Pancreatic Weight Research Articles

Endoscopic Ultrasound in an Alcoholic With Pancreatic Pain, Vomiting, and Weight Loss

Question: A 38-year-old man presented with recurrent episodes of epigastric pain radiating to the back for 1.5 years duration, with vomiting and weight loss for the past 4 months. He was a smoker with a significant history of alcohol consumption. General physical examination was unremarkable. Investigations revealed anemia, raised serum amylase and alkaline phosphatase with a normal CA 19-9. Ultrasound abdomen showed a dilated common bile duct (CBD) and main pancreatic duct (MPD). Contrast-enhanced computed tomography (CT) revealed a heterogeneous hyperdense enlargement of the head and uncinate process of the pancreas with duodenal wall thickening, cystic hypodense areas in the region between duodenal second part (D2) and head of pancreas, with dilatation of the MPD and CBD (Figure A–C).

Malignant Range Elevation of Serum Chromogranin A due to Inadvertent Use of Proton Pump Inhibitor in a Subject with Pancreatic Incidentaloma

We present a case of highly elevated tenfold rise of serum chromogranin A in a young, morbidly obese, hypertensive female being investigated for pancreatic mass, weight loss, and elevated ESR. Following extensive noninvasive investigations, an ultrasound-guided pancreatic biopsy confirmed benign haemorrhagic cyst. A clue to the etiology of the hyperchromogranin A was the elevated serum gastrin level leading to suspicion of proton pump inhibitor administration confirmed by admittance to its use. Withdrawal of the medication led to dramatic resolution of the neuroendocrine tumor marker.

Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg(-1)·day(-1)) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1β, IL-2, IL-6, MCP-1, IFNγ, and TNFα) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents.

Maternal obesity in ewes results in reduced fetal pancreatic β-cell numbers in late gestation and decreased circulating insulin concentration at term

About 30% of U.S. women of reproductive age are obese, a condition linked to offspring obesity and diabetes. This study utilized an ovine model of maternal obesity in which ewes are overfed to induce obesity at conception and throughout gestation. At mid-gestation, fetuses from these obese ewes are macrosomic, hyperglycemic, and hyperinsulinemic, and they exhibited markedly increased pancreatic weight and β-cell numbers compared with fetuses of ewes fed to requirements. This study was conducted to establish fetal pancreatic phenotype and function in late gestation and at term in this ovine model. Multiparous ewes were fed a control (C, 100% National Research Council [NRC] recommendations) or obesogenic (OB, 150% NRC) diet from 60 days before conception to necropsy at day 135 of gestation or to lambing. No differences were observed in fetal size or weight on day 135 or in lamb birth weights between C and OB ewes. In contrast to our previously published results at mid-gestation, pancreatic weights ( P < 0.01) and β-cell numbers ( P < 0.05) of OB fetuses were markedly lower than those from C fetuses, whereas the β-cell apoptotic rate was increased ( P < 0.05) in day 135 OB versus C fetuses. At birth, blood insulin concentration was lower ( P < 0.05) and glucose level was higher ( P < 0.05) in newborn lambs from OB versus C ewes. These data demonstrate differential impacts of maternal obesity on fetal pancreatic growth and β-cell numbers during early and late gestation. During the first half of gestation there was a marked increase in pancreatic growth, β-cell proliferation, and insulin secretion, followed by a reduction in pancreatic growth and β-cell numbers in late gestation, resulting in reduced circulating insulin at term. It is speculated that the failure of the pancreas to return to a normal cellular composition and function postnatally could result in glucose/insulin dysregulation, leading to obesity, glucose intolerance, and diabetes in postnatal life.

CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth

Dietary protein can stimulate pancreatic growth in the absence of CCK release, but there is little data on the regulation of CCK-independent growth. To identify mechanisms whereby protein stimulates pancreatic growth in the absence of CCK release, C57BL/6 control and CCK-null male mice were fed normal-protein (14% casein) or high-protein (75% casein) chow for 7 days. The weight of the pancreas increased by 32% in C57BL/6 mice and 26% in CCK-null mice fed high-protein chow. Changes in pancreatic weight in control mice were due to both cell hypertrophy and hyperplasia since there was an increase in protein-to-DNA ratio, total DNA content, and DNA synthesis. In CCK-null mice pancreatic growth was almost entirely due to hypertrophy with both protein-to-DNA ratio and cell size increasing without significant increases in DNA content or DNA synthesis. ERK, calcineurin, and mammalian target of rapamycin complex 1 (mTORC1) are activated in models of CCK-induced growth, but there were no differences in ERK or calcineurin activation between fasted and fed CCK-null mice. In contrast, mTORC1 activation was increased after feeding and the duration of activation was prolonged in mice fed high-protein chow compared with normal-protein chow. Changes in pancreatic weight and RNA content were completely inhibited, and changes in protein content were partially abated, when the mTORC1 inhibitor rapamycin was administered during high-protein chow feeding. Prolonged mTORC1 activation is thus required for dietary protein-induced pancreatic growth in the absence of CCK.

Analysis of the Pancreatic Low Molecular Weight Proteome in an Animal Model of Acute Pancreatitis

We used a peptidomic approach for the analysis of the low molecular weight proteome in rat pancreatic tissue extracts. The goal was to develop a method that allows identifying endogenous peptides produced in the pancreas in the course of acute pancreatitis. The workflow combines peptides enrichment by centrifugal ultrafiltration, fractionation by isoelectric focusing, and LC-MS/MS analysis without prior enzymatic digestion. The method was assessed on pancreatic extracts from 3 rats with caerulein-induced pancreatitis and 3 healthy controls. A qualitative analysis of the peptide patterns obtained from the different samples was performed to determine the main biological processes associated to the identified peptides. Comparison of peptidomic and immunoblot data for alpha-tubulin, beta-tubulin and coatomer gamma showed that the correlation between the number of identified peptides and the protein abundance was variable. Nevertheless, peptidomic analysis highlighted inflammatory and stress proteins, which peptide pattern was related to acute pancreatitis pathobiology. For these proteins, the higher number of peptides in pancreatitis samples reflected an increase in protein abundance. Moreover, for murinoglobulin-1 or carboxypeptidase B, peptide pattern could be related to protein function. These data suggest that peptidomic analysis is a complementary approach to proteomics for investigating pathobiological processes involved in acute pancreatitis.

P-158: Roux-en- Y gastric bypass increases pancreatic weight and decreases liver weight independent of oral intake

P-158: Roux-en- Y gastric bypass increases pancreatic weight and decreases liver weight independent of oral intake

Angiotensin II signaling through the AT1a and AT1b receptors does not have a role in the development of cerulein-induced chronic pancreatitis in the mouse

The intraorgan renin-angiotensin system (RAS) plays an important role in the pathophysiology of a variety of diseases and has been implicated in fibrogenesis. The role of RAS in the development of chronic pancreatitis is not well established. The blockade of RAS in rat models with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor 1 (AT1) blockers (ARBs) mostly have reduced pancreatic inflammation and fibrosis with a few exceptions. At the same time, the use of ACEi and ARBs in humans is associated with a modest risk of acute pancreatitis. The aim of this study was to elucidate the effect of the AT1 signaling pathway in the development of pancreatitis using AT1a- and AT1b-deficient mice as well as the ARB losartan. Chronic pancreatitis was induced by repetitive cerulein administration in C57BL/6J wild-type (WT) and AT1a- and AT1b-deficient mice (AT1a-/- and AT1b-/-), and pancreatic injury was assessed at day 10. Pancreatic weight of cerulein treated groups was significantly reduced. There was severe parenchymal atrophy and fibrosis assessed by histological examination. Fibrosis was accompanied by activation of pancreatic stellate cells (PSC) evaluated by Western blot analysis for alpha-smooth muscle actin. No differences were seen between cerulein-treated WT, AT1a-/- , AT1b-/- mice, or losartan treated-WT mice with regards to morphological or molecular alterations induced by cerulein. Our results demonstrate that AT1a and AT1b receptor pathways do not seem to be essential for the development of pancreatitis in the mouse model of pancreatitis induced by repetitive cerulein injury.

