Conservative Treatment of Chronic Pancreatitis: A Practical Approach.

BACKGROUND: Chronic pancreatitis is a long-standing, inflammatory condition of the pancreas that leads to the progressive damage and loss of function of pancreatic parenchyma and to the development of possible locoregional and systemic medical complications. MATERIALS AND METHODS: In this review, we tried to summarize the current evidence on non-surgical treatment trying to suggest a practical approach to the management of chronic pancreatitis. RESULTS: Besides the unclear pathophysiological mechanism and a poorly unknown epidemiology, chronic pancreatitis is a complex syndrome that displays different possible challenges for physicians. Despite being traditionally considered as a benign disease, chronic pancreatitis encompasses 10-year mortality rates which are superior to the ones reported for some of the most common cancers. CONCLUSIONS: Chronic pancreatitis encompasses the management of multiple and complex medical co-morbidities that needs to be understood and addressed in a multidisciplinary specialist context.

Endoscopic classification of the papilla of Vater. Results of an inter- and intraobserver agreement study.

BACKGROUND: Many endoscopists acknowledge that the appearance of the papilla of Vater seems to affect biliary cannulation. To assess the association between the macroscopic appearance of the papilla and biliary cannulation and other related clinical issues, a system is needed to define the appearance of the papilla. OBJECTIVE: The purpose of this study was to validate an endoscopic classification of the papilla of Vater by assessing the interobserver and intraobserver agreements among endoscopist with varying experience. METHODS: An endoscopic classification, based on pictures captured from 140 different papillae, containing four types of papillae was proposed. The four types are (a) Type 1: regular papilla, no distinctive features, 'classic appearance'; (b) Type 2: small papilla, often flat, with a diameter ≤ 3 mm (approximately 9 Fr); (c) Type 3: protruding or pendulous papilla, a papilla that is standing out, protruding or bulging into the duodenal lumen or sometimes hanging down, pendulous with the orifice oriented caudally; and (d) Type 4: creased or ridged papilla, where the ductal mucosa seems to extend distally, rather out of the papillary orifice, either on a ridge or in a crease. To assess the level of interobserver agreement, a web-based survey was sent out to 18 endoscopists, containing 50 sets of still images of the papilla, distributed between the four different types. Three months later a follow-up survey, with images from the first survey was sent to the same endoscopists. RESULTS: Interobserver agreement was substantial (κ = 0.62, 95% confidence interval (CI) 0.58-0.65) and were similar for both experts and non-experts. The intraobserver agreement assessed with the second survey was also substantial (κ = 0.66, 95% CI 0.59-0.72). CONCLUSION: The proposed endoscopic classification of the papilla of Vater seems to be easy to use, irrespective of the level of experience of the endoscopist. It carries a substantial inter- and intraobserver agreement and now the clinical relevance of the four different papilla types awaits to be determined.

Does the Frequency of Cholecystectomy Affect the Ensuing Incidence of Gallbladder Cancer in Sweden? A Population-Based Study with a 16-Year Coverage.

BACKGROUND: Gallbladder cancer (GBC) is rare among the different gastrointestinal cancers with a significant global variation in incidence. High cholecystectomy rates on benign indications have been assumed to prevent the development of gallbladder cancer. The aim of the present study was to explore the relationship between the rate of cholecystectomy at different time periods and regions of the country and the annual incidence of GBC. METHODS: Standardized cholecystectomy and GBC incidences for Swedish counties have been obtained from the Swedish national inpatient and National Cancer registries for the years 1998­2013. The incidences have been calculated for ages over 15 years and per 100,000 population. The relationships between cholecystectomy and GBC incidences have been analyzed using regression models. Correlation analyses were performed for the total cumulative incidence rates as well as the incidence rates calculated for the first and last 8 years of the entire study period. RESULTS: Cholecystectomy rates ranged from 99 to 205 per 100,000 and year, and the GBC incidence from 2.3 to 5.1. Overall, we observed a slow but steady decline in cholecystectomy rates­as well as GBC incidences during the 16-year period. No significant correlation between the cholecystectomy rates and GBC incidences was seen. CONCLUSIONS: This nationwide population-based study demonstrates substantial geographic differences in annual cholecystectomy rates without any significant inverse co-variation between cholecystectomy rates and the ensuing GBC incidence which would have supported the idea that frequent cholecystectomy affects the incidence of GBC.

