Pancreatic Secretion Research Articles

Mechanisms of ag85a/b DNA vaccine conferred immunotherapy and recovery from Mycobacterium tuberculosis-induced injury.

Our previous research developed a novel tuberculosis (TB) DNA vaccine ag85a/b that showed a significant therapeutic effect on the mouse tuberculosis model by intramuscular injection (IM) and electroporation (EP). However, the action mechanisms between these two vaccine immunization methods remain unclear. In a previous study, 96 Mycobacterium tuberculosis (MTB) H37 Rv-infected BALB/c mice were treated with phosphate-buffered saline, 10, 50, 100, and 200 μg ag85a/b DNA vaccine delivered by IM and EP three times at 2-week intervals, respectively. In this study, peripheral blood mononuclear cells (PBMCs) from three mice in each group were isolated to extract total RNA. The gene expression profiles were analyzed using gene microarray technology to obtain differentially expressed (DE) genes. Finally, DE genes were validated by real-time reverse transcription-quantitive polymerase chain reaction and the GEO database. After MTB infection, most of the upregulated DE genes were related to the digestion and absorption of nutrients or neuroendocrine (such as Iapp, Scg2, Chga, Amy2a5), and most of the downregulated DE genes were related to cellular structural and functional proteins, especially the structure and function proteins of the alveolar epithelial cell (such as Sftpc, Sftpd, Pdpn). Most of the abnormally upregulated or downregulated DE genes in the TB model group were recovered in the 100 and 200 μg ag85a/b DNA IM groups and four DNA EP groups. The pancreatic secretion pathway downregulated and the Rap1 signal pathway upregulated had particularly significant changes during the immunotherapy of the ag85a/b DNA vaccine on the mouse TB model. The action targets and mechanisms of IM and EP are highly consistent. Tuberculosis infection causes rapid catabolism and slow anabolism in mice. For the first time, we found that the effective dose of the ag85a/b DNA vaccine immunized whether by IM or EP could significantly up-regulate immune-related pathways and recover the metabolic disorder and the injury caused by MTB.

Compounds Interacting with Cholecystokinin as Potential Drugs Against Excessive Weight Gain and Obesity

Cholecystokinin (CCK) is a peptide family that functions pancreatic enzyme secretion, gallbladder contraction, intestinal motility, satiety, and stomach acid secretion. The CCK peptides are derived from pro-CCK with a specific amino acid sequence (Asp, Tyr, Met, Gly, Trp, Met, Asp, and Phe) at their C-terminus, where the Tyr residue is sulfated. The CCK peptides are ligands of the CCK receptors 1 (CCK1) and 2 (CCK2). In this study, we propose an approach for treating overweight and obese patients, preventing or reducing CCK1 activation using compounds that specifically interact with CCK peptides to regulate their interactions with CCK1. The compounds were selected by molecular docking using a chemical library with the selected residues (Asp, Tyr, Met, Gly, Trp, Met, Asp, and Phe) in CCK. Their effects were evaluated in a diet-induced obese mice model. We show that compounds K2 and K5 decreased and maintained the body weight of the diet-induced obese mice model, respectively, likely by preventing/hindering interactions between CCK peptides and CCK1, modifying its activity. This study demonstrates another approach to treating overweight and obesity by regulating CCK1 functions. The K2 and K5 compounds have properties supporting their continued development as new drugs against these risk factors.