Abstract 2927: Gefitinib, an EGFR inhibitor, prevents progression of PanINs to pancreatic carcinoma in a preclinical conditional LSL-K-rasG12D transgenic mice model

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy is a devastating disease with dismal prognosis (5-year survival rate of less than 5%), and is the fourth leading cause of cancer deaths in the USA. Developing novel strategies to prevent or delay the progression of pancreatic cancer is currently of intense interest. We studied chemopreventive efficacy of gefitinib, an EGFR inhibitor on pancreatic intraepithelial neoplasms (PanINs) and adenocarcinoma in conditional LSL-K-RasG12D transgenic mice. LSL-K-RasG12D and P48Cre mice were bred and offspring of activated K-rasG12D were generated. Six-week old male KrasG12D (20/group) and wild-type (12/group) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm gefitinib for 35 weeks. At the time of sacrifice, pancreas were collected, weighed, and were evaluated histopathologically for PanINs and PDAC. To understand the molecular mechanisms, expression levels of PCNA, p38, cyclin D1, C2GNT, RhoA, β catenin, pERK, EGFR and Cav1, were determined in pancreatic tissues by IHC, immuno-fluorescence, immunoblotting and/or RT-PCR. Results suggest that mice fed with 100 and 200 ppm gefitinib had significantly reduced (p&amp;lt;0.0001) ductal adenocarcinomas incidence than control diet fed mice. Importantly, significant reduction of pancreatic ducts with carcinoma (&amp;gt;94%, p&amp;lt; 0.0001) and suppression of PanIN 3 (∼34%) was observed in mice fed diet with gefitinib. We did find statistically significant dose dependent inhibition of PanIN 1 &amp; 2 lesions between control and gefitinib fed groups. Also, mice fed gefitinib showed reduced pancreatic tumor weights (∼50%) compared to control diet fed mice. Furthermore, treated mice showed &amp;gt;75% of pancreas free from carcinoma. Also, pancreas of mice fed gefitinib diets showed significantly reduced expressions of PCNA, p38, EGFR, RhoA, C2GNT, β-catenin, pERK, caveolin-1, and a significant increase in cyclin B1 (p&amp;lt;0.005) levels compared to pancreas of control diet fed mice. In summary, our results suggest that gefitinib prevents the progression of pancreatic cancer precursor lesions in PanIN 1, 2 and 3 stages from further progressing to adenocarcinoma in a preclinical model. These data highlight the promise of chemoprevention in pancreatic cancer and administration of EGFR inhibitors represents an important strategy to prevent pancreatic cancer in high-risk patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2927.

Effects of stage of gestation and nutrient restriction during early to mid-gestation on maternal and fetal visceral organ mass and indices of jejunal growth and vascularity in beef cows1

The objectives were to evaluate effects of maternal nutrient restriction and stage of gestation on maternal and fetal visceral organ mass and indices of jejunal growth and vascularity in beef cows. Thirty multiparous beef cows (BW = 571 +/- 63 kg; BCS = 5.4 +/- 0.7) carrying female fetuses (d 30 of gestation) were allocated to receive a diet of native grass hay (CON; 12.1% CP, 70.7% IVDMD, DM basis) to meet NRC recommendations for BW gain during early gestation or a nutrient-restricted diet of millet straw (NR; 9.9% CP, 54.5% IVDMD, DM basis) to provide 68.1% of NE(m) and 86.7% of MP estimated requirements. On d 125 of gestation, 10 CON and 10 NR cows were killed and necropsied. Five remaining CON cows received the CON diet, and 5 NR cows were realimented with a concentrate supplement (13.2% CP, 77.6% IVDMD, DM basis) and the CON hay to achieve a BCS similar to CON cows by d 220 of gestation. Remaining cows were necropsied on d 245 of gestation. Cow BW and eviscerated BW (EBW) were less (P < 0.01) for NR than CON at d 125 but did not differ (P > 0.63) at d 245. Cows fed the CON diet had greater (P < 0.09) total gastrointestinal (GI) tract, omasal, and pancreatic weights. Stomach complex, ruminal, and liver weights were greater for CON than NR cows (P < 0.09) on d 125. Total GI, stomach complex, and pancreatic weights increased (P < 0.001) with day of gestation. Restricted cows had decreased (P = 0.09) duodenal RNA:DNA compared with CON. Duodenal DNA was less (P = 0.01) and jejunal RNA:DNA (P = 0.09) was greater for cows at d 125 vs. 245. Cow jejunal capillary area density increased with day of gestation (P = 0.02). Fetal BW and EBW were unaffected by dietary treatment (P > or = 0.32). Total GI tract and all components increased in mass with day of gestation (P < 0.001). Fetuses from NR dams had greater (P = 0.003) reticular mass at d 245 than CON fetuses. Fetuses from NR cows had greater (P = 0.02) percent jejunal proliferation at d 125 and greater (P = 0.03) total intestinal vascularity (mL) at d 245. Fetal jejunal DNA decreased (P = 0.09), RNA:DNA increased (P = 0.05), and total jejunal proliferating cells increased (P < 0.001) with day of gestation. Jejunal capillary area density, number density, and surface density were greater (P < 0.008) during late gestation. Results indicate that maternal and fetal intestines undergo changes during gestation, which can be affected by nutrient restriction and may partially explain differences observed in fetal development and postnatal performance.