Randomised clinical trial: transoral incisionless fundoplication vs. sham intervention to control chronic GERD.

BACKGROUND: Until recently only two therapeutic options have been available to control symptoms and the esophagitis in chronic gastro-oesophageal reflux disease (GERD), i.e. lifelong proton pump inhibitor (PPI) therapy or anti-reflux surgery. Lately, transoral incisionless fundoplication (TIF) has been developed and found to offer a therapeutic alternative for these patients. AIM: To perform a double-blind sham-controlled study in GERD patients who were chronic PPI users. METHODS: We studied patients with objectively confirmed GERD and persistent moderate to severe GERD symptoms without PPI therapy. Of 121 patients screened, we finally randomised 44 patients with 22 patients in each group. Those allocated to TIF had the TIF2 procedure completed during general anaesthesia by the EsophyX device with SerosaFuse fasteners. The sham procedure consisted of upper GI endoscopy under general anaesthesia. Neither the patient nor the assessor was aware of the patients' group affiliation. The primary effectiveness endpoint was the proportion of patients in clinical remission after 6-month follow-up. Secondary outcomes were: PPI consumption, oesophageal acid exposure, reduction in Quality of Life in Reflux and Dyspepsia and Gastrointestinal Symptom Rating Scale scores and healing of reflux esophagitis. RESULTS: The time (average days) in remission offered by the TIF2 procedure (197) was significantly longer compared to those submitted to the sham intervention (107), P < 0.001. After 6 months 13/22 (59%) of the chronic GERD patients remained in clinical remission after the active intervention. Likewise, the secondary outcome measures were all in favour of the TIF2 procedure. No safety issues were raised. CONCLUSION: Transoral incisionless fundoplication (TIF2) is effective in chronic PPI-dependent GERD patients when followed up for 6 months. Clinicaltrials.gov: CT01110811.

Telemedicine: an important aid to perform high-quality endoscopic retrograde cholangiopancreatography in low-volume centers.

BACKGROUND AND STUDY AIMS: The aim of this study was to investigate whether telemedicine can help to ensure high-quality endoscopic retrograde cholangiopancreatography (ERCP) in patients living in rural areas. The study was conducted by investigators from two centers: the Karolinska University Hospital, a high-volume center which provided the teleguided support, and the Visby District Hospital, a low-volume center. PATIENTS AND METHODS: From September 2010 to August 2011, 26 ERCP procedures performed at a district hospital were teleguided by an experienced endoscopist at the Karolinska University Hospital. To ensure patient data protection, all communication went through a network (Sjunet) that was separate from the Internet and open only to accredited users. The indications for ERCP were common bile duct stones (n = 12), malignant strictures (n = 12), and benign biliary strictures (n = 2). In 15 cases, this was the patient's first ERCP procedure. RESULTS: The common bile duct was successfully cannulated in all 26 teleguided procedures. The local endoscopist scored the teleguided support as crucial for the successful outcome in 8 /26 cases, as an important factor in 8, and as being of less importance in the remaining 10. In the eight cases where the teleguided support was judged to be crucial, six subsequent percutaneous transhepatic cholangiography procedures and two repeat ERCPs were avoided. The overall cannulation rate at the district hospital improved from 85 % to 99 % after teleguided support was introduced. No procedure-related complications occurred. CONCLUSION: Distant guidance of advanced ERCP procedures in a low-volume center, through teleguided support from a high-volume center, has the potential to improve the quality of care, as reflected in high cannulation rates and the ability to complete the scheduled interventions.

Detection of cholangiocarcinoma with magnetic resonance spectroscopy of bile in patients with and without primary sclerosing cholangitis.