Suture Failure of Duodenum after Surgery for Complications of Duodenal Ulcer

INTRODUCTION: The incidence of failure of intestinal sutures in the early postoperative period reaches 26%. The failure of the duodenal sutures leads to formation of high duodenal fistulas, the treatment of which is one of the most complicated surgical tasks. The article describes a clinical case of failure of duodenal suture after surgery for a duodenal ulcer complicated with bleeding. The failure of the duodenal suture could be provoked by hypoproteinemia and anemia, despite the attempts of their compensation. The presented case demonstrates complexity of the clinical course of this pathology and the possibility of successful application of draining surgery with creation of a controllable duodenal fistula, the subsequent healing of which led to recovery of the patient. To create the controllable duodenal fistula, we used a method of external-internal triple drainage of the duodenal zone (retrograde duodenostomy, gastroenteroanastomosis with a short loop, nasogastral probe). At the initial stage, after surgery, the patient received full parenteral feeding, after restoration of the intestinal peristalsis, feeding was continued through a nasointestinal probe. Infusion therapy, transfusion of blood components were conducted, drugs suppressing gastric and pancreatic secretion, were used. On the 35th postoperative day, the discharge through the duodenal fistula and the nasogastral probe significantly decreased, and completely stopped on the 54th day (immediately after X-ray of stomach with barium sulfate as contrast substance). The patient was discharged with improvement for outpatient follow-up at the place of residence on the 60th day after surgery. In the follow-up period no complaints, good appetite, rapid gaining of weight, complete rehabilitation. In one-year follow-up, no long-term complications and consequences for health were observed.
 CONCLUSION: A choice of the surgical treatment method of duodenal suture failure remains a subject of discussion. In the presented clinical case, draining surgery with creation of a controllable duodenal fistula proved to be effective. The complete closure of the residual fistula of the duodenum was facilitated by stomach X-ray with use of barium sulfate.

Apigenin Alleviates Endoplasmic Reticulum Stress-Mediated Apoptosis in INS-1 β-Cells.

The improvement of type 2 diabetes mellitus induced by naturally occurring polyphenols, known as flavonoids, has received considerable attention. However, there is a dearth of information regarding the effect of the trihydroxyflavone apigenin on pancreatic β-cell function. In the present study, the anti-diabetic effect of apigenin on pancreatic β-cell insulin secretion, apoptosis, and the mechanism underlying its anti-diabetic effects, were investigated in the INS-ID β-cell line. The results showed that apigenin concentration-dependently facilitated 11.1-mM glucose-induced insulin secretion, which peaked at 30 µM. Apigenin also concentration-dependently inhibited the expression of endoplasmic reticulum (ER) stress signaling proteins, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleaved caspase-3, which was elevated by thapsigargin in INS-1D cells, with peak suppression at 30 µM. This was strongly correlated with the results of flow cytometric analysis of annexin V/propidium iodide (PI) staining and DNA fragmentation analysis. Moreover, the increased expression of thioredoxin-interacting protein (TXNIP) induced by thapsigargin was remarkably reduced by apigenin in a concentration-dependent manner. These results suggest that apigenin is an attractive candidate with remarkable and potent anti-diabetic effects on β-cells, which are mediated by facilitating glucose-stimulated insulin secretion and preventing ER stress-mediated β-cell apoptosis, the latter of which may be possibly mediated by reduced expression of CHOP and TXNIP, thereby promoting β-cell survival and function.

Glucocorticoid-mediated induction of ZBTB16 affects insulin secretion in human islets and EndoC-βH1 β-cells

Glucocorticoid use is associated with steroid-induced diabetes mellitus and impaired pancreatic β-cell insulin secretion. Here, the glucocorticoid-mediated transcriptomic changes in human pancreatic islets and the human insulin-secreting EndoC-βH1 cells were investigated to uncover genes involved in β-cell steroid stress-response processes. Bioinformatics analysis revealed glucocorticoids to exert their effects mainly on enhancer genomic regions in collaboration with auxiliary transcription factor families including AP-1, ETS/TEAD, and FOX. Remarkably, we identified the transcription factor ZBTB16 as a highly confident direct glucocorticoid target. Glucocorticoid-mediated induction of ZBTB16 was time- and dose-dependent. Manipulation of ZBTB16 expression in EndoC-βH1 cells combined with dexamethasone treatment demonstrated its protective role against glucocorticoid-induced reduction of insulin secretion and mitochondrial function impairment. In conclusion, we determine the molecular impact of glucocorticoids on human islets and insulin-secreting cells and investigate the effects of glucocorticoid targets on β-cell function. Our findings can pave the way for therapies against steroid-induced diabetes mellitus.

