Pancreatic Hypertrophy Research Articles

#1073 Changes in endothelial function in patients with impaired central and renal hemodynamics respiratory pathology

Abstract Background and Aims To determine the degree of influence of endothelial dysfunction on the hemodynamics of renal and central vessels in respiratory pathology, as well as to determine the effectiveness of complex therapy regimens with carvedilol. Method Studies were conducted in 26 patients with chronic obstructive pulmonary disease (COPD) of II- III severity (group 1, in whom the level of glomerular filtration rate of the kidneys eGFR CKD-EPI ≥6 ml/min/1.73 m2 was determined) and 32 patients with COPD of IV severity (group 2, they were determined e GFR CKD-EPI ≥60 ml/min/1.73 m2). Patients received one course of ten-day standard therapy (GOLD, 2020) in combination with a beta–blocker drug, T. carvedilol 5 mg (Vertex). Doppler echocardiographic examination of peripheral vessels, heart and renal vessels of patients was performed. Stable metabolites of nitric oxide (Cm NO) in blood plasma, ventilation and perfusion state of the lungs were determined. Results A significant decrease in the functional state of the respiratory system was parallel with a decrease in Cm NO synthesis, which was clearly reflected in the second group (by 11%) compared with the first group (by 7%). Pronounced structural changes with remodeling of the right parts of the heart, as well as a pronounced degree of pancreatic hypertrophy in the second group were accompanied by a sharp change in renal filtration function (eGFR ≤60 ml/min/1.73 m2). When measuring the state of diastolic dysfunction of the right parts of the heart, a decrease in E/As well as an increase in the circulatory vascular resistance index and mean blood pressure were significantly higher in the first group of patients (where еGFR ≥6 ml/min/1.73 m2). After a course of treatment with t. carvedilol, based on basic treatment, normalization of endothelial function was determined, reflected in an increase in the concentration of stable metabolites of nitric oxide by 1.05 and 1.5 times (p<0.05) in the biological fluid, respectively, in the first and second groups. In the dynamics of the course of therapy in groups of patients with 75% and 35% decrease in lung ventilation capacity, mean pulmonary arterial pressure decreased by 18.1 and 14.3%, respectively, and the hemodynamic resistance index decreased by 7.9% and 5.7% in parallel (p<0.05). Conclusion When monitoring the functional state of central and renal hemodynamics and ventilation-perfusion function of the bronchopulmonary system after complex treatment with carvedilol, a long-term hypotensive effect, a decrease in endothelial dysfunction, respectively, and an improvement in central and renal hemodynamics were determined.

The chronic pancreatitis (CP) Type Cambridge 2 as a cause of unclear upper abdominal pain: a radiologically underestimated diagnosis

AbstractThe time interval from symptom onset to the diagnosis of chronic pancreatitis (CP) remains disproportionately long today due to nonspecific symptoms and the absence of a definitive laboratory marker. Nevertheless, mortality is increased by 3.6 times compared to the general population. Additionally, the risk of developing pancreatic carcinoma is 16 times higher in the presence of CP. According to the current S3 guideline, the morphological staging of CP should be based on the Cambridge Classification for CT/MRCP. Most radiologists morphologically associate CP with Cambridge Stage 4, which is characterized by classic calcifications. The subtle morphologies of earlier Cambridge Stages are often unrecognized, leading to delayed diagnosis. The aim of this study was to diagnose CP at Cambridge Stage 2 as the cause of unexplained upper abdominal discomfort.A retrospective analysis was conducted on 266 patients with unexplained upper abdominal pain who underwent outpatient MRI with MRCP between January 1, 2021, and October 1, 2023. The criteria for Cambridge Stage 2 were evaluated: pancreatic duct in the corpus measuring between 2 and 4 mm, pancreatic hypertrophy, cystic changes < 10 mm, irregularities in the duct, or > 3 pathological side branches. Patients with known tumors or other leading diagnoses, which explained the discomfort, were excluded.25 patients (15 female, 10 male) met the criteria for CP Stage 2 (9%). Ductal dilation between 2 and 4 mm was visible in 21 cases. Pancreatic hypertrophy was observed in six cases. Cystic changes < 10 mm were identified in three cases. Irregularities in the duct (“wavy duct”) were diagnosed in 19 patients. Dilation of > 3 side branches was recognized in 17 cases. Lipase levels were additionally determined, with 13 patients showing pathologically elevated levels (> 60 U/l).CP at Cambridge Stage 2 is an important and underestimated diagnosis in patients with unexplained upper abdominal pain in the outpatient setting. Radiologists should pay attention not only to common signs like calcifications, large cysts, or duct strictures but also to subtle changes such as duct irregularities (“wavy duct configuration”) and pathologically dilated side branches, which could lead to a significantly earlier diagnosis of CP. Lipase determination may be an additional indication of chronic pancreatitis in this context.

