leptin and Pancreatitis

Acute pancreatitis (AP) is one of the most common diseases requiring hospitalization with increasing incidence. This pathology has variable severity and is associated with significant morbidity and mortality. Early diagnosis, including prognosis of clinical course of the disease is key in the initial clinical management. However, currently available prognostic markers have variable efficacy and the limited utility. Adipokines that are released from the peripancreatic adipose tissue during AP may represent the easy to use and practical AP prognostic markers. This review discusses the current state of knowledge concerning the clinical value of the adipokines in AP, such as adiponectin, ghrelin, interleukin 6, interleukin 8, interleukin 18, leptin, neutrophil gelatinase associated lipocalin, obestatin, resistin, visfatin. Among described adipokines, interleukin 6, neutrophil gelatinase associated lipocalin and resistin seem to be the most valuable as the diagnostic and prognostic markers in AP.

Topics: Adipokines; Adiponectin; Humans; Interleukin-6; Leptin; Lipocalin-2; Pancreatitis; Resistin; Severity of Illness Index

Acute pancreatitis is a nonbacterial disease of the pancreas. The severe form of this ailment is characterized by high mortality. Whether acute pancreatitis develops as the severe type or resolves depends on the intensity of the inflammatory process which is counteracted by the recruitment of innate defense mechanisms. It has been shown that the hormones ghrelin, leptin and melatonin are able to modulate the immune function of the organism and to protect the pancreas against inflammatory damage. Experimental studies have demonstrated that the application of these substances prior to the induction of acute pancreatitis significantly attenuated the intensity of the inflammation and reduced pancreatic tissue damage. The pancreatic protective mechanisms of the above hormones have been related to the mobilization of non-specific immune defense, to the inhibition of nuclear factor kappa B and modulation of cytokine production, to the stimulation of heat shock proteins and changes of apoptotic processes in the acinar cells, as well as to the activation of antioxidant system of the pancreatic tissue. The protective effect of ghrelin seems to be indirect and perhaps dependent on the release of growth hormone and insulin-like growth factor 1. Leptin and ghrelin, but not melatonin, employ sensory nerves in their beneficial action on acute pancreatitis. It is very likely that ghrelin, leptin and melatonin could be implicated in the natural protection of the pancreatic gland against inflammatory damage because the blood levels of these substances increase in the initial phase of pancreatic inflammation. The above hormones could be a part of the innate resistance system which might remove noxious factors and could suppress or attenuate the inflammatory process in the pancreas.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Ghrelin; Humans; Inflammation Mediators; Leptin; Melatonin; Pancreas; Pancreatitis; Signal Transduction

THE PURPOSE OF THE REVIEW: Analyze the basic data on the role of obesity in the pathogenesis of pancreatic cancer (PC) and the modern mechanisms of this association.. In the European Union and in Russia incidence of pancreatic diseases increases, such pancreatic cancer (PC) ranks 10th among cancer diseases. Obesity is a risk factor for not only of severe acute pancreatitis, but also PC at that independently of diabetes. In a meta-analysis the PC risk in obese increased by 47%, while the person with a central obesity have a higher PC risk compared to those with a peripheral type of obesity (odds ratio = 1,45, 95% CI: 1,02-2,07), but association between BMI and PC risk in this Japanese population may be different from that in Western populations, sometimes inversely. The link between obesity and PC is explained by insulin resistance and hyperinsulinemia: was proved a direct correlation between the level of circulating C-peptide and PC, low levels of serum adiponektin and leptin increase the PC risk. There are also genetic risk factors for PC: a statistically significant interaction between IVS1-27777C> and IVS1-23525A>T genotypes of the FTO gene with obesity and the PC risk: AA genotype in patients with BMI < 25 kg/m2 reduced PC risk by 22%-28% (p < 0,0001), and with BMI ≥ 25 kg/m2 was associated with 54%-60% increased PC risk (p < 0,0015). Lifestyle factors (smoking, consumption of saturated fats, etc.) increase the PC risk.

Topics: Humans; Leptin; Obesity; Pancreatic Neoplasms; Pancreatitis; Risk Factors

To analyze the prognostic value of adipokines in predicting the course, complications and fatal outcome of acute pancreatitis (AP).. We performed the search of PubMed database and the systemic analysis of the literature for both experimental and human studies on prognostic value of adipokines in AP for period 2002-2012. Only the papers that described the use of adipokines for prediction of severity and/or complications of AP were selected for further analysis. Each article had to contain information about the levels of measured adipokines, diagnosis and verification of AP, to specify presence of pancreatic necrosis, organ dysfunction and/or mortality rates. From the very beginning, study was carried out adhering to the PRISMA checklist and flowchart for systemic reviews. To assess quality of all included human studies, the Quality Assessment of Diagnostic Accuracy Studies tool was used. Because of the high heterogeneity between the studies, it was decided to refrain from the statistical processing or meta-analysis of the available data.. Nine human and three experimental studies were included into review. In experimental studies significant differences between leptin concentrations at 24 and 48 h in control, acute edematous and acute necrotizing pancreatitis groups were found (P = 0.027 and P < 0.001). In human studies significant differences between leptin and resitin concentrations in control and acute pancreatitis groups were found. 1-3 d serum adiponectin threshold of 4.5 μg/mL correctly classified the severity of 81% of patients with AP. This threshold yielded a sensitivity of 70%, specificity 85%, positive predictive value 64%, negative predictive value88% (area under curve 0.75). Resistin and visfatin concentrations differ significantly between mild and severe acute pancreatitis groups, they correlate with severity of disease, need for interventions and outcome. Both adipokines are good markers for parapancreatic necrosis and the cut-off values of 11.9 ng/mL and 1.8 ng/mL respectively predict the high ranges of radiological scores. However, the review revealed that all nine human studies with adipokines are very different in terms of methodology and objectives, so it is difficult to generalize their results. It seems that concentrations of the leptin and resistin increases significantly in patients with acute pancreatitis compared with controls. Serum levels of adiponectin, visfatin and especially resitin (positive correlation with Acute Physiology and Chronic Health Evaluation II, Ranson and C-reactive protein) are significantly different in mild acute pancreatitis and severe acute pancreatitis patients, so, they can serve as a markers for the disease severity prediction. Resistin and visfatin can also be used for pancreatic and parapancreatic necrosis prediction, interventions needs and possible, outcome.. High levels of adipokines could allow for prediction of a severe disease course and outcome even in small pancreatic lesions on computed tomography scans.

Topics: Acute Disease; Adipokines; Humans; Inflammation; Leptin; Necrosis; Nicotinamide Phosphoribosyltransferase; Pancreatitis; Pancreatitis, Acute Necrotizing; Prognosis; Resistin; Sensitivity and Specificity; Time Factors; Treatment Outcome

Our understanding of biliary motility under normal and pathophysiologic conditions is still incomplete, but there have been recent advances. Of particular interest are the mechanisms involved in gallbladder filling and emptying, with a focus on understanding the processes underlying impaired gallbladder emptying leading to gallbladder dyskinesia and the formation of gallstones or cholecystitis. The sphincter of Oddi (SO) is a complex neuromuscular structure. Recent studies have attempted to unravel the specific neural or hormonal mechanisms operating under normal physiologic conditions and those that may lead to SO dysfunction. Furthermore, new research fronts are emerging, including the role of leptin in obese patients with impaired biliary motility and the action of electroacupuncture for possible treatment of SO dysfunction. This review illustrates the broad front of current research regarding the effects of bioactive agents on biliary motility, including enteric hormones, nitric oxide, opioids, inflammatory mediators, leptin, protease inhibitors, neurotransmitters, and electroacupuncture.