Changes in pancreatic exocrine function, fat and fibrosis in diabetes mellitus: analysis using MR imaging.

To evaluate the relationships between hemoglobin A1c (HbA1c) levels with exocrine pancreatic function using cine-dynamic magnetic resonance cholangiopancreatography (MRCP) and the pancreatic parenchyma using fat-suppressed T1 mapping and the proton density fat fraction (PDFF). Patients who underwent 3T-MRI and HbA1c measurement were retrospectively recruited. MRI included cine-dynamic MRCP with a spatially selective inversion-recovery (SS-IR) pulse, fat-suppressed Look-Locker T1 mapping and multiecho 3D Dixon-based PDFF mapping. The pancreatic exocrine secretion grade on cine-dynamic MRCP, T1 values, and PDFF were analyzed in non-diabetic (n = 32), pre-diabetic (n = 44) and diabetic (n = 23) groups defined using HbA1c. PDFF was weakly correlation with HbA1c (ρ = 0.30, p = 0.002). No correlations were detected between HbA1c and secretion grade (ρ = - 0.16, p = 0.118) or pancreatic parenchymal T1 (ρ = 0.13, p = 0.19). The secretion grade was comparable between the three groups. The T1 value was higher in diabetic (T1 = 1006.2+/- 224.8 ms) than in non-diabetic (T1 = 896.2+/- 86.3 ms, p = 0.010) and pre-diabetic (T1 = 870.1+/- 91.7 ms, p < 0.010) patients. The PDFF was higher in diabetic (FF = 11.8+/- 8.7 %) than in non-diabetic (FF = 6.8+/- 4.2 %, p = 0.014) patients. Pancreatic exocrine function, T1, and FF showed no correlation with HbA1c. Pancreatic T1 and fat fraction is increased in patients with Type 2 diabetes mellitus. This study demonstrates unaffected exocrine function in pre-diabetes and diabetes and confirms that pancreatic parenchymal T1 and FF are increased in patients with diabetes.

Casting a Wider NET: Pancreatic Exocrine Insufficiency Induced by Somatostatin Analogues among Patients with Neuroendocrine Tumours?

Somatostatin-analogues (SSAs) are a first-line treatment of unresectable neuroendocrine tumours (NETs). However, SSAs inhibit pancreatic secretions, which could lead to pancreatic exocrine insufficiency (PEI). PEI is known to be detrimental to patient quality of life and nutritional status. This study aimed to evaluate the effect of SSAs on pancreatic exocrine function in patients with NETs, using the 13C-mixed triglyceride breath test (13C-MTGT). Exocrine function was assessed using the 13C-MTGT at baseline and after a third SSA injection (two months). A quotient of 13CO2/12CO2 was measured by mass spectrometry, and the cumulative percent dose recovered at 6 h (cPDR) is reported. The secondary endpoints investigated were change in weight, HbA1C, and vitamin D levels. Ten patients completed the study. Exocrine function reduced in all patients (n = 10) following SSA therapy (median reduction from baseline: -23.4% (range: -42.1-0.5%, p = 0.005)). vitamin D levels decreased in all but one patient (median decrease from baseline: -26.5%, (-44.7-10%; p = 0.038)), and median HbA1C levels increased by 8.0% (0-59.3%; p = 0.008). Change in weight was not significant (median decrease from baseline: -0.21% (-4.5-3.5%, p = 1.000)). SSA therapy has a consistent impact on exocrine function from early in the treatment course, but the long-term clinical effects of this remain to be defined. Further studies are required to determine the clinical relevance of this observation and optimise the management of PEI in this cohort.