Abstract A145: Atorvastatin (Lipitor) delays progression of PanINs to pancreatic carcinoma through AKT pathway in a conditional LSL-K-rasG12D transgenic mice

Abstract Pancreatic ductal adenocarcinoma (PDAC) a devastating disease with a dismal prognosis is the most common pancreatic malignancy and is the fourth leading cause of deaths in the U.S. with a 5-year survival rate of less than 5%. Thus, developing novel strategies to prevent or delay the progression of pancreatic cancer is of intense interest. In the present study, we studied chemopreventive efficacy of atorvastatin on pancreatic intraepithelial neoplasms (PanINs) and adenocarcinoma in conditional LSL-K-RasG12D transgenic mice. LSL-K-RasG12D and P48Cre mice were bred and offspring of activated K-rasG12D were generated. Six-week old male KrasG12D (20/group) and wild-type (12/group) mice were fed (AIN-76A) diets containing 0, 200, and 400 ppm Atorvastatin for 35 weeks. At the end of experimental feeding, pancreas were collected, weighed, and evaluated histopathologically for PanINs and adenocarcinomas. To understand the mechanisms, expression levels of PCNA, p21, Akt-1, cdK2, Cav1, cyclin E, survivin, Rho A and p2X7 were determined by IHC, Western blotting or RT-PCR. Results suggest that control diet fed mice showed 100% incidence of pancreatic ductal adenocarcinomas; whereas, mice fed with 200 and 400 ppm atorvastatin had significantly reduced (p&amp;lt;0.0001) ductal adenocarcinomas. Importantly, significant reduction of pancreatic ducts with carcinoma (56–94%, p&amp;lt; 0.0001) was observed in mice fed 200 and 400 ppm Atorvastatin. Similarly, significant suppression of PanIN 3 (22.63%) was observed in mice fed 400 ppm Atorvastatin. However, we did not find any statistically significant inhibition of PanIN 2 lesions between control and atorvastatin fed groups. Whereas, mice fed high dose Atorvastatin showed a significant increase in PanIN 1 lesions compared to mice fed with control diet. Also, mice fed Atorvastatin showed reduced pancreatic tumor weights (∼50%) compared to control diet fed mice. Furthermore, treated mice showed ∼75% of pancreas free from carcinoma. The pancreas of mice fed Atorvastatin diets showed significantly reduced expressions of PCNA, survivin, Akt-1, cyclin E, cdK2 and Cav1 with a significant increase in p21 (p&amp;lt;0.005) levels compared to pancreas of control diet fed mice. In summary, our results suggest that Atorvastatin delays the progression of pancreatic cancer precursor lesions in PanIN 1 and 2 stages from further progressing to adenocarcinoma in a preclinical model. These data highlight the promise of chemoprevention in pancreatic cancer and administration of statins represents an important strategy to prevent pancreatic cancer in high-risk patients. {Supported by NCI-NO1-CN53300} Citation Information: Cancer Prev Res 2010;3(1 Suppl):A145.