Topics: Animals; Biliary Tract; Electroacupuncture; Gabexate; Gallbladder; Gallbladder Emptying; Histamine; Humans; Immunohistochemistry; Inflammation Mediators; Leptin; Neurotransmitter Agents; Pancreatitis; Serine Proteinase Inhibitors; Sincalide; Somatostatin; Sphincter of Oddi

Lipodystrophy syndromes are rare complex multisystem disorders caused by generalized or partial lack of adipose tissue. Adipose tissue dysfunction in lipodystrophy is associated with leptin deficiency. Lipodystrophy leads to severe metabolic problems. These abnormalities include, but are not limited to, insulin-resistant diabetes, severe hypertriglyceridemia, and lipid accumulation in ectopic organs such as the liver, and are associated with end-organ complications. Metabolic abnormalities can be present at the time of diagnosis or may develop over time as the disease progresses. In addition to metabolic abnormalities, subtype-specific presentations due to underlying molecular etiology in genetic forms and autoimmunity in acquired forms contribute to severe morbidity in lipodystrophy.

Topics: Autoimmune Diseases; Diabetes Mellitus; Heart Diseases; Humans; Hypertriglyceridemia; Insulin Resistance; Kidney Diseases; Leptin; Lipid Metabolism; Lipodystrophy; Liver; Metabolic Syndrome; Neuromuscular Diseases; Non-alcoholic Fatty Liver Disease; Pancreatitis; Syndrome

Currently, the global prevalence of obesity among the worlds adult population is about 650 million people, which makes it possible to consider this chronic metabolic disease as a non-infectious pandemic of the 21st century. It has been proven that obesity is associated with several gastroenterological diseases, while the mechanisms of these associations are extremely heterogeneous and multifactorial. Hypertrophy and hyperplasia of adipocytes in obesity lead to a change in the profile of adipokine production (a decrease in adiponectin, an increase in leptin), an increase in the production of pro-inflammatory cytokines (interleukin-1, 6, 8, tumor necrosis factor ), C-reactive protein, free fatty acids, as well as active forms of oxygen (superoxide radicals, H2O2). All the above induces the development of chronic slowly progressive inflammation, oxidative stress, and insulin resistance. In addition, peptides secreted by adipocytes (adiponectin, leptin, nesfatin-1 and apelin) can modulate gastrointestinal motility, acting both centrally and peripherally. The qualitative and quantitative changes in the intestinal microbiota observed in obese patients (increased Firmicutes and decreased Bacteroidetes) lead to a decrease in the production of short-chain fatty acids and an increase in the intestinal permeability due to disruption of intercellular tight junctions, which leads to increased translocation of bacteria and endotoxins into the systemic circulation. Numerous studies have demonstrated the association of obesity with diseases of the esophagus (gastroesophageal reflux disease, Barretts esophagus, esophageal adenocarcinoma, esophageal motility disorders), stomach (functional dyspepsia, stomach cancer), gallbladder (cholelithiasis, gallbladder cancer), pancreas (acute pancreatitis, pancreatic cancer), liver (non-alcoholic fatty liver disease, hepatocellular carcinoma), intestine (diverticular disease, irritable bowel syndrome, colorectal cancer).. В настоящее время глобальная распространенность ожирения среди взрослого населения мира составляет около 650 млн человек, что позволяет рассматривать данное хроническое заболевание обмена веществ как неинфекционную пандемию XXI в. Доказано, что ожирение ассоциировано с целым рядом заболеваний гастроэнтерологического профиля, при этом механизмы этих связей крайне гетерогенны и мультифакториальны. Гипертрофия и гиперплазия адипоцитов при ожирении приводят к изменению профиля продукции адипокинов (снижение адипонектина, повышение лептина), повышению продукции провоспалительных цитокинов (интерлейкин-1, 6, 8, фактор некроза опухоли ), С-реактивного белка, свободных жирных кислот, а также активных форм кислорода (супероксидные радикалы, H2O2). Все перечисленное индуцирует развитие хронического медленно прогрессирующего воспаления, оксидативного стресса, а также инсулинорезистентности. Помимо этого, пептиды, секретируемые адипоцитами (адипонектин, лептин, несфатин-1 и апелин), способны модулировать моторику желудочно-кишечного тракта, действуя как центрально, так и периферически. Наблюдаемые у пациентов с ожирением качественные и количественные изменения микробиоты кишечника (повышение Firmicutes и снижение Bacteroidetes) приводят к сокращению продукции короткоцепочечных жирных кислот и росту проницаемости кишечной стенки вследствие нарушения межклеточных плотных контактов, что ведет к повышенной транслокации бактерий и эндотоксинов в системный кровоток. Многочисленными исследованиями продемонстрирована ассоциация ожирения с заболеваниями пищевода (гастроэзофагеальная рефлюксная болезнь, пищевод Баррета, аденокарцинома пищевода, нарушения моторики пищевода), желудка (функциональная диспепсия, рак желудка), желчного пузыря (желчнокаменная болезнь, рак желчного пузыря), поджелудочной железы (острый панкреатит, рак поджелудочной железы), печени (неалкогольная жировая болезнь печени, гепатоцеллюлярная карцинома), кишечника (дивертикулярная болезнь, синдром раздраженного кишечника, колоректальный рак).

Topics: Acute Disease; Adipokines; Adiponectin; Adult; Apelin; Barrett Esophagus; C-Reactive Protein; Cytokines; Digestive System; Endotoxins; Esophageal Neoplasms; Fatty Acids, Nonesterified; Humans; Hydrogen Peroxide; Interleukin-1; Leptin; Obesity; Oxygen; Pancreatitis; Risk Factors; Superoxides; Tumor Necrosis Factors

Acute pancreatitis (AP) is a life-threatening condition. Using antioxidants in AP is insufficient and conflicting. Therefore, this study compared the effect of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), leptin or curcumin pretreatment on AP induced by L-arginine.. Forty adult male rats were used and classified into: 1) control; 2) AP group [each rat was intraperitoneally (i.p.) injected with 2 doses of L-arginine of 250 mg/100 g body weight (b.w.) with an interval of 1 h]; 3) NaHS+AP group (each rat was i.p. injected with 10 mg/kg b.w. of NaHS 1 h before induction of AP); 4) leptin+AP group (each rat was pretreated with 10 μg/kg b.w. of leptin 30 min before induction of AP; and 5) curcumin+AP group (in which rats were i.p. injected with 150 mg/kg b.w. of curcumin 30 min before induction of AP). Serum amylase, lipase, nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and corticosterone (CORT) levels were assayed. In addition, pancreatic tissues were obtained for histopathological examination and malondialde-hyde (MDA), total antioxidant capacity (TAC), and inducible nitric oxide synthase (iNOS) levels were measured.. All AP treated groups showed significant decrease in serum levels of pancreatic enzymes, NO, and TNF-α, and pancreatic MDA and iNOS levels, while TAC levels were significantly increased. NaHS caused more limitation of inflammation than leptin and curcumin by affecting iNOS. Leptin was more potent than curcumin due to the stimulatory effect of leptin on glucocorticoid release to counteract inflammation.. NaHS was more effective in AP amelioration than the leptin and curcumin.

