important roles in pancreatic acinar cell secretion, endocytosis, growth, cytoskeletal integrity and apoptosis, although little is known of the specific SFKs involved. In this study we demonstrate the SFK, Lyn, is present in rat pancreatic acini and investigate its activation/signaling. Ca 2+-mobilizing agents, cAMP-mobilizing agents and pancreatic growth factors activated Lyn. CCK, a physiological regulator of pancreatic function, rapidly activated Lyn. The specific SFK inhibitor, PP2, decreased Lyn activation; however, the inactive analogue, PP3, had no effect. Inhibition of CCK-stimulated changes in [Ca 2+] i decreased Lyn activation by 55%; GFX, a PKC inhibitor by 36%; and the combination by 95%. CCK activation of Lyn required stimulation of high and low affinity CCK A receptor states. CCK stimulated an association of Lyn with PKC-δ, Shc, p125 FAK and PYK2 as well as with their autophosphorylated forms, but not with Cbl, p85, p130 CAS or ERK 1/2. These results show Lyn is activated by diverse pancreatic stimulants. CCK's activation of Lyn is likely an important mediator of its ability to cause tyrosine phosphorylation of numerous important cellular mediators such as p125 FAK, PYK2, PKC-δ and Shc, which play central roles in CCK's effects on acinar cell function.

Activation of Gab1 in pancreatic acinar cells: Effects of gastrointestinal growth factors/hormones on stimulation, phosphospecific phosphorylation, translocation and interaction with downstream signaling molecules

The scaffolding/adapter protein, Gab1, is a key signaling molecule for numerous stimuli including growth factors and G protein-coupled-receptors (GPCRs). A number of questions about Gab1 signaling remain and little is known about the ability of gastrointestinal (GI) hormones/neurotransmitters/growth factors to activate Gab1. Therefore, we examined their ability to activate Gab1 and explored the mechanisms involved using rat pancreatic acini. HGF and EGF stimulated total Gab1 tyrosine phosphorylation (TyrP) and TyrP of Gab1 phospho-specific sites (Y307, Y627), but not other pancreatic growth factors, GI GPCRs (CCK, bombesin, carbachol, VIP, secretin), or agents directly activating PKC or increasing Ca 2+. HGF-stimulated Y307 Gab1 TyrP differed in kinetics from total and Y627. Neither GF109203X, nor inhibition of Ca 2+ increases altered HGF's effect. In unstimulated cells > 95% of Gab1 was cytosolic and HGF stimulated a 3-fold increase in membrane Gab1. HGF stimulated equal increases in pY307 and pY627 Gab1 in cytosol/membrane. HGF stimulated Gab1 association with c-Met, Grb2, SHP2, PI3K, Shc, Crk isoforms and CrkL, but not with PLCγ1. These results demonstrate that only a subset of pancreatic growth factors (HGF/EGF) stimulates Gab1 signaling and no pancreatic hormones/neurotransmitters. Our results with Gab1 activation with different growth factors, the role of PKC, and its interaction with distant signaling molecules suggest the cellular mechanisms of Gab1 signaling show important differences in different cells. These results show that Gab1 activation plays a central role in HGF's ability to stimulate intracellular transduction cascades in pancreatic acinar cells and this action likely plays a key role in HGF's ability to alter pancreatic cell function (i.e., growth/regeneration).

Microparticles for delivering therapeutic peptides and proteins to the lumen of the small intestine

Several different peptides and proteins, such as the pancreatic trypsin inhibitor, growth factors and trefoil peptides, are known to play important roles in maintaining the structure and function of the gastrointestinal wall. With the advent of recombinant biotechnology, it has become feasible to test some of these proteins as therapeutics in different inflammatory conditions of the intestines. However, the harsh pH and enzymatic conditions of the stomach can lead to their inactivation. This research was aimed at the development of particulate, gastric-resistant pharmaceutical forms, incorporating those bioactive molecules. Mixtures of proteins in powder form were coated with cellulose acetate phthalate, Eudragit ® S100 or Eudragit ® RS PO, using simple preparation techniques based on single emulsion/solvent evaporation. Using aprotinin as a model drug, it was found that these procedures were effective in microencapsulating protein in the solid form without affecting its biological activity. Furthermore, and in particular with the first two polymers above, particles showed adequate in vitro release patterns for the applications envisioned.

Microencapsulation and tissue engineering as an alternative treatment of diabetes.

In the 70's, pancreatic islet transplantation arose as an attractive alternative to restore normoglycemia; however, the scarcity of donors and difficulties with allotransplants, even under immunosuppressive treatment, greatly hampered the use of this alternative. Several materials and devices have been developed to circumvent the problem of islet rejection by the recipient, but, so far, none has proved to be totally effective. A major barrier to transpose is the highly organized islet architecture and its physical and chemical setting in the pancreatic parenchyma. In order to tackle this problem, we assembled a multidisciplinary team that has been working towards setting up the Human Pancreatic Islets Unit at the Chemistry Institute of the University of São Paulo, to collect and process pancreas from human donors, upon consent, in order to produce purified, viable and functional islets to be used in transplants. Collaboration with the private enterprise has allowed access to the latest developed biomaterials for islet encapsulation and immunoisolation. Reasoning that the natural islet microenvironment should be mimicked for optimum viability and function, we set out to isolate extracellular matrix components from human pancreas, not only for analytical purposes, but also to be used as supplementary components of encapsulating materials. A protocol was designed to routinely culture different pancreatic tissues (islets, parenchyma and ducts) in the presence of several pancreatic extracellular matrix components and peptide growth factors to enrich the beta cell population in vitro before transplantation into patients. In addition to representing a therapeutic promise, this initiative is an example of productive partnership between the medical and scientific sectors of the university and private enterprises.