BACKGROUND: Early detection of cholangiocarcinoma (CC) is very difficult, especially in patients with primary sclerosing cholangitis (PSC) who are at increased risk of developing CC. PURPOSE: To evaluate 1H magnetic resonance spectroscopy ((1)H-MRS) of bile as a diagnostic marker for CC in patients with and without PSC. MATERIAL AND METHODS: The institutional review board approved the study, and all patients gave informed consent. Bile from 49 patients was sampled and investigated using 1H-MRS. MR spectra of bile samples from 45 patients (18 female; age range 22-87 years, mean age 57 years) were analyzed both conventionally and using computerized multivariate analysis. Sixteen of the patients had CC, 18 had PSC, and 11 had other benign findings. RESULTS: The spectra of bile from CC patients differed from the benign group in the levels of phosphatidylcholine, bile acids, lipid, and cholesterol. It was possible to distinguish CC from benign conditions in all patients with malignancy. Two benign non-PSC patients were misclassified as malignant. The sensitivity, specificity, and accuracy were 88.9%, 87.1%, and 87.8%, respectively. CONCLUSION: With 1H-MRS of bile, cholangiocarcinoma could be discriminated from benign biliary conditions with or without PSC.

Intramuscular autotransplantation of pancreatic islets in a 7-year-old child: a 2-year follow-up.

A 7-year-old girl with severe hereditary pancreatitis underwent total pancreatectomy. A total of 160,000 islet equivalents (6400 islet/kg) were transplanted to the brachioradialis muscle of the right forearm. Her plasma C-peptide level was undetectable after pancreatectomy but increased to 1.37 ng/mL after 17 days; at this time point, her insulin requirement was 0.75 units of insulin/kg/day. At 5- and 27-months, her hemoglobin A1c (HbA1c) and insulin requirements were 4.5 and 5.3% and 0.3 and 0.18 units/kg/day, respectively. Basal and stimulated C-peptide levels were 0.67 +/- 0.07 and 3.36 +/- 1.37 ng/mL, respectively. Stimulated insulin levels were 30% higher in the islet-bearing arm compared to the contralateral arm after glucagon stimulation. After surgery and islet transplantation, the quality of life improved dramatically and she gained 8 kg of weight. In summary, a normal HbA1c, a low insulin requirement and the absence of recurrent hypoglycemia and the gradient of insulin between the arms indicate that the intramuscularly transplanted islets contribute to a long-term clinically significant metabolic control.

An antireflux stent versus conventional stents for palliation of distal esophageal or cardia cancer: a randomized clinical study.

BACKGROUND: Self-expandable metal stents placed across the esophagogastric junction for palliative treatment of malignant strictures may lead to gastroesophageal reflux and pulmonary aspiration. This study compared the effects of a Dua antireflux stent with those of a conventional stent. METHODS: Patients with incurable cancer of the distal esophagus or gastric cardia were randomly assigned to receive an antireflux stent (n = 19) or a standard stent (n = 22) at nine Swedish hospitals during the period September 1, 2003 to July 31, 2005. Complications were recorded at clinical follow-up visits. Survival rates were assessed through linkage to the Population Register. Dysphagia, reflux symptoms, esophageal pain, dyspnea, and global quality of life were assessed as changes in mean scores between baseline and 1 month after stent insertion through validated questionnaires. RESULTS: No technical problems occurred during stent placement in the 41 enrolled patients. Fewer patients with complications were observed in the antireflux stent group (n = 3) than in the standard group (n = 8), but no statistically significant difference was shown (p = 0.14). The survival rates were similar in the two groups (p = 0.99; hazard ratio, 1.0; 95% confidence interval, 0.5-2.0). The groups did not differ significantly in terms of studied esophageal or respiratory symptoms or quality of life. Clinically relevant improvement in dysphagia occurred in both groups. Dyspnea decreased after antireflux stent insertion (mean score change, -11), and increased after insertion of standard stent (mean score change, +21). CONCLUSIONS: Antireflux stents may be used without increased risk of complications, mortality, esophageal symptoms, or reduced global quality of life. These results should encourage large-scale randomized trials that can establish potentially beneficial effects of antireflux stents.

Diagnostic and prognostic implications of DNA ploidy and S-phase evaluation in the assessment of malignancy in biliary strictures.