Topics: Animals; Arginine; Corticosterone; Curcumin; Cytoprotection; Leptin; Male; Nitric Oxide Synthase Type II; Pancreas; Pancreatitis; Protective Agents; Rats; Rats, Wistar; Signal Transduction; Sulfides

Obesity is an independent risk factor for severe acute pancreatitis (AP). Leptin plays an important role in energy homeostasis. It has been reported that leptin might also participate in the regulation of the intestinal mucosal barrier and inflammatory response. This study aimed to evaluate the effects of leptin on the intestinal mucosal barrier and inflammatory injury in obese mice with AP.. AP was induced in leptin-deficient (ob/ob) or wild type (WT) mice by peritoneal injection of caerulein. The animals were divided into 4 groups: WT mice with or without exogenous leptin injection and ob/ob mice with or without leptin treatment. The inflammatory scoring of the pancreas and intestine were evaluated. Intestinal permeability, ileal interleukin (IL)-6 and IL-1β, proliferation, apoptosis and intestinal expression levels of claudin-1 and occludin were measured.. Pancreatic pathologic scores (8.50 ± 0.96 vs. 3.78 ± 1.35, p < 0.001), pancreatic levels of IL-6 (8.34 ± 3.21 ng/mg vs. 4.99 ± 0.53 ng/mg, p = 0.022), intestinal oedema scores (2.25 ± 0.46 vs. 1.14 ± 0.69, p = 0.001) and intestinal permeability to FD4 (0.78 ± 0.06 μg/ml vs. 0.53 ± 0.11 μg/ml, p < 0.001) were significantly higher in ob/ob mice than those in WT mice. Leptin replacement in ob/ob mice greatly improved the intestinal permeability (FD4 0.66 ± 0.03 μg/ml, vs. 0.78 ± 0.06 μg/ml, p = 0.012), increased the ileal expression of claudin-1(1.07 ± 0.08 vs. 0.83 ± 0.07 relative densitometry, p = 0.001) and reduced intestinal IL-6 and IL-1β to levels comparable to those in WT mice. The pancreatic level of IL-6 in ob/ob mice treated with leptin was also significantly decreased relative to that of untreated ob/ob mice (4.45 ± 1.71 ng/mg vs. 8.34 ± 3.21 ng/mg, p = 0.010).. Obesity may aggravate intestinal inflammation and increase intestinal permeability under the condition of acute pancreatitis. Exogenous leptin supplementation was in favour of anti-inflammation and improvement of intestinal mucosal barrier.

Topics: Acute Disease; Animals; Inflammation; Intestinal Mucosa; Leptin; Male; Mice; Mice, Knockout; Mice, Obese; Obesity; Pancreas; Pancreatitis

The prevalence of metabolic diseases continues to rise worldwide, with a growing recognition of metabolic dysregulation after acute inflammatory diseases such as acute pancreatitis (AP). Adipokines and cytokines play an important role in metabolism and the course of AP, but there is a paucity of research investigating their relationship with pancreatic hormones after AP. This study aimed to explore associations between pancreatic hormones and adipokines as well as cytokines to provide insights into the pathophysiology of altered pancreatic hormone secretion following AP [corrected].. A total of 83 patients previously diagnosed with AP and no prior diabetes or pre-diabetes were recruited into this cross-sectional follow up study. Fasting venous blood samples were collected to analyse a panel of pancreatic hormones and derivatives (amylin, C-peptide, glucagon, insulin, pancreatic polypeptide, somatostatin), adipokines (adiponectin, leptin, retinol binding protein-4, and resistin), and cytokines (interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-α (TNF-α)). Linear regression analyses were used, and potential confounders were adjusted for in multivariate analyses.. Insulin was significantly associated with IL-6 in both unadjusted and adjusted models (p = .029 and p = .040, respectively). Amylin was significantly associated with MCP-1 in the unadjusted model (p = .046), and TNF-α in unadjusted and adjusted models (p = .025 and p = .027, respectively).. Insulin and amylin have a strong positive association with pro-inflammatory cytokines in patients following an episode of AP. These associations have possible relevance in the development of diabetes associated with diseases of the exocrine pancreas, providing the opportunity to develop novel treatment paradigms.

Topics: Acute Disease; Adiponectin; Adult; Aged; Chemokine CCL2; Cohort Studies; Cross-Sectional Studies; Cytokines; Fasting; Female; Follow-Up Studies; Humans; Inflammation Mediators; Insulin; Interleukin-6; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Pancreatitis; Resistin; Tumor Necrosis Factor-alpha

Acute pancreatitis (AP) is a common non‑bacterial disease compromising pancreatic tissues. Adipocyte‑derived leptin is closely associated with the severity and clinical outcome of pancreatitis. The potential protective effects of exogenous leptin administration on a rat model of severe AP (SAP) remain to be elucidated, and were examined in the present study. Male Wistar rats were divided into a sham operation group (SO), SAP model group (SAP) and leptin group (LEP). Each group was divided into three sub‑groups by observation time (24, 48 and 72 h). The SAP models were prepared by retrograde injection of 6% sodium taurocholate into the pancreatic‑bile duct. Following model establishment, exogenous leptin was intraperitoneally injected into mice at 50 mg/kg in the LEP group. Subsequently, serum amylase, lipase and glucose levels at particular time‑points were analyzed using a fully‑automatic biochemical analyzer, and serum levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 were detected using an enzyme‑linked immunosorbent assay. The pathological changes in pancreatic tissues were observed using hematoxylin and eosin staining, and the pancreatic expression of the long form of the leptin receptor (OB‑Rb) was detected and evaluated using Nest‑polymerase chain reaction analysis. The mortality rates of the model rats were compared between the groups. Following the administration of exogenous leptin, the serum level of amylase in the LEP group was significantly decreased at 48 h, compared with that in the SAP group, with serum lipase levels decreased at 48 and 72 h, and blood glucose levels decreased at 72 h. Regarding the serum inflammatory factors, the level of TNF‑α in the LEP group was significantly lower, compared with that in the SAP group at 24 h; whereas no significant difference was observed in the serum level of IL‑10 between the two groups. Regarding the pathological changes in the pancreas, the tissues in the LEP group showed significantly alleviated pancreatic inflammation. In addition, the pancreatic expression of OB‑Rb in the LEP group was significantly higher, compared with that in the SAP group at 24 and 48 h. No significant difference in 3‑day mortality rates were observed between the SAP group and the LEP group. Taken together, exogenous leptin administration regulated inflammatory factors and the expression of OB‑Rb at the early stage of AP, which exerted protective effects by through the immunological and endocrinal pathways.

Topics: Acute Disease; Amylases; Animals; Blood Glucose; Disease Models, Animal; Inflammation; Interleukin-10; Leptin; Lipase; Male; Pancreas; Pancreatitis; Protective Agents; Rats; Rats, Wistar; Receptors, Leptin; Severity of Illness Index; Taurocholic Acid; Tumor Necrosis Factor-alpha

Adipokines have many homeostatic roles, including modulation of glucose metabolism, but their role in the pathophysiology of hyperglycemia associated with acute and critical illnesses in general, and acute pancreatitis (AP) in particular, is largely unknown. This study aimed to investigate the relationship between a panel of adipokines and hyperglycemia in the early course of AP, as well as the role of adipokines as predictors of AP severity.Adiponectin, leptin, omentin, resistin, and visfatin were measured on a daily basis in the first 72 hours after hospital admission. A first set of analyses was undertaken with admission glycemia stratified by severity, and a second set of analyses was undertaken based on persistence of early hyperglycemia. All of the analyses were adjusted for confounders.A total of 32 patients with AP were included in this study. None of the studied adipokines was significantly associated with glucose level on admission. Leptin was significantly (P = 0.003) increased in patients with persistent hyperglycemia. Adiponectin was significantly associated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score in patients with persistent hyperglycemia (P = 0.015), visfatin with APACHE II score in patients with persistent hyperglycemia (P = 0.014), and omentin with APACHE II score in all of the patients regardless of the presence or absence of hyperglycemia (P = 0.021).Leptin is significantly associated with persistent hyperglycemia in the early course of AP. Omentin has a potential to become an accurate predictor of AP severity.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Humans; Hyperglycemia; Leptin; Male; Middle Aged; Pancreatitis; Prospective Studies; Severity of Illness Index; Young Adult