Nutritional and Biochemical Assessment of Field Peas (Pisum sativum L.) as a Protein Source in Poultry Diets

The effects of cultivar on the nutrient profile and protein quality of field pea (Pisum sativum) was investigated. A total of 19 samples representing five cultivars of field pea (Santana, Miami, Rex, Crusader and Courier) were analysed for proximate, fibre and carbohydrate components, minerals and amino acids. Starch was the major carbohydrate component in field pea, but it also contained significant quantities of non-starch polysaccharides. The pea protein was deficient in lysine, methionine, cystine and threonine. The results from the protein quality assay showed that there were no differences (P>0.05) in protein quality between pea cultivars. Compared to raw field pea, raw soybeans had a lower (P<0.05) protein efficiency ratio, and had higher (P<0.05) relative pancreatic weights and mortality rate, suggesting that raw soybeans contained high concentrations of anti-nutritional factors, especially protease inhibitors. Mortality of birds fed raw forms of field pea was low, suggesting that field pea do not have significant levels of any anti-nutrients. The relative pancreatic weights of birds fed pea diets also indicate that the level of protease inhibitors in pea cultivars tested were probably low. Overall, the present results demonstrate the nutritional potential of field pea as a protein source in poultry diets.

Hereditary pancreatitis in children: surgical implications with special regard to genetic background

Purpose Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature. Methods All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes). Results Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss. Conclusions Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications.

Effect of sporidesmin-induced liver damage in ewes before mating on growth of the foetus and placenta

Sporidesmin is a fungal toxin commonly found in pasture. It causes liver damage in sheep that resembles cholestasis in humans. We determined whether pre-mating sporidesmin-induced liver damage in ewes might provide a useful approach to the experimental induction of intrauterine growth restriction (IUGR). Romney ewes were drenched with sporidesmin extracts. Affected ewes (SP, n=44) and controls (CN, n=42) were mated. Sporidesmin treatment decreased pregnancy rate (non-pregnant; SP 43% vs. CN 12%, twin; SP 23% vs. CN 52%, both P&lt;0.05). SP foetuses were 6% lighter than CN foetuses at 89 days of gestation, but not at 134 days. Increasing maternal plasma gamma glutamyl transferase activities at mating were associated at 89 days with reduced maternal weight (-1.1: -1.9, -0.3 kg/100 U/l, mean effect size: 95% confidence intervals), increased visual liver damage and reduced placentome number (-1.4: -2.7, -0.1/100 U/l) and foetal pancreatic weight (-21: -38, -4 mg/100 U/l). They were also associated at 134 days with reduced weight of the foetal pancreas (-132: -221, -42 mg/100 U/l), spleen (-139: -231, -47 mg/100 U/l) and thyroid (-29: -48, -10 mg/100 U/l) and decreased A-type placentomes (-3.0: -5.0, -1.0/100 U/l). Pre-mating sporidesmin-induced liver damage is not useful for induction of experimental IUGR but does impair the growth of the foetal pancreas, spleen and thyroid and alter placental morphometry.

Involvement of sensory nerves in the protective effect of growth hormone on acute pancreatitis

Growth hormone (GH) has been shown to protect the intestinal barrier integrity and to stimulate the production of insulin-like growth factor 1 (IGF-1), which inhibits the development of acute pancreatitis. Sensory nerves are implicated in the protection of pancreatic tissue against acute inflammation. The aim of this study was to investigate the influence of exogenous GH on acute pancreatitis (AP) and to assess the involvement of sensory nerves and IGF-1 in above effect. Studies were performed on Wistar rats. AP was induced by subcutaneous administration of caerulein (25 μg/kg) to the conscious animals. GH (1 or 2 mg/kg) was administered to the rats as an intraperitoneal injection 30 min prior to the start of AP. To deactivate sensory nerves capsaicin was given at total dose of 100 mg/kg 10 days before the experiments. AP was confirmed by histological examination and manifested by the significant rises of pancreatic weight, and serum activities of lipase, TNFα and IL-10 (by 550%, 300% and 50%, respectively), whereas IGF-1 blood concentration was markedly reduced. Administration of GH prior to the caerulein infusion significantly increased GH, IGF-1 and IL-10 blood levels, attenuated harmful effects of AP and reduced histological manifestations of pancreatitis in the rats with intact sensory nerves. This was accompanied by the reduction of serum lipase, and TNFα activities. In the AP rats with capsaicin-deactivated sensory nerves GH failed to protect the pancreas against acute damage and, as a consequence of above deactivation, IGF-1 was low. Conclusion GH modulates the development of acute pancreatitis in the presence of active sensory nerves probably via stimulation of IGF-1 release.

Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-A y mice

Sergliflozin etabonate, a novel oral selective low-affinity sodium glucose cotransporter (SGLT2) inhibitor, improves hyperglycemia by suppressing renal glucose reabsorption, in which SGLT2 participates as a dominant transporter. In the present study, we examined the antidiabetic profile of sergliflozin etabonate in a diabetic model, KK-A y mice, with symptoms of obesity and hyperinsulinemia. The blood glucose level was monitored in non-fasted female KK-A y mice after a single oral administration of sergliflozin etabonate. The non-fasting blood glucose level was reduced in a dose-dependent manner after a single oral administration of sergliflozin etabonate (39% reduction at 2 h after a dose of 30 mg/kg). The effects of long-term administration of sergliflozin etabonate on the blood glucose level were assessed in female KK-A y mice in several studies (4-day, 8-week, and 9-week administration study), in which sergliflozin etabonate was administered in the diet. The non-fasting blood glucose and plasma insulin were both lowered dose-dependently in the 4-day administration study. Long-term treatment with sergliflozin etabonate dose-dependently improved the hyperglycemia and prevented body weight gain in the 8-week study. In addition to the improvement in glycemic control, fatty liver and pancreatic β-cell abnormalities were ameliorated in mice fed sergliflozin etabonate in the 9-week study. These data indicate that SGLT2 inhibitors could be useful to improve hyperglycemia resulting from insulin resistance without pancreatic β-cell abuse or body weight gain. SGLT2 inhibitors may simultaneously realize both a systemic negative energy balance and correction of hyperglycemia.

Maternal obesity accelerates fetal pancreatic β-cell but not α-cell development in sheep: prenatal consequences

Maternal obesity affects offspring weight, body composition, and organ function, increasing diabetes and metabolic syndrome risk. We determined effects of maternal obesity and a high-energy diet on fetal pancreatic development. Sixty days prior to breeding, ewes were assigned to control [100% of National Research Council (NRC) recommendations] or obesogenic (OB; 150% NRC) diets. At 75 days gestation, OB ewes exhibited elevated insulin-to-glucose ratios at rest and during a glucose tolerance test, demonstrating insulin resistance compared with control ewes. In fetal studies, ewes ate their respective diets from 60 days before to 75 days after conception when animals were euthanized under general anesthesia. OB and control ewes increased in body weight by approximately 43% and approximately 6%, respectively, from diet initiation until necropsy. Although all organs were heavier in fetuses from OB ewes, only pancreatic weight increased as a percentage of fetal weight. Blood glucose, insulin, and cortisol were elevated in OB ewes and fetuses on day 75. Insulin-positive cells per unit pancreatic area were 50% greater in fetuses from OB ewes as a result of increased beta-cell mitoses rather than decreased programmed cell death. Lambs of OB ewes were born earlier but weighed the same as control lambs; however, their crown-to-rump length was reduced, and their fat mass was increased. We conclude that increased systemic insulin in fetuses from OB ewes results from increased glucose exposure and/or cortisol-induced accelerated fetal beta-cell maturation and may contribute to premature beta-cell function loss and predisposition to obesity and metabolic disease in offspring.