Advances in basic research on glucagon and alpha cells.

The regulation of plasma amino acid levels by glucagon in humans first attracted the attention of researchers in the 1980s. Recent basic research using animal models of glucagon deficiency suggested that a major physiological role of glucagon is the regulation of amino acid metabolism rather than to increase blood glucose levels. In this regard, novel feedback regulatory mechanisms that are mediated by glucagon and amino acids have recently been described between islet alpha cells and the liver. Increasingly, hyperglucagonemia in humans with diabetes and/or nonalcoholic fatty liver diseases is reported to likely be a compensatory response to hepatic glucagon resistance. Severe glucagon resistance due to a glucagon receptor mutation in humans causes hyperaminoacidemia and islet alpha cell expansion combined with pancreatic hypertrophy. Notably, a recent report showed that the restoration of glucagon resistance by liver transplantation resolved not only hyperglucagonemia, but also pancreatic hypertrophy and other metabolic disorders. The mechanisms that regulate islet cell proliferation by amino acids largely remain unelucidated. Clarification of such mechanisms will increase our understanding of the pathophysiology of diseases related to glucagon.

Liver Transplantation in a Woman with Mahvash Disease

SummaryMahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

SAT139 Non-insulinoma Pancreatogenous Hypoglycemia Syndrome In A Patient With 1p36 Deletion Syndrome

Abstract Disclosure: E.D. Auckley: None. M.A. Arosemena: None. L. Philipson: None. Background: 1p36 deletion syndrome comprises a phenotypic presentation that includes central nervous system, cardiac, and craniofacial anomalies. There has been no report of associated hypoglycemia with this syndrome. Nesidioblastosis, also known as non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), is understood as a rare condition defined by diffuse pancreatic hypertrophy with subsequent hyperinsulinemic hypoglycemia. Diagnosis requires serologic workup consistent with endogenous hyperinsulinemic hypoglycemia, intraarterial calcium stimulation positive for inappropriately elevated insulin secretion, and imaging studies without identified masses. Clinical Case: A 21-year-old female with 1p36 deletion syndrome (seizure disorder, cerebral palsy, vision loss and heart failure) was admitted to the hospital due to persistent falls. On admission vital signs were within normal limits, and physical exam revealed a thin non-verbal patient without significant other findings. During hospitalization and prolonged fasting periods of approximately 14-18 hours related to poor appetite she developed several episodes of hypoglycemia with serum glucose as low as 57 mg/dl. As patient was non-verbal at baseline, symptoms of hypoglycemia such as sweating, lightheadedness or shakiness were not confirmed. Even when she started to eat, hypoglycemic events continued to occur. Dextrose containing fluids (Dextrose 5% and later 10%) were added to try to maintain blood sugars within the normal range. Nevertheless, she continued to develop hypoglycemia. Endocrinology service was consulted and recommended to obtain a critical sample. A critical sample revealed serum glucose of 59 mg/dl, insulin level of 20.6 mcU/mL, proinsulin of 33 pmol/L, and beta-hydroxybutyrate of <0.10 mmol/L. Insulin antibodies was negative. Adrenal insufficiency was unlikely due to a normal 9 am cortisol level of 13.7 ug/dl. Due to the presence of hyperinsulinemic hypoglycemia further workup was conducted. A CT of the abdomen with a pancreatic protocol and 68Ga-DOTATATE PET/CT scan was negative for a pancreatic mass. Endoscopic ultrasound did not reveal a clear pancreatic mass either. This was followed by a calcium stimulation test which showed a two-fold increase in insulin levels in all 3 catheterized pancreatic territories. In the absence of a discrete mass, non-surgical management was recommended. For hypoglycemia management patient was started on octreotide injections with resolution of hypoglycemia. Prior to discharge she was switched to lanreotide and was discharged to continue monthly lanreotide injections. Conclusion: To our knowledge, this is the first case reported of NIPHS in a patient with a mutation in 1p36 deletion. Hyperinsulinism in the setting of diabetes has been reported in this syndrome1 but to our knowledge no cases of hypoglycemia with NIPHS have been reported. Presentation: Saturday, June 17, 2023