The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is increasing in parallel with obesity rates. Stress-related alterations in endoplasmic reticulum (ER), such as the unfolded protein response (UPR), are associated with obesity. The aim of this study was to investigate ER imbalance in the pancreas of a mice model of adult and perinatal diet-induced obesity. Twenty female C57BL/6J mice were assigned to control (Con) or obesogenic (Ob) diets prior to and during pregnancy and lactation. Their offspring were weaned onto Con or Ob diets up to 6 months post-partum. Then, after sacrifice, plasma biochemical analyses, gene expression, and protein concentrations were measured in pancreata. Offspring of Ob-fed mice had significantly increased body weight (p < 0.001) and plasma leptin (p < 0.001) and decreased insulin (p < 0.01) levels. Maternal obesogenic diet decreased the total and phosphorylated Eif2α and increased spliced X-box binding protein 1 (XBP1). Pancreatic gene expression of downstream regulators of UPR (EDEM, homocysteine-responsive endoplasmic reticulum-resident (HERP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP)) and autophagy-related proteins (LC3BI/LC3BII) were differently disrupted by obesogenic feeding in both mothers and offspring (from p < 0.1 to p < 0.001). Maternal obesity and Ob feeding in their offspring alter UPR in NAFPD, with involvement of proapoptotic and autophagy-related markers. Upstream and downstream regulators of PERK, IRE1α, and ATF6 pathways were affected differently following the obesogenic insults.

Topics: Animals; Autophagy; Biomarkers; Diet, High-Fat; Dietary Sucrose; Endoplasmic Reticulum Stress; Female; Gene Expression Regulation, Developmental; Insulin; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Mice, Inbred C57BL; Obesity; Pancreas; Pancreatitis; Pregnancy; Pregnancy Complications; Unfolded Protein Response; Weaning

Topics: Body Mass Index; Calcium-Binding Proteins; DNA-Binding Proteins; Female; Ghrelin; Humans; Leptin; Male; Nerve Tissue Proteins; Pancreas; Pancreatitis

Hepatic steatosis (HS) can exacerbate acute pancreatitis (AP). This study aimed to investigate the relation between α1-antitrypsin (AAT) and acute pancreatitis when patients have HS. Using proteomic profiling, we identified 18 differently expressed proteins pots in the serum of rats with or without HS after surgical establishment of AP. AAT was found to be one of the significantly down-regulated proteins. AAT levels were significantly lower in hepatic steatosis acute pancreatitis (HSAP) than in non-HSAP (NHSAP) (P < 0.001). To explore the clinical significance of these observations, we measured the levels of AAT in the serum of 240 patients with HSAP, NHSAP, fatty liver disease (FLD), or no disease. Compared with healthy controls, serum AAT levels in patients with NHSAP were significantly higher (P < 0.01), while in patients with HSAP serum AAT levels were significantly lower (P < 0.01). Further studies showed that acute physiology and chronic health evaluation (APACHE-II) scores were negatively correlated with serum AAT levels (r = -0.85, P < 0.01). In conclusion, low serum levels of AAT in patients with HSAP are correlated with disease severity and AAT may represent a potential target for therapies aiming to improve pancreatitis.

Topics: Adolescent; Adult; Aged; alpha 1-Antitrypsin; Animals; Fatty Liver; Gene Expression Regulation; Humans; Leptin; Middle Aged; Pancreatitis; Proteome; Rats; Trypsin

Acute pancreatitis (AP) is a potentially fatal disease. In animal experiments leptin and ghrelin were shown to modulate the course of AP. The aim of the study was to estimate the relationship between the severity of acute biliary pancreatitis (ABP) and serum levels of leptin and ghrelin in nonobese patients in the first seven days of the hospitalization.. The study included nine patients with mild ABP (MABP), eleven patients with severe ABP (SABP) and twenty healthy controls, appropriately matched age, sex and weight. Serum concentrations of leptin and ghrelin were measured in patients on the first, third, fifth, and seventh days of hospitalization using leptin and ghrelin RadioImmunoAssay (RIA) kits.. At admission and throughout the study the mean serum leptin concentration in SABP patients was higher than in the controls but without statistical significance. Serum ghrelin concentrations on admission were significantly lower in patients with ABP than in the controls. We observed steadily increasing serum ghrelin levels in both groups of the patients during the course of ABP.. The results of our study do not support the role of leptin as a marker of the severity of ABP. On the other hand, rising serum ghrelin levels during the course of ABP may be a marker of recovery and an indicator of the healing process.

Topics: Acute Disease; Adult; Age Factors; Aged; Biliary Tract; Biomarkers; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Pancreatitis; Prognosis; Sex Factors; Time Factors

Early prediction of disease severity in acute pancreatitis (AP) is crucial. The aim of this study was to investigate the body-mass index (BMI), plasma leptin, nesfatin-1 and ghrelin levels as potential markers predicting peripancreatic necrosis and severity in acute pancreatitis.. In the study period, 97 consecutive patients with AP were prospectively analysed. Severe AP was defined according to the Atlanta Criteria. BMI was also calculated. To measure plasma Leptin, Nesfatin-1 and Ghrelin concentrations, the blood samples were obtained from patients within 24 hours of admission.. Out of 97 patients, 92(70 females, 22 males) were considered eligible for analysis. Of the 92 patients, 30 patients (32.6%) were assessed as severe pancreatitis. BMI and leptin levels were significantly higher in patients with severe pancreatitis. The pooled sensitivity and specificity of BMI as a predictor for the development of pancreatic necrosis were 0.90(95%CI = 0.56-0.99) and 0.70(95%CI = 0.58-0.79), respectively; with an overall area under curve value of 0.78.The pooled sensitivity and specificity of leptin levels as a predictor for development of pancreatic necrosis were 1(95%CI = 0.69-1) and 0.73(95%CI = 0.62-0.82),respectively; with an overall area under curve value of 0.82.Nesfatin-1 and ghrelin levels showed no significant difference in patients with mild pancreatitis (6.97 ± 0.84 ng/ml and 2.3(1.0-9.9);respectively) and severe pancreatitis (6.74 ± 0.65 ng/ml and 2.0(1.9-9.9); respectively) (p = 0.1923 and 0.8531;respectively).. BMI and plasma leptin levels both were correlated with the severity of pancreatitis. Leptin levels showed better area under the curve, sensitivity and specificity values compared to BMI in prediction of pancreatic necrosis.Nesfatin-1 and ghrelin levels were not found to be predictors of the severity of disease.