Natural orifice versus conventional laparoscopic distal pancreatectomy in a porcine model: a randomized, controlled trial

Natural orifice transluminal endoscopic surgery (NOTES) research has primarily involved case series reports of low-risk procedures. Distal pancreatectomy has significant postoperative morbidity and would permit rigorous examination in a controlled trial setting. To compare endoscopic transgastric distal pancreatectomy (ETDP) and laparoscopic distal pancreatectomy (LDP). Prospective, randomized, controlled trial. Academic hospital. Forty-one swine, 28 block randomized. LDP was performed with 3 trocars and stapled transection of the pancreas. ETDP was performed via a gastrotomy, with 1 trocar for visualization, by using endoloop placement, snare transection, and purse-string gastrotomy closure. Clinical examination, CT, serum chemistries, necropsy, peritoneal fluid analysis, and histologic examination. Swine were survived for 8 days. The procedure time for ETDP was significantly greater than for LDP (1:52 vs 0:33 [hours:minutes]; P = .00). Pancreatic specimen weight was similar (4.1 g vs 5.5 g; P = .108). Postoperatively, 26 of 28 animals thrived. In the LDP group, 1 death caused by pancreatic leak and renal failure occurred on day 1. In the ETDP group, 1 death caused by pneumothorax occurred intraoperatively. The necropsy, CT, and histologic examinations revealed focal resection-margin necrosis in 3 to 7 swine in the ETDP group with no proximal necrosis or pancreatitis. The groups were equivalent clinically, by survival, and by serum and peritoneal fluid analysis. The gastrotomy closure was associated with small serosal adhesions, but no gross abscess or necrosis. Animal study. In the largest controlled trial of NOTES orifice surgery to date, there was no clinical or survival difference between NOTES and laparoscopic approaches.

Acetyl-l-Carnitine Ameliorates Caerulein-induced Acute Pancreatitis in Rats

In the present study, we have addressed the possible protective role of acetyl-L-carnitine in caerulein-induced acute pancreatitis in male Swiss albino rats. Acute pancreatitis paradigm was developed by challenging animals with a supramaximal dose of caerulein (20 microg/kg, SC) four times at hourly intervals. Caerulein induced acute pancreatitis that was well-characterized morphologically and biochemically. Severe oedema with marked increased relative pancreatic weight, marked atrophy of acini with increased interacinar spaces, vacuolization, and extensive leucocytic infiltration were diagnostic fingerprints of the pancreatitis phenotype. A biochemical test battery that confirmed the model comprised increased plasma amylase and lipase activities, calcium levels as well as increased pancreatic enzymatic myeloperoxidase and glutathione-S-transferase activities, beside increased pancreatic contents of nitric oxide and malondialdehyde and reduced pancreatic glutathione level. Prior administration of acetyl-L-carnitine (200 mg/kg, IP) for seven consecutive days ahead of caerulein challenge alleviated all the histological and biochemical manifestations of acute pancreatitis. These results suggest a possible protective role of the carnitine ester in such a murine acute pancreatitis model probably via regulation of the oxidant/antioxidant balance, beside modulation of the myeloperoxidase and nitric oxide systems, which are involved in the inflammatory cascade that most often associate the disease.

Dietary protein stimulates pancreatic growth via CCK‐independent mTOR activation

Dietary protein can stimulate pancreatic growth in the absence of CCK release, but there is little data on the regulation of CCK‐independent growth. To identify mechanisms whereby protein stimulates pancreatic growth, male C57BL/6 and CCK‐null mice were fed control (20% protein) or protein‐enriched (75% protein) chow for 7 days. The weight of the pancreas increased by 32% in C57BL/6 mice and 36% in CCK‐null mice. Changes in pancreatic weight in C57BL/6 mice were due primarily to cell hypertrophy; with a 68% increase in protein content and a 24% increase in DNA content. Parallel changes were observed in CCK‐null mice. ERK, calcineurin, and mTOR are activated in models of CCK‐induced growth, but there were no differences in ERK or calcineurin activation between fasted and fed CCK‐null mice. In contrast, mTOR activation was increased after feeding and the duration of activation was prolonged in mice fed protein‐enriched chow compared to control chow. Changes in pancreatic weight and DNA content were completely inhibited, and changes in protein content were partially abated, when the mTOR inhibitor rapamycin was administered during protein‐enriched chow feeding. Thus, dietary protein stimulates pancreatic growth in the absence of CCK via prolonged mTOR activation.