Combined interventions on pancreatic ducts with external fistulas

The present paper describes clinical observation of successful treatment of a patient with chronic calcifying pancreatitis complicated by an external pancreatic fistula. Abdominal surgery after laparotomy and cholecystectomy had to be limited to bursoomentostomy due to the bleeding tissues and severe blood loss. Combined endoscopic intervention through the external pancreatic fistula was used for the treatment. The performed interventions included stone extraction in Wirsung’s duct, dilation and stenting of the distal stricture of the pancreatic duct. The fistula closed, a pain-free period lasted for 3 years. Similar transfistula interventions were performed in 7 patients with chronic pancreatitis and external pancreatic fistulas, lithiasis in Wirsung's duct (n = 5) and pancreatic duct strictures (n = 6). A total of 17 procedures were performed, 7 of 8 fistulas were closed. Complications developed in 3 observations, no lethal outcome was registered.Conclusion. Transfistula interventions in pancreatic ducts with combined X-ray guidance, oral and transfistula endoscopy can be used to remove stones, dilate strictures and restore natural passage of pancreatic secretions as an independent treatment or preparation for planned abdominal surgery.

Integrated microRNA-mRNA analysis reveals a possible molecular mechanism of enteritis susceptibility in Litopenaeus vannamei

Enteritis is one of the main diseases affecting Pacific whiteleg shrimp (Litopenaeus vannamei) in recent years, and it has resulted in huge losses to the aquaculture industry. Prior to this study, the molecular mechanism underlying enteritis in L. vannamei was unclear, and comprehensive multi-omics analysis had not been conducted. In this study, 1209 differentially expressed genes (DEGs) were identified from the hepatopancreas of L. vannamei with and without enteritis. Kyoto Encyclopedia of Genes and Genomes analysis showed that genes were significantly enriched in immune, metabolic, and endocrine regulatory pathways. Forty-eight significantly different microRNAs (miRNAs) were identified in the miRNA-Seq analysis. Further functional annotation analysis showed that the regulatory pathway of target gene enrichment of differentially expressed miRNAs was consistent with DEGs. Through miRNA-mRNA integration analysis, 47 meaningful miRNA-mRNA pairs were obtained, of which melanogenesis and pancreatic secretion were considered key pathways. Subsequent miRNA-mRNA interaction network analysis revealed that mja-miR-6493-3p, Mja-miR-6494, novel-198, novel-272, novel-261, novel-200, novel-183, novel-184, novel-237, and novel-192 may be key miRNAs involved in the regulation of these two signaling pathways. Finally, the RAS signaling pathway was found to inhibit the translation level of proteins in the hepatopancreas. These results suggest that target gene integration analysis of mRNA-miRNA can reveal the molecular mechanism underlying enteritis in L. vannamei and also provide valuable new insights for resisting enteritis.

Donor noradrenaline use is associated with better allograft survival in recipients of pancreas transplantation.

Outcomes following pancreas transplantation are suboptimal and better donor selection is required to improve this. Vasoactive drugs (VaD) are commonly used to correct the abnormal haemodynamics of organ donors in intensive care units. VaDs can differentially affect insulin secretion positively (dobutamine) or negatively (noradrenaline). The hypothesis was that some VaDs might induce beta-cell stress or rest and therefore impact pancreas transplant outcomes. The aim of the study was to assess relationships between VaD use and pancreas transplant graft survival. Data from the UK Transplant Registry on all pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Univariable- and multivariable-adjusted Cox regression analyses determined risks of graft failure associated with VaD use. In 2,183 pancreas transplants, VaDs were used in the following numbers of donors: dobutamine 76 (3.5%), dopamine 84 (3.8%), adrenaline 161 (7.4%), noradrenaline 1,589 (72.8%) and vasopressin 1,219 (55.8%). In multivariable models, adjusted for covariates and the co-administration of other VaDs, noradrenaline use (vs non-use) was a strong predictor of better graft survival (hazard ratio [95% confidence interval] 0.77 [0.64-0.94], p = 0.01). Noradrenaline use was associated with better graft survival in models adjusted for donor and recipient variables - this may be related to inhibition of pancreatic insulin secretion initiating pancreatic beta-cell 'rest'. Further research is required to replicate these findings and establish whether relationships are causal. Identification of alternative methods of inducing beta-cell rest could be valuable in improving graft outcomes.

Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes

Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals. To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes. This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years. Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo. The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis. Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group. In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks. ClinicalTrials.gov Identifier: NCT04233034.

Genome-wide identification of A-to-I RNA editing events provides the functional implications in PDAC.

RNA editing, a wide-acknowledged post-transcriptional mechanism, has been reported to be involved in the occurrence and development of cancer, especially the abnormal alteration of adenosine to inosine. However, fewer studies focus on pancreaticcancer. Therefore, we aimed to explore the possible linkages between altered RNA editing events and the development of PDAC. We characterized the global A-to-I RNA editing spectrum from RNA and matched whole-genome sequencing data of 41 primary PDAC and adjacent normal tissues. The following analyses were performed: different editing level and RNA expression analysis,pathway analysis, motif analysis, RNA secondary structure analysis, alternative splicing events analysis, and survival analysis.The RNA editing of single-cell RNA public sequencing data was also characterized. A large number of adaptive RNA editing events with significant differences in editing levels were identified, which are mainly regulated by ADAR1. Moreover, RNA editing in tumors has a higher editing level and more abundant editing sites in general. 140genes were screened out since they were identified with significantly different RNA editing events and were significantly different in expression level between tumor and matched normal samples. Further analysis showed a preference that in the tumor-specific group, they are mainly enriched in cancer-related signal pathways, while in the normal tissue-specific group, they are mainly enriched in pancreatic secretion. At the same time, we also found positively selected differentially edited sites in a series of cancer immune genes, including EGF, IGF1R, and PIK3CD. RNA editing might participate in pathogenisis of PDAC through regulating the alternative splicing and RNA secondary structure of important genesto further regulate gene expression and protein synthesis, including RAB27B and CERS4. Furthermore, single cell sequencing results showed that type2 ductal cells contributed the most to RNA editing events in tumors. RNA editing is an epigenetic mechanism involved in the occurrence and development of pancreatic cancer, which has the potential to diagnose of PDAC and is closely related to the prognosis.

Expression Silencing of Mitogen-Activated Protein Kinase 8 Interacting Protein-1 Conferred Its Role in Pancreatic β-Cell Physiology and Insulin Secretion.

Mitogen-activated protein kinase 8 interacting protein-1 (MAPK8IP1) gene has been recognized as a susceptibility gene for diabetes. However, its action in the physiology of pancreatic β-cells is not fully understood. Herein, bioinformatics and genetic analyses on the publicly available database were performed to map the expression of the MAPK8IP1 gene in human pancreatic islets and to explore whether this gene contains any genetic variants associated with type 2 diabetes (T2D). Moreover, a series of functional experiments were executed in a rat insulinoma cell line (INS-1 832/13) to investigate the role of the Mapk8ip1 gene in β-cell function. Metabolic engineering using RNA-sequencing (RNA-seq) data confirmed higher expression levels of MAPK8IP1 in human islets compared to other metabolic tissues. Additionally, comparable expression of MAPK8IP1 expression was detected in sorted human endocrine cells. However, β-cells exhibited higher expression of MAPK8IP1 than ductal and PSC cells. Notably, MAPK8IP1 expression was reduced in diabetic islets, and the expression was positively correlated with insulin and the β-cell transcription factor PDX1 and MAFA. Using the TIGER portal, we found that one genetic variant, "rs7115753," in the proximity of MAPK8IP1, passes the genome-wide significance for the association with T2D. Expression silencing of Mapk8ip1 by small interfering RNA (siRNA) in INS-1 cells reduced insulin secretion, glucose uptake rate, and reactive oxygen species (ROS) production. In contrast, insulin content, cell viability, and apoptosis without cytokines were unaffected. However, silencing of Mapk8ip1 reduced cytokines-induced apoptosis and downregulated the expression of several pancreatic β-cell functional markers including, Ins1, Ins2, Pdx1, MafA, Glut2, Gck, Insr, Vamp2, Syt5, and Cacna1a at mRNA and/or protein levels. Finally, we reported that siRNA silencing of Pdx1 resulted in the downregulation of MAPK8IP1 expression in INS-1 cells. In conclusion, our findings confirmed that MAPK8IP1 is an important component of pancreatic β-cell physiology and insulin secretion.