Topics: Acute Disease; Area Under Curve; Biomarkers; Body Mass Index; Calcium-Binding Proteins; Cohort Studies; DNA-Binding Proteins; Early Diagnosis; Female; Ghrelin; Humans; Leptin; Male; Necrosis; Nerve Tissue Proteins; Nucleobindins; Pancreas; Pancreatitis; Prognosis; Prospective Studies; Sensitivity and Specificity

Levels of the hormones ghrelin and leptin in rat models of acute pancreatitis (AP) have been investigated in several experimental studies. However, there are very few clinical studies addressing the connection between hormone levels and AP. A few recent studies investigating the changes in ghrelin and leptin levels in patients with AP have been reported; however, our study is the first clinical study to investigate the change of nesfatin-1 levels in patients with gallstone-induced AP.. Forty patients were enrolled in this study, eight of which presented with severe AP. Two blood samples were obtained from each study patient. The first blood samples were obtained at patient admission to the hospital and the second was obtained at patient discharge. All samples were collected after at least 6 h of fasting. Plasma nesfatin-1, leptin, and ghrelin levels were measured.. In all 40 patients, nesfatin-1 and leptin levels were higher at admission and had decreased at discharge. In contrast, the ghrelin levels at discharge were significantly higher than those at admission. Only the changes in these hormones in the mild AP group were significant.. Levels of these hormones were altered during the course of gallstone-induced AP. These changes might be associated with the clinical outcomes of the disease. To clarify whether the magnitude of the change in hormone levels at AP onset can be used as a biomarkers to predict the severity of the disease requires further investigation.

Topics: Acute Disease; Adult; Aged; Calcium-Binding Proteins; DNA-Binding Proteins; Female; Gallstones; Ghrelin; Humans; Leptin; Male; Nerve Tissue Proteins; Nucleobindins; Pancreatitis; Predictive Value of Tests; Prognosis; Severity of Illness Index

Obesity markedly increases the risk of severe acute pancreatitis (AP). Several adipokines have been ascribed a role as a predictor of clinical severity in AP. Therefore, the aim of this study was to investigate a possible relationship between leptin and adiponectin and mild biliary AP.. We included 24 consecutive patients with mild biliary AP and 24 consecutive healthy age- and sex-matched controls. Clinical severity was classified by the Ranson score. ELISA was used to assess leptin and adiponectin levels on admission and in remission. Complete blood cell counts and other laboratory tests were also performed at baseline and in remission.. Leptin, adiponectin, insulin and HOMA-IR measurements showed no difference in pancreatitis patients both on admission and in remission compared to the control group. No difference was found in leptin, insulin or HOMA-IR levels in the course of pancreatitis. However, adiponectin levels were higher in remission compared to admission.. Increased adiponectin levels in remission may be an indication of improvement in this condition. Further studies are needed to determine whether adiponectin provides protection from AP.

Topics: Acute Disease; Adiponectin; Adult; Aged; Body Mass Index; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Pancreatitis

Acute pancreatitis is a substantial clinical problem accounting for 240,000 hospital admissions yearly in the United States. Obesity is epidemic and is clearly an independent risk factor for increased severity of acute pancreatitis (AP). Adipose tissue is an endocrine organ that secretes a variety of metabolically active substances termed adipokines. However, the role of adipokines in modulating acute pancreatitis severity remains incompletely understood. Dietary fish oil is rich in omega-3 free fatty acids and attenuates adipose tissue-induced inflammation. Therefore, we hypothesized that feeding obese mice diets rich in fish oil would alter the adipokine milieu and attenuate the severity of pancreatitis.. Lean (C57BL/6 J) and obese (LepDb) mice were fed either a soybean oil- or fish oil-rich diet for 4 weeks. AP was induced by six hourly intraperitoneal injections of cerulein (50 μg/kg). Serum adipokine levels were measured, and pancreatitis severity was assessed histologically and by measuring pancreatic concentrations of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), myleoperoxidase (MPO), and monocyte chemoattractant protein-1 (MCP-1).. Obese mice developed more severe pancreatitis than lean mice. Fish oil significantly decreased serum leptin (lean and obese) and increased serum adiponectin (lean only). Fish oil did not alter the baseline pancreatic inflammatory milieu, nor did it change histologic or biochemical pancreatitis severity.. These data demonstrate that a diet rich in fish oil altered the adipokine milieu in lean and congenitally obese mice; however, fish oil did not improve pancreatitis severity induced with cerulein hyperstimulation.

Topics: Adipokines; Adiponectin; Animals; Ceruletide; Chemokine CCL2; Dietary Fats, Unsaturated; Female; Fish Oils; Interleukin-1beta; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Obesity; Pancreatitis; Pancrelipase; Peroxidase; Severity of Illness Index; Soybean Oil

Differential adipokine expression in obesity influences the inflammatory milieu, and may explain in part obesity's negative impact on pancreatic disease. Pancreatic juice analysis may provide a good means to evaluate the local pancreatic inflammatory milieu. The presence of adipokines in pancreatic juice is unknown.. This proof-of-concept study was designed to determine the presence of adipokines and cytokines in human pancreatic juice.. With institutional review board approval, pancreatic juice was obtained from ten patients with a broad range of diagnoses at the time of endoscopic retrograde cholangiopancreatography. Pancreatic juice was assayed using enzyme-linked immunosorbent assay (ELISA) for insulin, the proinflammatory adipokine leptin, the anti-inflammatory adipokine adiponectin, and the inflammatory mediators interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and monocyte chemoattractant protein-1 (MCP-1). Correlation between adipokine and inflammatory mediator expression was determined by linear regression analysis. Data are presented as mean +/- standard error of the mean (SEM); P < 0.05 was considered statistically significant.. Leptin (0.16 +/- 0.05 ng/ml) and adiponectin (0.63 +/- 0.02 microg/ml) were both present, as were the inflammatory mediators IL-6 (112.6 +/- 28.1 pg/ml), TNF-alpha (49.0 +/- 18.8 pg/ml), and MCP-1 (32.2 +/- 0.9 pg/ml). Paradoxically, the expression of the anti-inflammatory adipokine adiponectin correlated strongly with that of the proinflammatory cytokine IL-6 (R(2) = 0.98, P < 0.001).. This report is the first to describe adipokine expression in human pancreatic juice. Human pancreatic juice inflammatory mediators and adipokines may provide an important measurement of the local pancreatic inflammatory milieu.

Topics: Adipokines; Adiponectin; Adult; Aged; Cholangiopancreatography, Endoscopic Retrograde; Cytokines; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation Mediators; Insulin; Leptin; Linear Models; Male; Middle Aged; Pancreatic Function Tests; Pancreatic Juice; Pancreatitis; Predictive Value of Tests; Probability; Prognosis; Risk Assessment; Sampling Studies; Severity of Illness Index

Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.

Topics: Acute Disease; Acute-Phase Reaction; Adipose Tissue; Amylases; Animals; Calcium; Disease Susceptibility; Female; Gene Expression Regulation; Interferon-gamma; Interleukin-12; Interleukin-18; Interleukin-6; Leptin; Lipase; Lithostathine; Mice; Mice, Obese; Necrosis; Obesity; Pancreatitis; Pancreatitis-Associated Proteins; Proteins; RNA, Messenger; Time Factors

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.

Topics: Acute Disease; Adipokines; Adiponectin; Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Chemokines; Cytokines; Disease Models, Animal; Female; Insulin; Leptin; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreas; Pancreatitis; Peroxidase; Severity of Illness Index

The WBN/Kob-Lepr(fa) rat is a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr(fa) rats provide a model of non-insulin-dependent diabetes with obesity. Here, we describe the characteristics of this new animal model in detail. At 7 weeks of age, both male and female obese WBN/Kob rats showed inflammatory cell infiltration of the pancreas that suggested pan-pancreatitis and an abnormal OGTT. At 3 months of age, both male and female obese WBN/Kob rats developed overt diabetes mellitus associated with severe chronic pancreatitis. In contrast, lean female WBN/Kob rats do not develop pancreatitis or diabetes. In WBN/Kob rats, this mutation might promote the onset of severe pancreatitis, leading to the rapid development of diabetes mellitus.