Lactational changes in the rat exocrine pancreas somatostatin receptors and modulation of guanylate cyclase

Hyperplasia of the pancreatic tissue during late lactation (third week) and lasting for at least the first two weeks after weaning has been observed by several authors. Since the tetradecapeptide somatostatin (SS) inhibits pancreatic growth and its plasma levels are elevated during these periods, the aim of the present study was to determine the possible implication of the somatostatinergic system in the pancreatic changes cited above. Thus, the present study investigated 125I-Tyr 11-somatostatin ( 125I-Tyr 11-SS) binding and the effects of SS on guanylate cyclase activity as well as pancreatic somatostatin-like immunoreactivity (SSLI) levels in pancreatic acinar membranes from control, lactating and weaning rats. SS receptors were identified using 125I-Tyr 11-SS and isolated pancreatic acinar membranes in vitro. There was an increase in the number of SS receptors after the third week of lactation (244 ± 6 vs. 155 ± 12 mol/mg protein, P < 0.01) and the first two weeks after weaning (327 ± 8 vs. 155 ± 10 mol/mg protein, P < 0.001). No change in the affinity of the receptor site was detected at either study time. In addition, SS-stimulated guanylate cyclase activity was markedly increased at the third week of lactation (119%) and at the second week after weaning (158%) when compared with the control group. In contrast, basal guanylate cyclase activity was not modified at either study period. Thus, SS-stimulated guanylate cyclase activity is increased in pancreatic acinar membranes at late lactation and at the second week after beginning weaning probably due to an increase in the number of SS receptors. Significant decreases in SSLI content were observed at the third week of lactation (69%) and the second week after weaning (37%) when compared with the respective controls. The present results suggest that pancreatic acinar cell growth observed at the third week of lactation and the second week after weaning is associated with up-regulation of SS receptors which would represent a mechanism promoted by the cell that would negatively regulate the mitogenic activity of the increased number of pancreatic growth factors observed during both periods.

Somatostatin binding capacity, guanylate cyclase and tyrosine phosphatase activities during pancreatic proliferation in the rat induced by gastrectomy

Gastrectomy increased pancreatic growth and this effect was associated with an increase in the number of somatostatin-14 (SS) receptors (146% of control) without altering their affinity. SS increased guanylate cyclase activity twofold in pancreatic acinar membranes from gastrectomized rats. The gastrectomy decreased pancreatic SS-like immunoreactivity (SS-LI) content (55% of control levels) and tyrosine phosphatase activity (74% of control levels). Administration of proglumide (20 mg/kg, IP), a gastrin/cholecystokinin (CCK) receptor antagonist, suppressed the inhibitory effect of gastrectomy on basal tyrosine phosphatase activity and SS-LI content, which returned to control levels. Furthermore, proglumide suppressed the increase of the number of SS receptors and of SS-stimulated guanylate cyclase activity induced by gastrectomy. All this suggests that pancreatic acinar cell growth is associated with upregulation of SS receptors, which could represent a mechanism promoted by the cell to negatively regulate the mitogenic activity of pancreatic growth factors such as CCK. In addition, the results also suggest that the negative regulation of tyrosine phosphatase activity may be important in the events involved in the pancreatic hyperplasia observed after gastrectomy.

The role of pancreatic and nonpancreatic hormones in normal pancreatic function and growth

To come further in the understanding of this disease it is essential to understand the biology of the disease and to evaluate the pronounced metabolic disturbances observed in patients with pancreatic cancer~ Almost no other malignant disease has a more powerful impact on body metabolism and composition than pancreatic cancer, especially if related to tumor size. A marked weight-loss often seen and the mortality is more often associated with cachexia rather than to carcinomatosis per se. Studies at our institution indicate that the tumor's endocrine activity plays an important role in the biology of pancreatic carcinoma. This is indicated by the fact that up to 80% of the patients with pancreatic carcinoma have an impaired glucose tolerance at diagnosis (3). The present workshop with the title "Endocrine aspects of exocrine pancreatic cancer" will highlight the current knowledge of pancreatic hormones and growth factors in relation to pancreatic cancer.

Nutritional aspects of the short bowel syndrome

Adequate oral nutrition in patients with short bowel syndrome after operation is limited by the amount of intestine left after resection. The remnant small intestine has an important capacity to compensate for the loss of mucosal tissue and develops intestinal hyperplasia when stimulated by a variety of luminal and extraluminal factors such as nutrients, pancreatic biliary secretions, growth factors and hormones. In order to provide appropriate stimuli for the intestinal adaptation after resection, oral feeding is necessary as early as possible after operation. Among nutrients fat, especially LCT and free fatty acids, are the most stimulating nutrients besides proteins and carbohydrates. They increase pancreatic biliary secretions and the excretion of growth promoting hormones such as enteroglucagon. Because of gastric acid hypersecretion the administration of H2 receptor blocking agents (cimetidine) is recommended in these patients. As oral caloric intake is not sufficient in most patients with short bowel syndrome after operation total parenteral nutrition (TPN) or home-TPN has to be installed for longer periods to supplement the appropriate nutritional needs. Both early oral feeding together with TPN or home-TPN have increased considerably the survival rate of children with short bowel syndrome.

Corticosteroids and CCK-PZ as potential pancreatic growth factors in nursing rats

Corticosteroids and CCK-PZ as potential pancreatic growth factors in nursing rats