Increase In Pancreas Weight Research Articles

214-LB: Activating and Disrupting the Liver–Alpha-Cell Axis Respectively Enhances and Impairs Amino Acid Metabolism and Alpha-Cell Growth

Amino acids control alpha cell secretion and growth, while glucagon stimulates hepatic amino acid uptake and ureagenesis, forming the liver-alpha cell axis. Patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes have increased levels of glucagon and amino acids pointing to a disrupted liver-alpha cell axis. Both glucagon agonism and antagonism are explored for diabetes and NAFLD therapy but their effects on the axis are unclear. Female C57Bl/6JRj mice were treated with a long-acting glucagon analogue (GCGA, NNC9204-0043, Novo Nordisk A/S) or PBS twice daily, or once weekly with a GCGR antibody (GCGR Ab, REGN1193, Regeneron) or control antibody (Ctl. Ab, REGN1945, Regeneron) . After four weeks, total plasma amino acids were decreased by 48% in GCGA mice (P=0.0006) and increased by 285% in GCGR Ab mice (P<0.0001) versus week 0. At week 4, 18 of 19 amino acids were reduced in GCGA mice and increased in GCGR Ab mice. Asparagine changed the most in both groups, with a mean fold change of 0.21 and 7.50 in GCGA and GCGR Ab mice, respectively. Plasma urea index ([urea]/[amino acids]) was increased by 36% in GCGA mice (P=0.055) and decreased by 61% in GCGR Ab mice (P=0.001) . Liver RNA-sequencing revealed opposite effects of GCGA and GCGR Ab on expression of amino acid transporters (e.g. Slc43a) and ureagenesis genes (e.g. Ass1) . Activity of carbamoyl phosphate synthetase 1 was increased by 27% in GCGA versus PBS mice (P=0.007) and decreased by 33% in GCGR Ab mice versus Ctl. Ab (P=0.002) . GCGA lowered pancreas weight and glucagon content by 15% (P=0.004) and 95% (P<0.0001) compared to PBS. Conversely, GCGR Ab mice had a 34% increase in pancreas weight versus Ctl. Ab (P=0.0009) . Thus, chronically increased GCGR signaling leads to hypoaminoacidemia and decreased alpha cell mass, while chronically decreased GCGR signaling leads to hyperaminoacidemia and increased alpha cell mass. These changes must be considered when developing glucagon-based therapeutics. Disclosure E. E. Christensen: None. J. J. Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. N. J. Wewer albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc., Speaker's Bureau; Merck & Co., Inc., Mercodia AB. K. D. Galsgaard: None. C. D. Johansen: None. S. Trammell: None. A. B. Bomholt: None. J. Hunt: None. T. Kruse: Employee; Novo Nordisk. J. F. Lau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. T. Grevengoed: None. Funding Nicolai J. Wewer Albrechtsen is supported by NNF Excellence Emerging Investigator Grant ? Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude (1052-00003B) . Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (grant agreement NNF14CC0001) .

Gut Microbiota Regulate Pancreatic Growth, Exocrine Function, and Gut Hormones.

Growing evidence indicates an important link between gut microbiota, obesity, and metabolic syndrome. Alterations in exocrine pancreatic function are also widely present in patients with diabetes and obesity. To examine this interaction, C57BL/6J mice were fed a chow diet, a high-fat diet (HFD), or an HFD plus oral vancomycin or metronidazole to modify the gut microbiome. HFD alone leads to a 40% increase in pancreas weight, decreased glucagon-like peptide 1 and peptide YY levels, and increased glucose-dependent insulinotropic peptide in the plasma. Quantitative proteomics identified 138 host proteins in fecal samples of these mice, of which 32 were significantly changed by the HFD. The most significant of these were the pancreatic enzymes. These changes in amylase and elastase were reversed by antibiotic treatment. These alterations could be reproduced by transferring gut microbiota from donor C57BL/6J mice to germ-free mice. By contrast, antibiotics had no effect on pancreatic size or exocrine function in C57BL/6J mice fed the chow diet. Further, 1 week vancomycin administration significantly increased amylase and elastase levels in obese men with prediabetes. Thus, the alterations in gut microbiota in obesity can alter pancreatic growth, exocrine function, and gut endocrine function and may contribute to the alterations observed in patients with obesity and diabetes.