Trypsin inhibitors, antinutrients or bioactive compounds? a mini review

Trypsin inhibitors are proteins found in plant-based foods, mainly legumes and cereals. They have traditionally been described as anti-nutrients since their consumption leads to lower protein digestibility along with pancreatic hypertrophy. Given the problems which can arise, there are various technologies used in food processing which help reduce trypsin inhibitors to safe levels. It has also been described that trypsin inhibitors can be related with beneficial effects for human health. The present review seeks to evaluate the evidence about trypsin inhibitors’ health benefits in both in vitro and in vivo studies.

PSUN280 A Rare Genetic Disorder With Recurrent Hypoglycemic Episodes and Ketonemia Requiring Multidisciplinary Team Management During Pregnancy

Abstract Introduction Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a multisystem human genomic imprinting disorder of chromosome 11p15.5. It is characterized by overgrowth and cancer susceptibility and is known to have a highly variable clinical spectrum. The main features include lateralized overgrowth and hypoglycemia due to prolonged hyperinsulinism. Most case reports on BWS are focused on the pediatric population with very scarce data in adults. Clinical case A 29-year-old, paralympic swimmer and genetically diagnosed female with BWS had recurrent episodes of hypoglycemia during her second pregnancy. She had a history of six previous first trimester miscarriages, anti-phospholipid syndrome, hypoglycaemic seizures, asthma, and migraines. Pre-pregnancy, she was investigated for a neurological cause of her seizures and an electroencephalogram and brain imaging were unremarkable. She underwent extensive investigations for evaluation of hypoglycemia and was diagnosed as having hyperinsulinemia secondary to pancreatic hypertrophy. Factitious hypoglycemia was also ruled out. Tumor localization studies were all negative. A supervised fast could not be conducted due to the inability of the patient to tolerate the test. Her first viable pregnancy was 2 years back, during which she required a prolonged hospital (including the intensive care unit) admission with multiple in-hospital complications and requiring enteral feeding. During her current pregnancy, she experienced recurrent episodes of severe disabling hypoglycemia resulting in seizures. She was commenced on diazoxide, however, despite that, she continued to have hypoglycemic episodes for which she had to self-inject Glucagon several times. She also had unexplained weight loss with ketonemia undeterred by a high-caloric diet. She refused to be on naso-jejunal feeding or enteral feeding. She self funded a flash glucose monitor which recorded her blood glucose levels between 2.0 to 3.4 mmol/L during the episodes of hypoglycemia. Dietitians were continually involved in her care to provide nutritional support and to optimize blood glucose control through dietary manipulation. Conclusion This was a very interesting and complicated case of a genetic disorder that presented multiple challenges during pregnancy. Management focused on psychological concerns, the severe catabolic state leading to rapid weight loss, recurrent hypoglycemic episodes, ketonemia, nutritional support, and fetal well-being monitoring. A multi-disciplinary team approach to management involved the obstetrics, endocrinology, dietetics, and gastroenterology teams. This resulted in a successful outcome for her pregnancy. Very limited data is available on health issues associated with BWS in adulthood and there is no data available on the obstetric management of women with BWS. Additionally, the unexplained weight loss and ketonemia associated with hypoglycemia make this case unique. Further studies are warranted and national guidelines are required to ensure that women with BWS achieve optimum pregnancy outcomes. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

S1902 A Rare Case of Lipomatous Pseudohypertrophy of the Pancreas Diagnosed With EUS-FNA