Insulin Autoimmune Syndrome: A Systematic Review.

Insulin autoimmune syndrome (IAS) is a rare endocrine disorder characterized by recurrent episodes of severe hypoglycemia, markedly elevated serum insulin, and positive insulin autoantibodies. In recent years, various countries have reported it one after another. It can be seen that we must pay attention to this disease. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. High levels of insulin autoantibodies are found in patients, and C-peptide is not parallel to insulin, which could be diagnostic. IAS is a self-limiting disease with a good prognosis. Its treatment mainly includes symptomatic supportive treatment, such as adjusting the diet and using acarbose and other drugs to delay the absorption of glucose to prevent hypoglycemia. For patients with severe symptoms, available treatments may include drugs that reduce pancreatic insulin secretion (such as somatostatin and diazoxide), immunosuppressants (glucocorticoids, zaprin, and rituximab), and even plasma exchange to remove autoantibodies from the body. This review provides a comprehensive analysis of the epidemiology, pathogenesis, clinical manifestations, diagnosis and identification, and monitoring and treatment management of IAS.

2,3-Dihydrosorbicillin and chrysopanol stimulate insulin secretion in INS-1 cells

Pancreatic β-cell function and insulin secretion are important in antidiabetic drug development. In an effort to discover small molecules to regulate insulin secretion, an endophytic fungus, Penicillium sp. SSP-1CLG, was selected for chemical investigation. Large scale cultures of the strain followed by extraction and chromatographic analysis led to the isolation of 10 anthraquinone and alkaloid-type compounds. The isolated compounds were identified by comprehensive analysis of NMR, MS, and ECD data. The effect of compounds 1–10 on insulin secretion in INS-1 cells was investigated. 2,3-Dihydrosorbicillin (1), chrysophanol (2), and glandicolin B (10) at non-cytotoxic concentrations resulted in an increase of glucose-stimulated insulin secretion (GSIS) in rat INS-1 pancreatic β-cells. Furthermore, we investigated the signaling pathway involved in 2,3-dihydrosorbicillin (1) and chrysophanol (2) action in the activation of peroxisome proliferator-activated receptor γ (PPARγ), pancreatic and duodenal homeobox-1 (PDX-1), insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt. Treatment of INS-1 cells with 2,3-dihydrosorbicillin (1) and chrysophanol (2) increased the expression of these proteins. Our findings indicate that 2,3-dihydrosorbicillin and chrysophanol may play roles in the regulation of insulin secretion in pancreatic β-cells, at least in part, by targeting PPARγ and PDX-1 via the IRS-2/PI3K/Akt signaling pathway.