The effect of melatonin on adrenal gland and pancreas function in alloxan – induced diabetes in adult female rabbits

The present study was carried out to investigate the ameliorative effect of melatonin on pancreatic and adrenal dysfunction induced by alloxan in adult female rabbits. Twenty four adult female rabbits were randomly divided into four equal groups treated for 42 days as follows: control group received 2 ml of distal water intraperitoneally, animals of the second group received single dose of 150 mg /kg of alloxan (group T1), while the third group received single dose of 150 mg/kg of alloxan and after 7 days received 10mg/kg I/P of melatonin for 42 days of experiment (T2 group). The fourth group received 10 mg/kg I/P of melatonin for 42 days .After the 7 days of alloxan injection the blood is collected from (T1) and (T2) animals, to investigate of diabetes induction in these groups. Also blood samples were collected at zero time, 14, 28 and 42 days of the experiment for measuring the serum concentration of glucose, total protein, total cholesterol, reduce glutathione and hormones concentration (insulin and cortisol). The result of present study indicated that melatonin administration is not affected in body weight in rabbits to T2 and T3 as compared with control group, while (T1) group showed significant decrease in these parameters as compared with other groups. The adrenal gland weight to body weight ratio showed significant increase in adrenal weight in (T1) as compared with all other group while T2 and T3 groups showed significant decrease as compared with T1 groups. While the pancreas gland weight to body weight ratio showed significant increase in pancreas weight in (T3) group as compared with other groups. Animals T1 and T2 groups showed significant decrease as compared with T3 and control groups. Animals T1 group showed significant elevation in serum glucose, total cholesterol and serum cortisol concentration as compared with control, T2 and T3 groups. The results also showed a significant decrease in total serum protein, serum insulin and reduce glutathione concentrations in alloxan treated group (T1) as compared with control, T2 and T3 animals. Inferred from the result of this experiment is treatment of diabetic female rabbits with melatonin (10 mg /kg .B.W) for 42 days lead to improve the function of adrenal gland and pancreas gland. Also it showed the possibility of reducing oxidative stress triggered by alloxan through the use of melatonin.

Effect of Pectin on the Activity of Pancreatic α-Amylase in Growing Rats with Lead Intoxication

This study was conducted to know the effect of pectin on the α-amylase activity in the pancreas, intestine content and blood in growing rats with lead intoxication. After a single oral administration of lead acetate (80 mg/kg) to growing rats pectin was administered (400 mg/kg/12h) for 4 days. It is revealed that the administration of lead acetate causes an increase in pancreas weight, protein content in the pancreas and α-amylase activity in the pancreas and blood and reduced activity of the enzyme in the intestinal cavity in rats. Regular oral administration of pectin has a normalizing effect on pancreatic weight, protein content and on the level of the activity α-amylase in the pancreas, intestinal contents and blood in the 48-72 hours of observation in rats. These results support our suggestion about the possibility of the use of pectin for correcting of pancreatitis similar shifts at lead intoxication.

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks' duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks' dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.

The ontogeny of the endocrine pancreas in the fetal/newborn baboon

Erratic regulation of glucose metabolism including hyperglycemia is a common condition in premature infants and is associated with increased morbidity and mortality. The objective of this study was to examine histological and ultrastructural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons. Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140d GA, or 175d GA. Eight animals were delivered at term (185d GA); half were fed for 5 days. Seventy-three nondiabetic adult baboons were used for comparison. Pancreatic tissue was studied using light microscopy, confocal imaging, and electron microscopy. The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of α-β-δ-cell type were similar within each fetal and newborn GA (NS) but were higher than the adults (P<0.05) regardless of GA. The ratio of β cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons, which survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared with their counterparts killed at birth (P=0.01). Endocrine cells were also found in exocrine ductal and acinar cells in 125, 140 and 175d GA fetuses. Subpopulation of tissue that coexpressed trypsin and glucagon/insulin shows the presence of cells with mixed endo-exocrine lineage in fetuses. In summary, the fetal endocrine pancreas has no prevalence of a α-β-δ-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long-term implications.