Introduction: Lipomatous pseudohypertrophy (LPH) of the pancreas is a rare benign entity of undetermined pathogenesis characterized by the enlargement of the pancreas due to replacement of exocrine parenchyma with adipose tissue in patients without obesity, diabetes, or pancreatitis. Adipose infiltration may be local or diffuse and forms a pseudotumor that mimics pancreatic malignancies, which has led to unnecessary resections. Endoscopic ultrasound with biopsy (EUS- FNA) has improved the ability to diagnose LPH and rule out malignancy. LPH is typically asymptomatic, however, abdominal pain may be a presenting symptom with steatorrhea due to exocrine insufficiency or jaundice due to mass effect seen in late stages. Case Description/Methods: 48-year-old female with history of hypothyroidism and migraines presented with epigastric pain, poor oral intake due to postprandial vomiting, and non-bloody mucoid diarrhea. Prior to admission, she had been having chronic GI symptoms and recent MRI demonstrated near complete fatty replacement of an enlarged pancreas causing mass effect with only a small amount of normal parenchyma remaining. She had been diagnosed with exocrine pancreatic deficiency and started on replacement therapy. Surgery was consulted for potential resection of the body and tail of the pancreas due to compressive symptoms. Due to concern for other malignant process including liposarcoma, EUS-FNA was pursued (Figure). The body and tail of the pancreas appeared diffusely hyperechoic and homogeneous, consistent with fatty replacement. Biopsies showed bland pancreatic islets in a background of mature adipose tissue consistent with fatty replacement of the pancreas. These pathology findings in conjunction with pancreatic hypertrophy and compression on surrounding organs without a history of obesity, diabetes, or pancreatitis, supported the diagnosis of LPH of the pancreas. She was ultimately treated conservatively with monitoring and pancreatic enzyme replacement therapy with improvement in symptoms. Discussion: LPH is a rare, benign disorder typically managed with enzyme therapy when symptoms develop. The mass formed by LPH mimics that of malignant disease which has led to unnecessary resections. The use of EUS-FNA to observe histological features and confirm diagnosis has led to a decrease in resections and differentiation from other causes of pancreatic fat infiltration. The pathogenesis remains unknown but is distinct from pancreatic steatosis commonly seen in metabolic syndromes or inflammation.Figure 1.: EUS showing pancreatic parenchymal abnormalities consisting of diffuse echogenicity with homogenous appearance in the Neck (A), Body (B), and Tail (C) of the pancreas. These findings consistent with fatty replacement of the pancreas. There is no focal mass noted, the pancreatic duct was not visualized.

The effect of feed processing of novel unheated, low trypsin inhibitor soybeans on the performance of young female turkeys reared from hatch to 21 days of age

The objective of this study was to evaluate the effects of dietary inclusion of a novel low trypsin inhibitor soybean (LTI) fed as mash or crumbled pellet form on the productive performance and digestibility in turkey poults from hatch to 21 d. A total of 336 Hybrid Converter turkey poults were allocated in groups of 7 to 6 treatments, each with 8 replicate cages. Treatments were arranged as a 3 × 2 factorial with inclusion level of the low trypsin-inhibitor soybean (0, 20, and 40% LTI) and feed form (mash and crumbled pellet). A single batch of feed was mixed for each inclusion level and divided into 2 aliquots: one remaining as mash and the other conditioned at 82°C for approximately 30 s, pelleted and then crumbled. On d 7, 14, and 21 posthatching, BW, and feed intake (FI) were recorded and BW gain (BWG) and feed conversion ratio (FCR) calculated. Excreta samples were collected from d 19 to 21 and pooled by cage. At d 21, intestines were excised, pancreas weights recorded (PRW), and ileal contents collected. There were no interactions (linear, P > 0.05) between LTI inclusion and feed form on BW, BWG, FI, or FCR at d 7 or 21. Increasing LTI resulted in a linear reduction in BW at 7, 14, and 21 d (P < 0.006). Poults fed crumbles were significantly heavier at d 21 than those fed mash feed (P < 0.027) with no interaction of LTI level with feed form. FCR was not significantly greater with increasing LTI. However, poults fed crumbles had a better, lower FCR that those fed mash feed from d 0 to 21 (P < 0.018). There was a significant interaction between feed form and LTI level at 14 d (P < 0.031), but not 7 or 21 d. Pancreatic hypertrophy (PRW) increased linearly with increasing LTI (P < 0.001) with a significant linear interaction with feed form (P < 0.001). Poults fed crumbles had less pancreatic hypertrophy. At 21 d of age, dietary fat digestibility (ALD, %) was linearly reduced with increasing LTI (P < 0.001). However, poults fed crumbles had significantly better fat absorption than poults fed mash (91.2 vs. 85.8%) (P < 0.001), and there was a significant linear interaction between feed form and LTI level (P < 0.001). AMEn was significantly better for the poults fed crumbles compared to mash (3228 vs. 3132 kcal/kg) (P < 0.001), and there was a significant linear interaction between feed form and LTI level (P < 0.001). Based on the results this trial, it is possible to include up to 20% unheated full fat LTI soybeans into poult starter diets after pelleting. Pelleting improves nutrient utilization, allowing for greater incorporation of the LTI soybean in the crumbled diet compared to the mash diet.

