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Prevention of autoimmune diabetes by oral administration of syngeneic pancreatic extract to young NOD mice.

Oral administration of relevant autoantigens is being considered as a realistic approach for the prevention of several autoimmune diseases. In this study we administered, orally, to young female NOD/Ak mice (diabetes incidence, 40%) and NOD/LtJ mice (diabetes incidence, 70%) whole pancreatic extract on days 19, 20, 21, 22, 23, 26, and 27 and studied its effects on the development of diabetes until day 250. The cumulative incidence of diabetes in both the colonies after pancreatic extract treatment was compared with the incidence after oral administration of syngeneic liver extract or in untreated mice. In the NOD/Ak mice, the incidence of diabetes in the pancreatic extract group was significantly lower (6%; n = 34, p = 0.004) and was delayed compared with 33% in the liver group (n = 34) and 44% in the untreated group (n = 18). Significant protection from diabetes and a delay in its onset also were observed in the NOD/LtJ mice treated with pancreatic extract (16%; n = 19, p = 0.002) compared with those liver extract treated (72%; n = 18) and in untreated mice (60%; n = 22). Pancreatic histology at day 90 from all the study groups showed that the protection from diabetes in the pancreatic-extract group was not associated with reduced insulitis. We speculate that the marked disease protection observed in this study with orally administered pancreatic extract may be associated with the presence of immunoregulatory cells with a predominant Th2 cytokine bias. Our studies may have implications for the prevention of insulin-dependent diabetes mellitus (IDDM) in humans.

Administration, Oral↗

Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis.

Dysuria, uric acid crystalluria and hyperuricosuria developed in a child with cystic fibrosis and normal serum uric acid. Hyperuricosuria in this patient and two other children was directly related to ingestion of large amounts of pancreatic extract. In these three children, reducing pancreatic extract dosage by 85 percent lowered their purine intake by 307, 225, and 148 mg, respectively; urinary uric acid excretion decreased by 245, 239, and 158 mg. Overmedication resulted from parents' decisions to increase enzyme dosages. In our cystic fibrosis clinic, 15 of 32 patients screened at random were taking higher than the prescribed dose of pancreatic enzymes, and 14 of these 15 children were hyperuricosuric. On the basis of this information, we suggest that the minimal effective dose of pancreatic extract should be determined and adhered to for each child with cystic fibrosis to avoid potential renal injury from hyperuricosuria.

Administration, Oral↗

Pancreatic extract lung sensitivity.

Seven patients with respiratory tract sensitivity to powdered pig pancreatic extract were studied with regard to their atropic status and the immunological nature of this sensitivity. The results confirmed the role of allergen specific antibodies to pig pancreatic extract in this sensitization and underlined susceptibility of atopic subjects to develop respiratory sensitivity to allergens to which they are exposed.

Adolescent↗

Effect of insulin, proinsulin and pancreatic extract on myelination and remyelination in organotypic nerve tissue in culture.

The effect of insulin, proinsulin and crude pancreatic extract was studied in organotypic nerve tissue cultures, principally in relation to the development of myelin. Cultures were exposed to media supplemented with these substances beginning on the first day of explantation. By 4 days in vitro, there was a good neuritic outgrowth from all the fragments. That from the insulin and pancreatic extract-fed were more profuse and extended further than from the control group. By 8-12 days in vitro it was also possible to observe more myelinated axons in these treated groups. The pattern of changes in the myelin associated enzyme activity, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) paralleled the differential increase in myelination. Insulin-fed cultures showed a more rapid increase in CNPase activity, which, after 21 days in vitro reached a plateau about 30-50% over that of the controls. Cultures treated with pancreatic extract showed a similar pattern of increased activity, while in proinsulin-treated explants the activity was only significantly higher after 21 days in vitro. To study the effect of these substances on remyelination, well myelinated cultures were completely demyelinated by exposure to anti-white matter antiserum and were subsequently exposed to the same normal control or supplemented media. The amount of myelin and concomitantly the CNPase activity increased rapidly and in the same proportion between the various groups as was observed previously during primary myelination. Insulin as well as crude pancreatic extract and, to some extent, proinsulin demonstrated a marked effect on the time of onset and principally on the total amount of myelin developed by treated cultures as compared to those maintained in normal nutrient medium.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

[Effect of orally administered pancreatic extract on Vibrio cholerae infection during protein deficiency].