The gastrin receptor promotes pancreatic growth in transgenic mice.

We demonstrated previously, in two different rodent models of pancreatic cancer, that the gastrin receptor is present on malignant pancreatic tumors in spite of the fact that the normal adult rat and mouse pancreas does not express gastrin receptors. To determine whether gastrin receptors mediate pancreatic growth or promote carcinogenesis or both, we created a transgenic mouse that constitutively expresses gastrin receptors in the exocrine pancreas. The transgene construct contained the full-length rat gastrin receptor cDNA sequence under the control of the rat elastase promoter. Receptor presence and function on exocrine pancreatic tissue of transgenic but not control mice were confirmed by (125)I-gastrin-I binding studies and by gastrin stimulation of intracellular calcium release. Eighteen-month-old transgenic animals had larger pancreas-to-body weight ratios than their nontransgenic littermate controls (p < 0.001 for females; p < 0.01 for males); however, histopathologic examination revealed no neoplasms or other abnormalities. In both female and male transgenic mice, the expression of the gastrin receptor in the exocrine pancreas is associated with a significant increase in pancreas weight, but it does not appear to promote the development of spontaneous pancreatic tumors.

Effect of troglitazone on exocrine pancreas in rats with streptozotocin-induced diabetes mellitus.

Abnormality of pancreatic exocrine secretion has been observed in patients with diabetes mellitus. Troglitazone is a novel insulin-sensitizing agent that improves hyperglycemia and hyperinsulinemia in insulin-resistant diabetes mellitus. We investigated the effect of troglitazone on exocrine pancreas in streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal injection of STZ (25 mg/kg), and then 0.2% troglitazone containing rat chow was given for 2 weeks. Control diabetic animals received normal rat chow for 2 weeks. Glucose tolerance tests were performed before and after the administration of troglitazone. Pancreas weight, enzyme, protein, and insulin contents in the pancreas were measured. For the exocrine secretory study, pure pancreatic juice was collected hourly. Plasma glucose concentrations stimulated by the oral administration of 2.5 g/kg glucose in the troglitazone-treated group were significantly lower than those in the control group, but not plasma insulin concentrations. Pancreas weight in diabetic rats was less than that in normal rats. Administration of troglitazone resulted in a significant increase in pancreas weight and amylase and trypsin output. However, protein and insulin contents were not affected by the treatment with troglitazone. Both basal and cholecystokinin (CCK-8; 26 pmol/kg/h) stimulated exocrine secretion in juice volume, amylase, and trypsin output were markedly decreased in diabetic rats, compared with those in normal rats. Impaired basal and CCK-stimulated pancreatic exocrine secretion in diabetic rats recovered to the normal levels when troglitazone was given. In conclusion, troglitazone might be effective to restore exocrine pancreatic insufficiency in STZ-diabetic rats.

The Effect of Faba Beans (Vicia faba L.) on the Performance of Turkey Poults and Broiler Chicks from 0–4 Weeks of Age

Experiments were conducted with turkey poults and broiler-type chicks to evaluate faba beans (Vicia faba L.) in poultry rations.Feeding starter rations containing 5, 10 or 20% ground raw faba beans to turkey poults produced no adverse effects on growth and feed efficiency, but inclusion of autoclaved ground faba beans reduced growth as the level of the beans in the diet was increased from 5 to 20%, suggesting a loss in the availability of some amino acids due to heat treatment.Feeding either raw or autoclaved ground faba beans in chick starter rations at levels of 5, 10 or 20 percent produced no deleterious effects on growth rate, hemoglobin concentration or pancreas weight. However, when the diet contained 35% ground faba beans there was a non-significant reduction in weight gain and a significant increase in pancreas weight. Feeding autoclaved ground faba beans at the 35% level increased weight gain and decreased pancreas weight.The tannin content of 4 varieties of faba beans was determined. The concentration of tannins in whole faba beans ranged from 0.34% to 0.50%. The testa contained a greater proportion of the total tannins (phenolics) than the embryo.The trypsin inhibitor activity of crude faba bean extract was found to be about one twenty-fifth that of crude raw soybean extract.