The effects of dietary myo-inositol on growth and physiological, biochemical, and molecular responses in the Pacific white shrimp Litopenaeus vannamei

Myo-inositol serves as an essential nutrient in many animal species. However, the optimal requirements of myo-inositol and the mechanisms by which myo-inositol is involved in nutritional regulation in crustaceans are unclear. An 8-week trial was conducted to comparatively evaluate the effects of 6 levels of dietary myo-inositol (20, 528, 1030, 2060, 3180 and 4235 mg/kg diet) on growth performance, body composition, serum metabolite composition, hepatopancreatic metabolite content, and digestive enzyme activity in juvenile Pacific white shrimp Litopenaeus vannamei (0.78 ± 0.039 g). The weight gain and conditioning factors of shrimp fed myo-inositol were significantly higher than those of the 20 mg/kg myo-inositol group. The maximal hepatosomatic index was found in the 1030 mg/kg myo-inositol group. On the other hand, serum triglyceride, total cholesterol, and low-density lipoprotein contents in the control group were significantly lower than those in the other groups, and glucose content in the hepatopancreas in the control group was significantly lower than that in the 2060 and 3180 mg/kg myo-inositol groups. Metabolome and transcriptome analyses revealed that myo-inositol significantly affected glycerophospholipid metabolism, transport and catabolism in lysosomes, pancreatic secretion, and bile secretion pathways. The highest growth was achieved with the inclusion of 528 mg/kg dietary myo-inositol. This study has suggested that myo-inositol may promote growth in L. vannamei by improving lipid utilization.

Endoplasmic reticulum stress inhibition ameliorated WFS1 expression alterations and reduced pancreatic islets’ insulin secretion induced by high-fat diet in rats

Endoplasmic reticulum (ER) stress is involved in the development of glucose homeostasis impairment. When ER stress occurs, the unfolded protein response (UPR) is activated to cope with it. One of the UPR components is WFS1 (Wolfram syndrome 1), which plays important roles in ER homeostasis and pancreatic islets glucose-stimulated insulin secretion (GSIS). Accordingly and considering that feeding high-fat food has a major contribution in metabolic disorders, this study aimed to investigate the possible involvement of pancreatic ER stress in glucose metabolism impairment induced by feeding high-fat diet (HFD) in male rats. After weaning, the rats were divided into six groups, and fed on normal diet and HFD for 20 weeks, then 4-phenyl butyric acid (4-PBA, an ER stress inhibitor) was administered. Subsequently, in all groups, after performing glucose tolerance test, the animals were dissected and their pancreases were removed to extract ER, islets isolation and assessment of GSIS. Moreover, the pancreatic ER stress [binding of immunoglobulin protein (BIP) and enhancer-binding protein homologous protein (CHOP)] and oxidative stress [malondialdehyde (MDA), glutathione (GSH) and catalase] biomarkers as well as WFS1 expression level were evaluated. HFD decreased pancreatic WFS1 protein and GSH levels, and enhanced pancreatic catalase activity, MDA content, BIP and CHOP protein and mRNA levels as well as Wfs1 mRNA amount. Accordingly, it increased BIP, CHOP and WFS1 protein levels in the extracted ER of pancreas. In addition, the HFD caused glucose intolerance, and decreased the islets’ GSIS and insulin content. However, 4-PBA administration restored the alterations. It seems that, HFD consumption through inducing pancreatic ER stress, altered WFS1 expression levels, reduced the islets’ GSIS and insulin content and finally impaired glucose homeostasis.

Liver-expressed antimicrobial peptide 2 is associated with improved pancreatic insulin secretion in adults with overweight and obesity.