Two groups of 5 and 6 Vervet monkeys respectively were fed a protein-free diet. Both groups of protein depleted Vervets developed a minor decrease of serum and intestinal immunoglobulins, as well as marked impairment of exocrine pancreatic function. Thereafter the groups were challenged with Vibrio cholerae, while one group received purified pancreatic extract by oral administration. The group without pancreatic extract developed severe and significantly longer lasting diarrhea than the group with pancreatic extract. Vibrios were excreted for much longer in the former group. It is concluded that exocrine pancreatic function is involved in the local defence mechanism against cholera during protein deficiency.

Animals↗

Comparison of carboxymethyl-cellulose cation-exchange chromatography and high-performance liquid chromatography in the purification of guinea-pig insulin from pancreatic extracts.

Guinea-pig insulin was purified from pancreatic extracts either by carboxymethyl-cellulose cation-exchange chromatography with a sodium chloride gradient or by high-performance liquid chromatography (HPLC) on octadecyl silica with mixtures of acetonitrile and phosphate buffer. HPLC proved to be superior to ion-exchange chromatography in the purification of insulin with respect both to time saving and to the purity of the product.

Animals↗

Hypersensitivity to pancreatic extracts in parents of patients with cystic fibrosis.

Because immediate hypersensitivity reactions can occur in individuals exposed to powdered pancreatic extracts, 36 patients with cystic fibrosis and 51 patents of such patients wwer studied for evidence of sensitization. Sensitivity to the extracts as evidence by history and skin testing was infrequent in the children with cystic fibrosis. However, skin testing for immediate hypersensitivity with either crude pancreatic extracts or inactivated trypsin correlated well in their patents with a history of clinical symptoms. IgE mediation of these reactions in sensitized individuals was demonstrated by antigen-induced histamine release from leukocytes, passive transfer studies, and immediate response to inhalation challenge.

Adult↗

Urotensin-II is present in pancreatic extracts and inhibits insulin release in the perfused rat pancreas.

OBJECTIVE: Previous work from our laboratory has demonstrated that frog urotensin-II (UII), at a high concentration, inhibits glucose-induced insulin release in the rat pancreas. We have investigated the effect of rat UII and two structural analogs on insulin secretion and searched for the presence of UII-immunoreactivity in rat pancreatic extracts. METHODS: The study was performed in the perfused rat pancreas. UII as well as its analogs were synthesized by solid phase methodology. Pancreatic extracts were analyzed for UII by reversed-phase HPLC combined with a sensitive UII RIA. RESULTS: Infusion of synthetic rat UII inhibited glucose-induced insulin release in a dose-dependent manner (IC(50): 0.12 nmol/l). UII (1 nmol/l) also inhibited the insulin responses induced by carbachol, glucagon-like peptide-1, and a calcium channel agonist (BAY K 8644). The inhibitory effect of UII was mimicked by the potent G protein-coupled receptor (GPR14) agonist [3-iodo-Tyr(6)]UII(4-11). In contrast, [Ala(8)]UII(4-11), a UII analog devoid of contractile activity on rat aortic rings, did not affect glucose-induced insulin secretion. Analysis of rat pancreatic extracts revealed the presence of an immunoreactive peptide exhibiting the same retention time as synthetic rat UII. CONCLUSIONS: Our results demonstrate that UII is a potent insulinostatic peptide. The observation that UII is actually present in the pancreas suggests that this peptide may play a physiological role in the control of insulin secretion. Concerning the two UII analogs tested, only [3-iodo-Tyr(6)]UII(4-11), reportedly possessing GPR14-mediated contractile activity, mimics the insulinostatic effect of UII. This finding would support the view that UII acts on the pancreatic beta cell through the GPR14 receptor.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Enhancement of mouse pancreatic regeneration and HIT-T15 cell proliferation with rat pancreatic extract.

In this study, the effects of rat pancreatic extract (RPE) on regeneration of impaired mouse pancreas and proliferation of beta-cell line (HIT-T15) were investigated. RPE from the regenerating pancreas (2 days after 60% pancreatectomy) was treated to cure streptozotocin (STZ) induced diabetes in BALB/c mice. RPE-treated BALB/c mice for 21 consecutive days became euglycemic by day 30 and remained normoglycemic during a 150 day follow-up. Saline treated mice remained hyperglycemic sustained uncontrolled hyperglycemia. Islet neogenesis was observed in RPE-treated mice and confirmed by use of immunocytochemistry. Morphometric analysis of pancreas in reverted RPE-treated mice showed a new population of small islets compared with saline controls and an increased islet number. When HIT-T15 cells were treated with RPE, HIT-T15 cell proliferation and insulin secretion increased with increases in the RPE concentration. These results imply that RPE have the regeneration factors and help in the cure of diabetes.