Topics: Animals; Animals, Congenic; Diabetes Mellitus, Type 2; Disease Models, Animal; Leptin; Obesity; Pancreatitis; Rats; Receptors, Leptin

Severe acute pancreatitis is characterized by lipase-induced peripancreatic fat cell necrosis. Because adipocytes secret several highly active molecules, the aim of the present study was to investigate the hypothesis that adipocytokines could serve as potential markers predicting peripancreatic necrosis and severity in acute pancreatitis.. A total of 23 patients (11 females, 12 males) with acute pancreatitis were included and a computed tomography (CT) examination was available in 20 patients. Balthazar score, Schröder score, pancreatic necrosis score, Ranson score and APACHE II score were calculated, correlated with biochemical parameters and analyzed using receiver-operator characteristics (ROC) analysis. Adipocytokine serum levels were measured daily by enzyme-linked immunosorbent assay (ELISA) over 10 days after admission.. Resistin and leptin were significantly elevated in patients with severe pancreatitis and were correlated with a radiological scoring system for extrapancreatic necrosis. Whereas resistin correlated positively with clinical scoring systems, time until discharge and the need for interventions, leptin was correlated positively with C-reactive protein (CRP) levels. Resistin levels measured on the day of admittance had a positive predictive value of 93.3% (cut-off: >6.95 ng/mL) in predicting a Schröder score >3.. Resistin, and to a lesser extent leptin, but not adiponectin levels are novel potential markers for extrapancreatic necrosis and severity of acute pancreatitis and should therefore be tested in larger cohorts of patients.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; APACHE; Female; Humans; Leptin; Male; Middle Aged; Necrosis; Pancreas; Pancreatitis; Pilot Projects; Predictive Value of Tests; Resistin; Severity of Illness Index

Ghrelin and leptin are the hormones that influence endocrine and exocrine functions of the pancreas and regulate feeding behaviors and energy metabolism. The aim of this study was to investigate the levels of ghrelin and leptin in pancreatitis of different severities and the relation of these hormones with blood glucose level and proinflammatory cytokines. The study was performed on 90 Wistar Albino rats. Three experimental groups composed of 30 rats were established: control group, 0.9% NaCl solution was injected intraperitoneally (i.p); acute edematous pancreatitis (AEP) group, 1 microg/100 g cerulein was injected i.p. five times, at 1-hr intervals; and acute necrotizing pancreatitis (ANP) group, 500 mg/100 g L-arginine was injected i.p. Ten animals in each group were sacrificed under anesthesia 12, 24 and 48 hr after the last injection. After blood withdrawal, the pancreas was totally excised. The levels of blood sugar, lipase, serum tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), ghrelin, and leptin were investigated and histopathologic examination was performed. Following pancreatitis induction, serum ghrelin levels increased at 24 hr and reached the peak level at 48 hr. Its level in the AEP group was higher than in the ANP group. Serum leptin levels in the AEP and ANP groups increased after 12 hr and stayed at high levels until 48 hr compared with the control group. Similarly to ghrelin and leptin, blood glucose levels increased in both pancreatitis groups, but the increase was more prominent in the ANP group, with levels >200 mg/ml at 48 hr. The levels of TNF-alpha and IL-1beta in the AEP and ANP groups reached the peak level at 24 hr and then decreased to a level close to that of the control group at 48 hr. We conclude that serum leptin and ghrelin levels increase in the first 48 hr of AEP and ANP. As the serum ghrelin levels in ANP are higher than in AEP, it can be used as a marker to show the severity of pancreatitis. While TNF-alpha and IL-1beta can be used as a prognostic factor in the first 24 hr, ghrelin and leptin can be used subsequently.

Topics: Acute Disease; Animals; Biomarkers; Blood Glucose; Ghrelin; Interleukin-1beta; Leptin; Lipase; Male; Pancreas; Pancreatitis; Pancreatitis, Acute Necrotizing; Peptide Hormones; Prognosis; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

To determine the effect of exogenous leptin on acute lung injury (ALI) in cerulein-induced acute pancreatitis (AP).. Forty-eight rats were randomly divided into 3 groups. AP was induced by intraperitoneal (i.p.) injection of cerulein (50 microg/kg) four times, at 1 h intervals. The rats received a single i.p. injection of 10 mug/kg leptin (leptin group) or 2 mL saline (AP group) after cerulein injections. In the sham group, animals were given a single i.p. injection of 2 mL saline. Experimental samples were collected for biochemical and histological evaluations at 24 h and 48 h after the induction of AP or saline administration. Blood samples were obtained for the determination of amylase, lipase, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, macrophage inflammatory peptide (MIP)-2 and soluble intercellular adhesion molecule (sICAM)-1 levels, while pancreatic and lung tissues were removed for myeloperoxidase (MPO) activity, nitric oxide (NOx) level, CD40 expression and histological evaluation.. Cerulein injection caused severe AP, confirmed by an increase in serum amylase and lipase levels, histopathological findings of severe AP, and pancreatic MPO activity, compared to the values obtained in the sham group. In the leptin group, serum levels of MIP-2, sICMA-1, TNF-alpha, and IL-1beta, pancreatic MPO activity, CD40 expression in pancreas and lung tissues, and NOx level in the lung tissue were lower compared to those in the AP group. Histologically, pancreatic and lung damage was less severe following leptin administration.. Exogenous leptin attenuates inflamma-tory changes, and reduces pro-inflammatory cytokines, nitric oxide levels, and CD40 expression in cerulein-induced AP and may be protective in AP associated ALI.

Topics: Acute Disease; Animals; CD40 Antigens; Ceruletide; Chemokine CXCL2; Chemokines, CXC; Female; Interleukin-1beta; Leptin; Lung; Nitric Oxide; Pancreas; Pancreatitis; Peroxidase; Random Allocation; Rats; Rats, Wistar; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Obesity is a risk factor for a severe form of acute pancreatitis (AP). Because the underlying mechanisms are poorly known, we studied relationship between the severity of AP and plasma levels of leptin and adiponectin, 2 adipokines regulating the course of systemic inflammation.. The study comprises 12 patients with severe AP and 12 control patients with mild AP matched by age (+/-10 years), body mass index (+/-3 kg/m), sex, and etiology of AP. Quantikine Human Adiponectin and Quantikine Human Leptin Immunoassays (R&D Systems, Minneapolis, Minn) were used to measure the adipokine levels in the patients' plasma on admission and during the hospital stay.. Median leptin concentrations on admission were 6.1 ng/mL (range, 1.6-72.9 ng/mL) in the severe AP group and 9.0 ng/mL (range, 2.5-36.3 ng/mL) in the mild AP group (P > 0.05). In severe AP, the value at days 2 to 4 (7.7 ng/mL; range, 1.6-13.9 ng/mL) did not differ from respective on-admission value (P > 0.05). In mild AP, the value at days 2 to 4 (3.8 ng/mL; range, 1.6-12.9 ng/mL) was lower than the respective on-admission value (P = 0.005). Adiponectin concentrations on admission were 5642 ng/mL (range, 1201-19,400 ng/mL) for severe AP and 6314 ng/mL (range, 1980-24,340 ng/mL) for mild AP (P > 0.05). Maximum variation of adiponectin level (the highest value minus the lowest value) was greater in severe AP than in mild AP (P = 0.001).. In patients matched by age, sex, body mass index, and etiology, the on-admission plasma levels of adiponectin and leptin do not correlate with disease severity, suggesting that the adipokines do not affect the course of AP.