The effect of trypsin inhibitors on pancreatopeptidase E, trypsin, chymotrypsin and amylase in the pancreas and intestinal tract of chicks receiving raw and heated soya-bean diets.

1. Feeding on a raw soya-bean diet (RSD) increased the levels of trypsin, chymotrypsin and pancreatopeptidase E but decreased the level of amylase in the pancreas of chicks as compared to a heated soya-bean diet (HSD), while supplementation of HSD with soya-bean trypsin inhibitors increased the activity of all four enzymes. HSD + trypsin inhibitors caused significant enlargement of the pancreas but only a slight depression in growth rate.2. Fasting for 24 h of chicks previously given RSD and HSD increased the activity of all four enzymes but the increase was much greater in chicks previously given RSD than in those previously given HSD.3. Feeding RSD for 4 d to chicks previously adapted to HSD resulted in a dramatic inhibition in growth rate, a small increase in pancreas weight, and an increase in the activity of all proteolytic enzymes, while no change in the amylase was detectable.4. Trypsin, chymotrypsin and pancreatopeptidase E activities were assayed in the contents of the small intestine and caecum of chicks fed on RSD or HSD over a period of 35 d. Trypsin and chymotrypsin activities in the small intestine were lower in chicks fed on RSD while pancreatopeptidase E activity was almost equal or even higher in RSD-fed chicks, especially at the age of 35 d. Trypsin activity in the caecum of RSD-fed chicks was lower at all stages of the experiment, while the pancreatopeptidase E and chymotrypsin activities in the caecum of RSD-fed chicks exceeded the levels in the HSD group at the age of 21 and 35 d respectively. It would appear therefore that pancreatopeptidase E may play an important part in overcoming the inhibition of the proteolytic activity in the intestine of chicks fed on RSD.

Overcoming the Inhibition of Intestinal Proteolytic Activity Caused by Raw Soybean in Chicks of Different Ages

The response of the chicks to transfer from a heated soybean diet (HSD) to a raw soybean diet (RSD) was studied at different ages from one to 6 weeks. The proteolytic activity in the small intestine, nitrogen content of intestinal chyme and pancreas hypertrophy were investigated. An initial inhibition of proteolytic activity was observed at all ages studied. The ability to overcome the inhibition when examined between 1 to 6 weeks generally appears to increase with age. Increase in pancreas weight was noticed after the raw soybean diet had been fed for even one day. Nitrogen content of the chyme was higher in chicks with the RSD than with the HSD indicating an interference of the RSD with normal protein digestion. The study with underprocessed soybean diet showed intermediate results between the HSD and RSD. The probable factors responsible for the rate and length of inhibited proteolytic activity in the small intestine are discussed.

THE INFLUENCE OF THE THYROID GLAND ON THE ISLETS OF LANGERHANS AND THE PANCREAS

When sufficiently large amounts of desiccated thyroid gland were administered to intact or hypophysectomized rats there was an increase in the weight of the pancreas, weight of the islets of Langerhans, and islet weight per unit of body weight. In intact rats the concentration of islet tissue in the pancreas was not significantly altered, but in hypophysectomized animals the concentration of islet tissue in the pancreas was reduced because of the large increase in pancreas weight. The great reduction in pancreas weight occasioned by hypophysectomy was to a large extent prevented by the administration of desiccated thyroid gland.

THE INFLUENCE OF THE THYROID GLAND ON THE ISLETS OF LANGERHANS AND THE PANCREAS

When sufficiently large amounts of desiccated thyroid gland were administered to intact or hypophysectomized rats there was an increase in the weight of the pancreas, weight of the islets of Langerhans, and islet weight per unit of body weight. In intact rats the concentration of islet tissue in the pancreas was not significantly altered, but in hypophysectomized animals the concentration of islet tissue in the pancreas was reduced because of the large increase in pancreas weight. The great reduction in pancreas weight occasioned by hypophysectomy was to a large extent prevented by the administration of desiccated thyroid gland.