Sex-age features of the prevalence and structure of heart rhythm disorders in the patients with severe Covid-infection

There is growing evidence that arrhythmias are a major complication of COVID-19 infection. Inflammation of the myocardium, cytokine storm, hypoxia, changes of electrolyte levels, coronary vasospasm, microcloths may be factors that contribute to the development of arrhythmias and changes of the ECG. The aim of the study was to determine the sex and age characteristics of the prevalence and structure of cardiac arrhythmias in patients with severe COVID infection. In the study were examined 133 patients with severe COVID-19 infection, who were in the intensive care unit of the city clinical hospital №1 in Vinnytsia at the period from April to December 2020 and as a result of treatment with improved health were discharged from the hospital. Statistical processing of the obtained data was performed using the statistical software package SPSS 12.0 for Windows using parametric and non-parametric methods of statistical analysis. It was found that the most common comorbid pathologies of the patients with severe COVID-19 were – arterial hypertension 90 (67.7%), coronary heart disease 91 (68.4%), chronic heart failure 65 (48.9%), obesity 47 (35.3%) and diabetes mellitus 32 (24.1%). It was found that the prevalence of cardiac arrhythmias in patients with severe COVID-19 was 86 (64.7%) patients. Among all arrhythmias, tachyarrhythmias predominated – 68 (51.1%), in the structure of which sinus tachycardia was the most common in 45 (33.8%) and atrial fibrillation (AF) – in 19 (14.3%) patients, respectively. In turn, sinus tachycardia was significantly more common among women. The prevalence of bradyarrhythmias was 60 (45.1%), in the structure of which were dominated sinus bradycardia 16 (12%) and blockade of the right branch of the His bundle 30 (22.6%). Among men, there was a tendency to the predominance of complete left bundle branch block. The prevalence of ischemic changes and/or repolarization disorders according to the ECG was 119 (89.5%), in the structure of which were dominated the presence of inversion of the T wave 91 (68.4%) and depression of the ST segment 54 (40.6%). The mean age of the patients with ischemic ECG changes was significantly higher compared to patients without signs of repolarization disorders. Among men, there was a predominance of pancreatic hypertrophy and a tendency to predominance of left ventricular hypertrophy.

SOME PATHOLOGICAL ASPECTS OF RAW LIMA BEAN (Phaseolus lunatus Linn. FEEDING TO GROWING

Some pathological changes: accompanying raw lima bean (RLB) feeding to growing rats were investigated. Among the gross patholo­gical observations were severe pancreatic hypertrophy and spleen atrophy. The rela­tive weight of the liver was significantly (P&lt; 0M5) decreased while the kidney weight was significantly (P&lt; 0.05) increas­ed. The relative weight of the heart was unaffected. At necropsy, the small intestine of rats fed 40% RLB and aoove were dilated and filed with light-yellow gassy liquid. Histopathologically, livers of rats fed 40% RLB and above showed focuses of coagulative necrosis and marked congestion of hepatic sinusoids and centrolobular veins. The spleen showed marked depletion of lymphoid follicles and medullary' sinu­soids. There was evidence of marked conges­tion of renal blood vessels in the high RLB diets. No lesions were observed in the heart tissues. The morphology of the intestinal apicalmicrovilli were generally disrupted. They appeared stunted and fragmented especially in the rats fed 40% RLB and above. Mononuclei cell infilterate characterized the lamina propria of the small api Large inte­stinal rnicrovilli. No microvilli abnormalities were detected in rats fed 100% cooked lima bean (control) diet.