Topics: Acute Disease; Adiponectin; Adult; Aged; Aged, 80 and over; Female; Humans; Leptin; Male; Middle Aged; Pancreatitis; Retrospective Studies

To evaluate the relationship between leptin and systemic inflammation in acute pancreatitis.. Consecutive patients with acute pancreatitis were included. Body mass index and serum samples were obtained at admission. Leptin, TNF-alpha, IL-6, -8 and -10 levels were determined by ELISA. Severity was defined according to Atlanta criteria.. Fifty-two (29 females) patients were studied. Overall body mass index was similar between mild and severe cases, although women with severe pancreatitis had lower body mass index (P = 0.04) and men showed higher body mass index (P = 0.05). No difference was found in leptin levels regarding the severity of pancreatitis, but higher levels tended to appear in male patients with increased body mass index and severe pancreatitis (P = 0.1). A multivariate analysis showed no association between leptin levels and severity. The strongest cytokine associated with severity was IL-6. Correlations of leptin with another cytokines only showed a trend for IL-8 (P = 0.058).. High body mass index was associated with severity only in males, which may be related to android fat distribution. Serum leptin seems not to play a role on the systemic inflammatory response in acute pancreatitis and its association with severe outcome in males might represent a marker of increased adiposity.

Topics: Acute Disease; Adiposity; Adult; Body Mass Index; Disease Progression; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Leptin; Male; Middle Aged; Multivariate Analysis; Obesity; Pancreatitis; Prognosis; Severity of Illness Index; Sex Characteristics; Tumor Necrosis Factor-alpha

Diagnosis of pancreatitis is based on the determination of serum amylase and lipase levels. However, recent identification of specific leptin receptors in the pancreas suggests that this peptide may also play some roles in the modulation of pancreatic function. The objective of the present study was to investigate the relationship between serum leptin levels and pancreatitis. Thirty male Wistar rats were divided into 3 groups: the control group, acute pancreatitis group and chronic pancreatitis group. Pancreatitis was induced by injection of ethyl alcohol into the common biliary duct. A sham laparotomy was performed in the control group. Control and acute pancreatitis groups were sacrificed 24 hours later, and chronic pancreatitis group was sacrificed on postoperative day 7. Blood was taken by cardiac puncture for the determination of plasma leptin levels, and the pancreatic tissue was excised for histopathologic confirmation of pancreatitis. Plasma leptin rose significantly from the median of 0.78 +/- 0.12 ng/ml in the control group to 1.92 +/- 0.10 ng/ml and 1.86 +/- 0.13 ng/ml in acute and chronic pancreatitis groups, respectively (p < 0.001, for both). There was no significant difference in the plasma leptin levels between the acute pancreatitis group and the chronic pancreatitis group (p > 0.05). These findings confirm that leptin has a role in pancreas inflammation, and the inflamed tissue can be the source of local production of leptin.

Topics: Acute Disease; Animals; Chronic Disease; Humans; Leptin; Male; Pancreatitis; Rats; Rats, Wistar

Leptin is a hormone implicated in the regulation of the food intake and body weight, but also increasing number of evidence suggest that leptin participates in the regulation of inflammatory processes. The aim of our study was to examine the influence of exogenous leptin administration on the development and the course of acute ischemic pancreatitis. Acute pancreatitis was induced by temporary limitation of pancreatic blood flow, followed by reperfusion. Leptin was administered three times daily at the dose 10 or 50 micrograms/kg. Studies were terminated at 1, 3, 5, 10 and 21 days after induction of acute pancreatitis. Leptin administration reduced development of pancreatic damage and accelerated pancreatic regeneration. It was manifested by the decrease in serum lipase and amylase activity, the reduction in serum interleukin-1 beta concentration and the improvement of pancreatic histology. Additionally, treatment with leptin caused the increase in the pancreatic blood flow and pancreatic DNA synthesis. Serum interleukin-10 concentration was not effected by leptin administration. Leptin at the dose 50 micrograms/kg was more effective than 10 micrograms/kg. We conclude that leptin is able to limit the pancreatic damage in the course of ischemic pancreatitis and accelerates the pancreatic tissue repair. These effects of leptin seem to be dependent on the increase in pancreatic cell growth, the limitation of pro-inflammatory interleukin-1 beta release and the improvement of pancreatic blood flow.

Topics: Acute Disease; Animals; DNA; Dose-Response Relationship, Drug; Interleukin-1; Interleukin-10; Leptin; Male; Pancreas; Pancreatitis; Rats; Rats, Wistar; Regional Blood Flow; Reperfusion Injury; Time Factors

Recent identification of specific leptin receptors in the pancreas suggests that this peptide may also play some role in this gland.. To examine the effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of leptin in rats on caerulein-induced pancreatitis (CIP), pancreatic gene expression of leptin and inflammatory cytokine production.. Caerulein (25 micrograms/kg) was infused subcutaneously into conscious rats over 5 h to produce CIP. Leptin (1, 5, or 10 micrograms/kg) was injected i.p. or i.c.v. 30 min prior to the CIP induction. The plasma level of TNF alpha and IL-4 was determined by ELISA, while plasma leptin was measured by RIA and leptin gene expression in pancreas by RT-PCR.. CIP was characterized by the usual pancreatic edema, reduction in pancreatic blood flow (PBF) and an increase in serum levels of amylase, TNF alpha and IL-4. Pretreatment with i.p. or i.c.v. leptin of the CIP rats partially reversed the harmful effects of CIP on the pancreas, and reduced pancreatic inflammation and the fall in PBF. This was accompanied by a dose-dependent reduction in serum levels of amylase and TNF alpha, while serum IL-4 in the CIP rats pretreated with leptin rose dose-dependently as compared to control rats with CIP alone. Pretreatment with leptin resulted in the dose-dependent rise in plasma leptin level over that observed in vehicle-treated controls. Leptin mRNA expression in the pancreas was dose-dependently increased after infusion of caerulein. Leptin content in isolated pancreatic acini was also increased dose-dependently by caerulein added to the incubation medium bathing these acini.. (1) Exogenous leptin protects the pancreas against damage by CIP; (2) endogenous leptin seems to limit the extend of pancreatic damage, and (3) these protective effects of leptin could be attributed to the reduction in TNF alpha and to the increase in IL-4 production.