To examine association of liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous ghrelin antagonist with anorexiant effects, to key cardiometabolic risk factors in people with overweight and obesity. In this cross-sectional study, we sought to identify associations between LEAP2 levels and cardiometabolic risk factors, including body composition (dual X-ray absorptiometry), insulin and glucose metabolism (oral and intravenous glucose tolerance tests and hyperinsulinaemic-euglycaemic clamps), plasma lipids and inflammation markers (ELISA and multiplex assays). In 65 participants with overweight or obesity (63.1% male, mean age 31.3 ± 8.5 years), LEAP2 levels were associated with total body fat, but not with body mass index or waist-hip ratio in both univariable and age- and sex-adjusted models (P < 0.05). Higher LEAP2 level was also positively associated with higher insulin secretion in univariable (P=0.047) and multivariable models adjusted for age, sex and body fat (P=0.03), but not with fasting glucose levels (P ≥ 0.05). Higher LEAP2 levels were associated insulin resistance (P=0.07) after adjustment for age and sex, but the association disappeared after an additional adjustment for body fat (P=0.2). There was an inverse association between LEAP2 levels and nuclear factor kappa-B (NFκB) activity in the peripheral blood mononuclear cells in age-, sex- and body fat-adjusted models (P=0.04). There were no associations with cardiovascular risk factors (lipids, blood pressure) or other inflammation markers. These results provide important insights into the association between LEAP2 and cardiometabolic health in a high-risk population of individuals with overweight and obesity. This is a first report of an association between LEAP2 and insulin secretion, insulin sensitivity and NFκB activity. LEAP2 may represent an important potential therapeutic target to promote insulin secretion in people with type 2 diabetes and obesity.

Stent placement in pancreatic disease, when, which and why? – a current perspective

IntroductionStenting of the pancreas is a challenging task for the interventional gastroenterologist. The indications for pancreatic stent implantation are either prophylactic or therapeutic. We give an overview of currently available literature and techniques for the respective indications of pancreatic stent placement.MethodsA structured literature research was conducted (Pubmed.gov) primarily using the following key words: interventional endoscopy, pancreatic stenting, post-ERCP pancreatitis, pancreatic Q8 fistulae, pancreas divisum.ResultsProphylactic stent implantation aims to prevent PEP by using thin (3-5 Fr) and short (3-5 cm) designated pancreatic stents at least in high-risk patients. Therapeutic stent placement is intended to restore the proper flow of pancreatic secretion with stenoses, leaks, fistulas or anatomical malformation of the pancreatic duct. Depending on the etiology, plastic stents or SEMSs are used. Another field of pancreatic stenting represents EUS-guided puncture with stent implantation as an alternative access to the main pancreatic duct when transpapillary access is impossible. In addition to the implantation of plastic stents, which achieve good results, LAMS implantation can be discussed as an alternative access route.DiscussionThe field of pancreatic stenting is complex and belongs in the hands of experienced endoscopists in specialized institutions. This can ensure that the patient receives the optimal treatment with the best possible outcome.

Inactivation of potassium channels by ceramide in rat pancreatic β-cells

Lipid regulation of ion channels is a fundamental mechanism in physiological processes as of neurotransmitter release and hormone secretion. Ceramide is a bioactive lipid proposed as a regulator of several voltage-gated ion channels including potassium channels (Kv). It is generated either de novo or by sphingomyelin (SM) hydrolysis in membranes of mammalian cells. In pancreatic β-cells, ceramide is the main sphingolipid associated with lipotoxicity and likely involved in cell dysfunction. Despite of the wealth of information regarding regulation of potassium channels by ceramides, the regulation of Kv channels by accumulated ceramide in native pancreatic β-cells has not been investigated. To do so, we used either the C2-ceramide, a cell-permeable short-chain analogue, or a sphingomyelinase (SMase C), a hydrolase causing ceramide to elevate from an endogenous production, in pancreatic β-cells of rat. C2-ceramide markedly accelerates steady-state current inactivation according to kinetic changes in the channel machinery. Interestingly, only C2-ceramide accelerates current inactivation while SMase C decreases both, peak-current and step-current amplitude supporting differential effects of ceramide derivatives. A specific inhibitor of the Kv2.1 channel (GxTX-1E), readily inhibits a fraction of the Kv channel current while no further inhibition by C2-ceramide superfusion can be observed supporting Kv2.1 channel involvement in the ceramide inhibition. Thus, intramembrane ceramide accumulation, as a lipidic metabolite released under cell-stress conditions, may alter pancreatic β-cell repolarization and secretion. These results may provide a new insight regarding lipid-protein regulation and advance our understanding in ceramide actions on Kv channels in pancreatic β-cells.