INCLUSION RATE AND PHYSIOLOGICAL EFFECTS OF PROLONGED FEEDING OF COCOA BEAN CAKE ON LAYERS

The effect of inclusion of cocoa bean cake (CBC) on productive performance and physiological response of Isa Brown pullets to prolonged feeding of CBC were investigated. Dietary inclusion of CBC (0, 50, 100 and 200g kg-1 diet) were monitored in typical poultry diet from day old to 51 weeks of age. Sexual maturity and attained of 50% hen-day production were delayed with increasing level of CBC. Egg quality indices were higher (P &lt; 0.05) at 200g kg-1 CBC diet but with reduced (P &lt; 0.05) shell thickness. CBC had no significant influence on yolk or whole egg cholesterol, follicular weight and number. Layers on 0 and 50 kg-1 CBC diets had higher (P &lt; 0.05) percentage of yellow follicles but lower white follicles. Liver and pancreatic hypertrophy were observed for CBC-fed layers but with reduced (P &lt; 0.05) abdominal fat and oviduct length. The long term feeding of CBC at level more than 50g kg-1 diet progressively had a deteriorating effect on laying performance and follicular development.

Imatinib-induced pancreatic hypertrophy in patients with gastrointestinal stromal tumor: Association with overall survival

ObjectivesTo investigate the frequency of imatinib-induced pancreatic complications and determine whether these are survival prognostic factors in patients with gastrointestinal stromal tumor (GIST). MethodsThis retrospective multicenter study included patients with histopathologically diagnosed GIST treated with imatinib who underwent computed tomography (CT) within 100 days before (pretreatment CT) and 500 days after (post-treatment CT) imatinib initiation (January 2004–December 2019). Forty-eight patients (63.0 ± 12.1 years, 30 men) were included. Two blinded radiologists independently measured pancreatic volumes. Pancreatic volume on pretreatment CT was compared with that of the control (within 1 year prior to pretreatment CT) and the first two post-treatment CTs using paired t-tests. Thresholds for pancreatic hypertrophy and atrophy were defined using a log-rank test. The prognostic importance of pancreatic hypertrophy was further analyzed using multivariate Cox proportional hazard regression models. ResultsPancreatic volume was significantly higher for the first post-treatment CT than pretreatment CT (71.5 cm3 vs. 67.4 cm3, P = .027), whereas no significant difference was observed between the pretreatment and control CTs. Optimal thresholds for pancreatic hypertrophy and atrophy were defined as an 22% increase and 30% decrease and found in 20 and three patients, respectively. Pancreatic hypertrophy was significantly associated with reduced survival [hazard ratio = 2.9 (95% confidence interval, 1.3–6.5), P = .0088]. No patients showed serum lipase elevation, nor were they suspected of having acute pancreatitis. ConclusionThere was frequent asymptomatic pancreatic swelling in patients with GIST after imatinib treatment, and a ≥22% increase in pancreatic volume was a predictor of reduced survival.

Dietary substitution of SFA with MUFA within high-fat diets attenuates hyperinsulinaemia and pancreatic islet dysfunction.

Preliminary evidence has suggested that high-fat diets (HFD) enriched with SFA, but not MUFA, promote hyperinsulinaemia and pancreatic hypertrophy with insulin resistance. The objective of this study was to determine whether the substitution of dietary MUFA within a HFD could attenuate the progression of pancreatic islet dysfunction seen with prolonged SFA-HFD. For 32 weeks, C57BL/6J mice were fed either: (1) low-fat diet, (2) SFA-HFD or (3) SFA-HFD for 16 weeks, then switched to MUFA-HFD for 16 weeks (SFA-to-MUFA-HFD). Fasting insulin was assessed throughout the study; islets were isolated following the intervention. Substituting SFA with MUFA-HFD prevented the progression of hyperinsulinaemia observed in SFA-HFD mice (P < 0·001). Glucose-stimulated insulin secretion from isolated islets was reduced by SFA-HFD, yet not fully affected by SFA-to-MUFA-HFD. Markers of β-cell identity (Ins2, Nkx6.1, Ngn3, Rfx6, Pdx1 and Pax6) were reduced, and islet inflammation was increased (IL-1β, 3·0-fold, P = 0·007; CD68, 2·9-fold, P = 0·001; Il-6, 1·1-fold, P = 0·437) in SFA-HFD - effects not seen with SFA-to-MUFA-HFD. Switching to MUFA-HFD can partly attenuate the progression of SFA-HFD-induced hyperinsulinaemia, pancreatic inflammation and impairments in β-cell function. While further work is required from a mechanistic perspective, dietary fat may mediate its effect in an IL-1β-AMP-activated protein kinase α1-dependent fashion. Future work should assess the potential translation of the modulation of metabolic inflammation in man.