Topics: Animals; Ceruletide; Cytokines; Gene Expression; In Vitro Techniques; Injections, Intraperitoneal; Injections, Intraventricular; Interleukin-4; Leptin; Male; Osmolar Concentration; Pancreas; Pancreatitis; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

Leptin is a pleiotropic hormone that is involved in the regulation of food intake and body weight. Recent findings demonstrated that leptin receptors are present in the pancreas but the involvement of leptin in pancreatitis remains unknown. The aim of the present study was: (1) to assess plasma leptin levels in rats with caerulein-induced pancreatitis (CIP) and humans with acute pancreatitis; and (2) to determine the effects of exogenous leptin on the course of acute CIP in rats.. CIP was produced in Wistar rats by s.c. infusion of 5 microg of caerulein for 5 h. Plasma leptin was measured by specific RIA and leptin expression in the pancreas was determined at the transcriptional and protein levels. In addition, the effects of exogenous leptin at the doses of 1 or 10 microg/kg i.p. on the course of CIP and the plasma levels and mRNA expression in pancreas of cytokines TNFalpha and IL-4 were studied. Furthermore, pancreatic cNOS and iNOS expression at mRNA level were measured in rats with CIP and pretreated with leptin. Parallel to these studies, the plasma levels of leptin were measured in 15 patients with acute edematous pancreatitis and in 30 healthy controls of comparable age and body mass index.. In rats, plasma leptin rose significantly from the median of 0.14 (0.03-0.3 ng/ml) in the control group to 0.56 (0.2-3.2 ng/ml) in rats with CIP. The CIP was associated with an upregulation of mRNA and protein for leptin in the pancreas. The administration of exogenous leptin significantly reduced the weight of pancreas, histological manifestations of pancreatitis, plasma TNFalpha and mRNA expression for iNOS in the pancreatic tissue. The assessment of leptin plasma level in humans demonstrated significantly higher median values of plasma leptin in patients with acute pancreatitis [7.5 (4.3-18.4 ng/ml)] than in healthy controls [2.1 (1.0-11.8 ng/ml)].. (1) Acute pancreatitis in rats and in humans is associated with a marked increase in the plasma level of leptin. (2) The transcriptional upregulation of leptin in the pancreas after induction of pancreatitis indicates that the inflamed pancreas could be the source of local production of leptin. (3) Exogenous leptin protects the pancreas against development of acute CIP in rats and one possible mechanism of action of leptin might be attributed to the activation of nitric oxide pathway.

Topics: Acute Disease; Animals; Ceruletide; Female; Humans; Interleukin-1; Interleukin-4; Leptin; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pancreatitis; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Leptin is involved in the regulation of food intake and previous studies have shown that leptin affects the inflammatory response in various tissues. The objective of this study was to examine the influence of leptin administration on the development and the course of acute ischemic pancreatitis. Acute pancreatitis was induced by limitation of pancreatic blood flow by clamping of inferior splenic artery for 30 min, followed by reperfusion. Leptin was administered three times daily at the dose 10 or 50 microg/kg. Animals were sacrificed 1, 3, 5, 10 and 21 days after removal of vascular clips. Administration of leptin reduced development of pancreatic damage and accelerated pancreatic regeneration what was manifested by the improvement of pancreatic histology, the decrease in serum lipase and amylase activity, and the reduction in serum interleukin-1beta concentration. Also, treatment with leptin caused the increase in the pancreatic blood flow and pancreatic DNA synthesis. Leptin administration was without effect on serum interleukin-10 concentration. Leptin at the dose 50 microg/kg was more effective than 10 microg/kg. We conclude that leptin reduces the pancreatic damage in the course of ischemic pancreatitis and accelerates the pancreatic tissue repair. The beneficial effects of leptin appear to be dependent on the improvement of pancreatic blood flow, the increase in pancreatic cell growth, and the limitation of pro-inflammatory interleukin-1beta release.

Topics: Amylases; Animals; Disease Progression; DNA; Interleukin-1; Interleukin-10; Ischemia; Leptin; Lipase; Male; Pancreas; Pancreatitis; Rats; Rats, Wistar; Recombinant Proteins

Central nervous system affects pancreatic secretion of enzymes however, the neural modulation of acute pancreatitis has not been investigated. Leptin and melatonin have been recently reported to affect the inflammatory response of various tissues. The identification of specific receptors for both peptides in the pancreas suggests that leptin and melatonin could contribute to the pancreatic protection against inflammation. The aim of this study was: 1/ to compare the effect of intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administration of leptin or melatonin on the course of caerulein-induced pancreatitis (CIP) in the rat, 2/ to examine the involvement of sensory nerves (SN) and calcitonin gene-related peptide (CGRP) in pancreatic protection afforded by leptin or melatonin, 3/ to assess the effect of tested peptides on lipid peroxidation products (MDA + 4-HNE) in the pancreas of CIP rats, 4/ to investigate the influence of leptin or melatonin on nitric oxide (NO) release from isolated pancreatic acini and 5/ to determine the effects of caerulein and leptin on leptin receptor gene expression in these acini by RT-PCR. CIP was induced by subcutaneous (s.c.) infusion of caerulein (25 microg/kg) to the conscious rats, confirmed by the significant increases of pancreatic weight and plasma amylase and by histological examination. This was accompanied in marked reduction of pancreatic blood flow and significant rise of MDA + 4-HNE in the pancreas. Leptin or melatonin were administered i.p. or i.c.v. 30 min prior to the start of CIP. Deactivation of SN was produced by s.c. capsaicin (100 mg/kg). An antagonist of CGRP, CGRP 8-37 (100 microg/kg i.p.), was given together with leptin or melatonin to the CIP rats. MDA + 4-HNE was measured using LPO commercial kit. NO was determined using the Griess reaction. Pretreatment of CIP rats with i.p. leptin (2 or 10 microg/kg) or melatonin (10 or 50 mg/kg) significantly attenuated the severity of CIP. Similar protective effects were observed following i.c.v. application of leptin (0.4 or 2 microg/rat) but not melatonin (10 or 40 microg/rat) to the CIP rats. Capsaicin deactivation of SN oradministration of CGRP 8-37 abolished above beneficial effects of leptin on CIP, whereas melatonin-induced protection of pancreas was unaffected. Pretreatment with i.p. melatonin (10 or 50 mg/kg), but not leptin, significantly reduced MDA + 4-HNE in the pancreas of CIP rats. Leptin (10(-10) - 10(-6) M) but not melatonin (10(-8) -

Topics: Amylases; Animals; Antioxidants; Calcitonin Gene-Related Peptide; Carrier Proteins; Central Nervous System; Ceruletide; Free Radicals; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Melatonin; Neurons, Afferent; Organ Size; Pancreas; Pancreatitis; Peripheral Nervous System; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Regional Blood Flow

Lipopolysaccharides (LPS) are responsible for septic shock but low doses of LPS reduce pancreatic damage produced by caerulein-induced pancreatitis (CIP) in rats. Leptin, produced by adipocytes attenuates the severity of CIP. The aim of this study was to evaluate the effect of intracerebroventricular (i.c.v.) administration of LPS on CIP and plasma leptin level and to investigate the involvement of sensory nerves (SN) in the effects of LPS on CIP.. CIP was produced by subcutaneous (s.c.) infusion of caerulein (25 Kg/kg) to conscious rats. SN were deactivated with capsaicin (100 mg/kg s.c.). LPS (0.2, 2, or 20 Kg/rat) were applied to the right cerebral ventricle 30 min prior to CIP.. CIP was manifested by an increase in plasma levels of amylase, lipase, leptin and an anti-inflammatory interleukin 10 (IL-10), (by 400%, 1000%, 700% and 50%, respectively), confirmed by histological examination and accompanied by 40% reduction in pancreatic blood flow. Pretreatment of CIP rats with i.c.v. LPS resulted in significant reduction of CIP accompanied by dose-dependent increase in plasma levels of leptin and IL-10. Deactivation of SN, which by itself failed to affect CIP, completely reversed the beneficial effects of i.c.v. administration of LPS on CIP and reduced plasma leptin and IL-10 concentrations.. Pretreatment with LPS given i.c.v. prevents the development of caerulein-induced pancreatitis through the activation of SN and though the release of leptin.

Topics: Acute Disease; Adipocytes; Afferent Pathways; Amylases; Animals; Capsaicin; Ceruletide; Escherichia coli; Injections, Intraventricular; Interleukin-10; Leptin; Lipase; Lipopolysaccharides; Neurons, Afferent; Pancreatitis; Rats; Rats, Wistar; Sympathectomy, Chemical