Animals↗

IgE mediated hypersensitivity to pancreatic extract (PE) in parents of cystic fibrosis (CF) children.

On exposure to pancreatic extract (PE), four parents of cystic fibrosis (CF) children developed immediate hypersensitivity-like symptoms: i.e. rhinoconjunctivitis, asthma, and/or anaphylaxis. IgE to PE was demonstrated in the subjects by skin testing, leucocyte histamine release and radioallergosorbent test (RAST). No serum precipitating antibodies were found. Bronchial challenge caused an immediate asthmatic response. No delayed asthmatic response or hypersensitivity pneumonitis-like reaction occurred. The responsible antigen for PE induced asthma is unknown; trypsin failed to inhibit PE-RAST and is therefore not responsible in these subjects. Caution should be exercised in using PE for skin testing and bronchial challenge in subjects with suspected hypersensitivity to PE. Certain measures were found useful in preventing the occurrence of symptoms in the four subjects.

Adult↗

Assessment of the effectiveness of drug therapies on nutritional status in the elderly: "concerning a randomised, double-blind clinical study of the activity of pancreatic extracts and a placebo during the renutrition of elderly subjects suffering from protein caloric undernutrition".

AIMS: to study, versus placebo, the value of administering pancreatic extracts in elderly subjects suffering from denutrition. METHODS: 52 subjects over 70 years of age, living in the Toulouse region of France, were included in this study. Each subject was required to present with an impaired nutritional status of their food intake, anthropometric and laboratory markers. RESULTS: among the 52 patients included in the study, 26 received the placebo and 26 received a pancreatic extract (Créon 12,000). 88% of these patients were women and 12% were men, the mean age of patients was 87+/-6 years. The groups were comparable at entry into the study. Nutritional intake increased in the two groups. There was a non-significant increase in body weight in the treated group when compared with the placebo group. DISCUSSION: we think that in the future, it would be preferable to conduct studies in convalescent subjects, reducing the frequency of nutritional assessments (food intake on D0 and D90, to reduce interference with the patient's habits.

Aged↗

Microbial adjuvant and autoimmunity. IV. Production of lesions in the exocrine pancreas of mice by repeated injection of syngeneic pancreatic extract together with the capsular polysaccharide of Klebsiella pneumoniae.

Definite lesions in the exocrine pancreas were produced when SMA mice were immunized eight times at intervals of 30 days with a mixture of extract of pooled pancreas from syngeneic mice and the capsular polysaccharide of Klebsiella pneumoniae type I Kasuya strain (CPS-K), whereas no pancreatic lesions were produced in mice given CPS-K alone or pancreatic extract alone. The typical histological changes were characterized by infiltration with lymphocytes, plasma cells, and other mononuclear cells, degeneration and lysis of the acinar cells, destruction of the lobular architecture, and replacement of fatty tissue and fibrous connective tissue. The endocrine islets were well preserved. No specific histological changes were produced in the organs other than the pancreas in these mice. Most of mice immunized with pancreatic extract mixed with CPS-K produced serum precipitins to syngeneic pancreatic antigens. However, severe pancreatic lesions were also produced in mice showing no definite precipitin production.

Adjuvants, Immunologic↗

Bronchial asthma due to allergy to pancreatic extract: a hazard in the treatment of cystic fibrosis.

The mother of two children suffering from cystic fibrosis developed marked allergic symptoms affecting the eyes, nose and bronchi and severe bronchial asthma ensued. The cause of this allergy proved to be the powder released on opening the capsules of pancreatic extract which she provided for her children at each mealtime. The risk of pancreatic extract to those handling it, and possibly also to patients suffering from cystic fibrosis, is emphasized.

Adult↗

Pancreatic extract and the intestinal uptake of vitamin B12. II. Inhibitory effect of trypsin and trypsinogen.

Pancreatic extract (PE) contained small-molecular, thermo-stable as well as macro-molecular, thermo-labile factors capable of reducing the uptake of 57CoB12 bound to rat intrinsic factor by perfused rat intestinal segments (p less than 0.01 and p less than 0.01). Neither non-radioactive vitamin B12 nor non-pacreatic protein reduced the 57CoB12-uptake (p greater than 0.5 and p greater than 0.1) Crystalline trypsin and trypsinogen, but not chymotrypsin, also inhibited the uptake (p less than 0.05, p less than 0.02 and p greater than 0.05). The tryptic inhibition was abolished by soybean trypsin inhibitor (p greater than 0.05).

Animals↗