Histology of Rat Pancreas Treated with Calliandra calothyrsus Leaf in the Diets during Pregnancy and Lactation

For cattle, red calliandra (Calliandra calothyrsus) is a good protein source of forage but the condensed tannin content is the highest compared to other legume plants. Tannin can reduce the activity of digestive enzymes and protein digestibility, which can lead to pancreatic hypertrophy and hyperplasia. This study aimed to determine the pancreatic histology of pregnant rats treated with C.calothyrsus leaf flour during pregnancy and lactation period. This study used a completely randomized design with 24 pregnant female rats which were divided into four groups i.e. control and treatments of 10, 17.5 and 25% of C.calothyrsus leaf flour in the diets. The treatment started from the first day of pregnancy until the young rats were weaned at the age of 21 days. Pancreatic histological structure of the mother showed an increase lack of normal tissue density and an increase connective tissues in the pancreas descriptively, especially at the highest level of C.calothyrsus leaf flour (25%) in the diets.

A Chromosome 13 locus is associated with male-specific mortality in mice.

Mortality is a highly complex trait influenced by a wide array of genetic factors. We examined a population of 1200 mice that were F2 generation offspring of a 4-way reciprocal cross between C57BL6/J and DBA2/J strains. Animals were sacrificed at age 200, 500, or 800days and genotyped at 96 markers. The 800days old cohort, which were the survivors of a much larger breeding group, were examined for enriched frequency of alleles that benefit survival and depletion of alleles that reduce survival. Loci on Chr 13 in males and on Chr X in females were significantly distorted from Mendelian expectations, even after conservative correction for multiple testing. DBA2/J alleles between 35 and 80Mb on Chr 13 were underrepresented in the age 800 male animals. D2 genotypes in this region were also associated with premature death during behavioral testing. Furthermore, confirmatory analysis showed BXD recombinant inbred strains carrying the D2 alleles in this region had shorter median survival. Exploration of available pathology data indicated that a syndrome involving dental malocclusions, pancreatic islet hypertrophy, and kidney lipidosis may have mediated the effects of DBA alleles on mortality specifically in male mice. The heterozygote advantage locus on the X Chr was not found to be associated with any pathology. These results suggest a novel locus influencing survival in the B6/D2 genetic background, perhaps via a metabolic disorder that emerges by 200days of age in male animals.

Karakteristik Trypsin Inhibitor dan Penjajagan Sebagai Komponen Makanan Fungsional Penderita Diabetes (IIDM)

Trypsin inhibitors (TI) are substances which, when added to a mixture of a trypsin and a subtrate, bind to the enzyme and render it to decrease in the rate of substrate cleavage. These inhibitors are nonglycosylated, water-soluble (albumin) that account for about 0,2-2 % of the total soluble protein of the legume seeds. Two major families of trypsin inhibitors have been described in legumes: the Bowmen-Brix-type (BBI) and the Kunitz-type inhibitors (KTI). They are distinct families of proteins, as evidenced by their molecular weights, compositions, and amino acid sequences. Because of their unique pharmacological properties, these inhibitors hold considerable promise in clinical applications in their field of medicine. At least one inhibitor in soybeans, the BM, has been shown to have clear anticarcinogenic activity in both in vitro and in vivo carcinogenic Trypsin inhbitors (TI) are substances which, when added to a mixture of a trypsin and a substrate, bind to the enzyme and render it to decrease in the rate of substrate cleavage. These inhibitors are nonglycosylated, water-soluble (albumin) that account for about 0,2 –2 % of the total soluble protein of the legume seeds. Two major families of trypsin inhibitors have been described in legumes: the Bowmen-Birk-type (BBI) and the Kunitz-type inhibitors (K7'I). They are distinct families of proteins, as evidenced by their molecular weights, compositions, and amino acid sequences. Because of their unique pharmacological assay systems. increasing need and awareness for functional food has motivated food scientists and industries to search functional food components and ingredients for certain target group, including functional food for diabetes. Soy TI may enhance the production of more trypsin and probably insulin as well. The dietary 77evokes pancreatic enzyme secretion by forming inactive trypsinT1 complex. As the level of trypsin goes below a threshold level, the pancreas is induced to produce more enzymes. The mediating agent between the enzymes and the pancreas is cholecystokinin (CCK), which is released from the jejunul endocrine cells when the level of trypsin in the intestine becomes depleted. CCK is intestinal hormone which stimulate insulin secretion. Ti regenerated 13-cells which indicate the beneficial effect of TI on the insulin production of the pancreas. These novel findings provide evidence to support the potential utility of TI in the treatment of type 2 diabetes (11DM/ Insulin-Independent Diabetic Mellitus). However, TI are also known as anti nutrient substances and to cause pancreatic hypertrophy.

Abstract 4117: Increased pancreatic adipocyte hypertrophy in EL-Kras/PEDF null mice with versus without pancreatic cancer

Abstract Understanding non-parenchymal contributions to disease etiology and factors that assess risk and prognosis are currently key points of interest in pancreatic cancer research. One such focus is in regards to fat, where obesity and increased visceral fat enhance risk and predict worse prognosis for pancreatic cancer patients. Pigment epithelium-derived factor (PEDF), initially identified for its potent anti-angiogenic activity, has been recently implicated in metabolism and adipogenesis, and loss of PEDF in mice promotes pancreatic hyperplasia and visceral obesity. In an attempt to create a model of pancreatic cancer that emulates metabolic features related to fat content, we generated PEDF knockout mice with KrasG12D-induced pancreatic neoplasia, where oncogenic Kras can also induce adipogenesis (typically observed as lipoatrophy). We have recently shown that EL-KrasG12D/PEDF null mice developed invasive pancreatic cancer associated with increased peripancreatic fat with adipocyte hypertrophy and pancreatic steatosis. Indeed, the stroma within the pancreas of these mice demonstrated higher levels of tail interacting protein 47 (TIP47, Perilipin 3) and adipose differentiation-related protein (ADRP, Perilipin 2), two lipid droplet associated proteins. In this study, we expanded upon this work to demonstrate that in most EL-Kras/PEDF null mice, there appeared to be greater number of neoplastic lesions near neighboring fat stores. In addition, there was a significant increase in the size of adipocytes (greater adipocyte hypertrophy) in EL-Kras/PEDF null mice with invasive cancer as opposed to age-matched mice with an identical genotype without the presence of cancer. Despite increased adipocytes in mice with cancer, there was no significant difference in overall body weight between these cohorts of animals. Future work aims at identifying if neoplastic lesions near adipocytes have a greater proliferative index and hence an increase in size. Ultimately, we hope to demonstrate that larger and more numerous adipocytes contribute to the development of pancreatic cancer. These data highlight the importance of lipid metabolism in the tumor microenvironment and identify PEDF as a critical negative regulator of both adiposity and tumor invasion in the pancreas, with implications that PEDF's effect on fat stores may induce cellular events leading to invasive disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4117. doi:1538-7445.AM2012-4117

Pancreatic Hypertrophy in Ki-ras-Induced Actin-Interacting Protein Gene Knockout Mice

Pancreatic functions were determined in a Ki-ras-induced actin-interacting protein (KRAP)-deficient (-/-) mouse mutant. Pancreatic enzyme, protein, and DNA contents were measured, and histological examinations were conducted. The mixture of bile-pancreatic juice was collected, and amylase and bile acid outputs were determined. Oral glucose tolerance test was determined. Moreover, the gene expression of KRAP was determined in cholecystokinin (CCK)-A(1) receptor (-/-) mice. The body weight was smaller, and the ratio of pancreatic wet weight/body weight was higher in KRAP(-/-) mice compared with wild-type mice. The enzyme contents, but not DNA content, in the pancreas of KRAP(-/-) mice were higher than those of wild-type mice. Histological examination revealed the increase in the number of zymogen granules in the pancreatic acinar cells of KRAP(-/-) mice. Amylase secretions in response to CCK-octapeptide sulfate were significantly higher in KRAP(-/-) than wild-type mice, whereas the basal secretion did not differ between the 2 genotypes. A normal glucose tolerance was observed in KRAP(-/-) mice. The gene expression of KRAP in CCK-A(1) receptor (-/-) mice was significantly lower than in wild-type mice. The lack and/or decrease in KRAP level in the pancreas may promote the pancreatic growth and hypertrophy.

Diabetogenic Effect of a Series of Tricyclic Delta Opioid Agonists Structurally Related to Cyproheptadine

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.