BACKGROUND AND STUDY AIMS: Brush cytology of biliary strictures has a low sensitivity for diagnosing malignancy, and additional diagnostic tools are needed. The aim of the present study was to assess the diagnostic and prognostic importance of DNA measurements as an adjunct to brush cytology in patients with biliary strictures. PATIENTS AND METHODS: All patients (n = 225) with bile duct strictures who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 1997 and October 2003 at the Department of Radiology at Karolinska University Hospital, Huddinge, Sweden, were included in the study. While 66 patients had an unclear final diagnosis and were therefore excluded, the remaining 159 patients were assessed with brush cytology and DNA flow cytometry. RESULTS: Sensitivity and specificity of DNA aneuploidy for tumor detection were 43 % and 96 %. Using DNA analysis in addition to brush cytology, the sensitivity was 62 % compared with 57 % for brush cytology alone (not significant). Patients with diploid DNA tumors had a significantly better survival than patients with aneuploid DNA tumors ( P = 0.02). The mean survival was 10 months for diploid cancers and 6 months for aneuploid cancers. CONCLUSION: DNA ploidy measurement may be a diagnostic method that could supplement brush cytology in the identification of malignancy in biliary strictures. DNA aneuploidy is a marker of poor prognosis in patients with malignant biliary strictures.

Chronically administered islet amyloid polypeptide in rats serves as an adiposity inhibitor and regulates energy homeostasis.

AIMS/HYPOTHESIS: Islet amyloid polypeptide (IAPP) reduces food intake and body weight in laboratory animals. In addition, IAPP appears to regulate nutrient metabolism. In the present studies, we investigated the effect of chronic IAPP treatment on different aspects of energy homeostasis. METHODS: IAPP was infused (25 pmol/kg/min) from subcutaneous osmotic pumps for 2-7 days. Rats in 2 saline-infused control groups were fed ad libitum (AF) or pair-fed (PF) against the IAPP-treated rats. RESULTS: As expected, the IAPP infusion reduced food intake and body weight gain. In addition, the IAPP treatment decreased the epididymal fat pad (vs. PF rats, p < 0.05) and lowered circulating levels of triglycerides (vs. PF rats, p < 0.05), free fatty acids (vs. PF rats, p < 0.05), leptin (vs. both AF and PF rats, p < 0.05) and insulin (vs. AF rats, p < 0.05). In contrast, glucose and protein metabolism in the IAPP-treated rats was largely unchanged, as shown in results regarding serum glucose, glucose transport in skeletal muscle, blood urea nitrogen, and glycogen and protein content in the liver and in skeletal muscle. CONCLUSION/INTERPRETATION: In summary, chronic IAPP exposure led to a changed lipid metabolism, which was characterized by decreased adiposity, hypolipidemia and hypoleptinemia, and to unchanged glucose and protein homeostasis. These results were similar to those seen in rodents during chronic exposure to another satiety/adiposity regulator, leptin. In conclusion, chronically administered IAPP plays a role as a satiety and adiposity signal in rats, and helps regulate energy homeostasis.

Intraoperative endoscopic retrograde cholangiopancreatography (ERCP) to remove common bile duct stones during routine laparoscopic cholecystectomy does not prolong hospitalization: a 2-year experience.

BACKGROUND: There is still some controversy regarding the optimal timing and best method for the removal of common bile duct stones (CBDS). Intraoperative endoscopic retrograde cholangiopancreaticography (IO-ERCP) is an alternative method that should be considered for this procedure. The aim of our study was to investigate the clinical outcome of a single-step procedure (IO-ERCP) to remove CBDS, thereby combining two existing high-volume clinical modalities-i.e., laparoscopic cholecystectomy (LC) and ERCP. METHODS: Between January 2000 and December 2001, 674 patients, 192 male and 482 female, underwent cholecystectomy at our hospital. There were 612 LC (90.8%), 37 converted procedures (5.5%), and 25 open operations (3.7%). In 592 of the patients, (87.8%) intraoperative cholangiography (IOC) was performed. In 34 (5.7%) of those who had and IOC, an IO-ERCP was performed. While the surgeon waited for the endoscopist, care was taken to introduce a thin guidewire through the lOC catheter and pass it through the sphincter of Oddi, out into the duodenum. This complementary procedure greatly facilitated the subsequent cannulation of the bile ducts. RESULTS: The cannulation frequency of the CBD was 100%. Common bile duct stones were successfully extracted in 93.5%. Endoscopic sphincterotomy (EST), followed by the insertion of a plastic endoprosthesis, was performed in two patients with remaining stones. The CBD of these two patients was cleared by postoperative ERCP. None of the patients developed postoperative pancreatitis. The operating time was prolonged as compared with the time for LC (192 vs 110 mins; p < 0.05). The length of hospitalization for IO-ERCP patients did not differ from that for patients undergoing cholecystectomy alone (2.6 vs 2.1. days; NS). CONCLUSIONS: The study suggests that elective IO-ERCP is a safe and efficient method for removing CBDS that has a low risk of inducing postoperative pancreatitis and does not prolong postoperative hospitalization. This technique enables perioperative extraction of CBDS without open or laparoscopic surgical exploration of the CBD and can be used safely in a routine clinical setting.

Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: Strictures of the bile ducts due to malignant changes are difficult to distinguish from benign changes, particularly in patients with primary sclerosing cholangitis (PSC). The aim of this study was to evaluate diagnostic methods for malignancy in biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography (ERCP). PATIENTS AND METHODS: Bile duct strictures were identified during ERCP in 57 patients, who were thus included in the present study. Brush samples from the strictures were taken for cytology and for evaluation of DNA content by flow cytometry. The tumor markers CA 19-9 and CEA were determined both in serum and bile fluid. Two independent radiologists evaluated all cholangiograms. The diagnostic sensitivity, specificity, and accuracy of each diagnostic method were evaluated separately and in combination. RESULTS: 32 patients were found to have malignant strictures and when the four methods: brush cytology, DNA analysis, serum CA 19-9 and serum CEA were combined, a diagnostic sensitivity of 88 % and specificity of 80 % were reached. Seven of the 20 patients with PSC were found also to suffer from cholangiocarcinoma, yielding a sensitivity and specificity of 100 % and 85 %, respectively. Analyses of CA 19-9 and CEA in bile fluid had no diagnostic significance. CONCLUSION: An ERCP procedure with brush cytology, a DNA analysis, combined with serum analysis of CA 19-9 and CEA, can increase the possibility of distinguishing between malignant and benign biliary strictures, especially in PSC patients.

Cystic tumors of the pancreas.

The discovery of a cystic lesion in the pancreas implies a challenge for the physician. Approximately 10% are cystic tumors, benign to highly malignant, or true cysts, showing all stages of cellular differentiation, from benign to highly malignant tumors. Malignant cystic tumors are rare and comprise only about 1% of all pancreatic malignancies, they are potentially curable. Therefore, correct diagnosis and treatment of these lesions are of great importance. It is usually not possible to separate a pseudocyst from a benign cyst or a cystic tumor, but there are some signs and findings that could be helpful in the clinical decision. The diagnosis of a cystic pancreatic tumor requires different imaging techniques, including ultrasonography, computerized tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography, but to distinguish a pseudocyst or a benign cyst from a potentially malignant lesion can be very difficult. The usefulness of blood tests and investigations of cyst fluid can be questionable. Today, surgical treatment of cystic pancreatic tumors can be performed with low morbidity. Therefore, we conclude that an active strategy with resection of cystic tumors of the pancreas should be recommended.

Effect of carbohydrate feeding on insulin action in skeletal muscle after surgical trauma in the rat.

Metabolic stress after surgery is associated with peripheral insulin resistance. Recent studies have suggested that preoperative glucose can ameliorate postoperative decreases in insulin-stimulated glucose disposal. In the present experiments, we used a bowel-resection model of surgical trauma to test the hypothesis that elevations of serum insulin induced by preoperative oral glucose or ad libitum feeding affects postoperative insulin-stimulated glucose uptake in skeletal muscle. Insulin-stimulated glucose transport was measured in vitro in soleus muscles after surgical trauma in fasted rats given oral glucose or water before surgery. Insulin-stimulated glucose transport was also assessed in vitro in fasted or fed traumatized rats and non-traumatized control animals. In addition, stress hormones (glucagon, corticosterone, and adrenaline) were measured before and after surgical trauma in fasted rats and rats fed ad libitum. In vitro skeletal-muscle insulin sensitivity and responsiveness were reduced postoperatively in fasted animals that received oral glucose loads before bowel resections and in rats fed ad libitum or fasted before surgery versus non-traumatized rats (all P < 0.05). Stress-hormone concentrations after trauma did not differ between fed and fasted animals. In the current study, insulin sensitivity and responsiveness were reduced in isolated skeletal muscles after bowel resection, but neither preoperative glucose supplementation nor free intake of mixed nutrients ameliorated the development of postoperative insulin resistance.

Comparative effects of amylin and cholecystokinin on food intake and gastric emptying in rats.

CCK is a physiological inhibitor of gastric emptying and food intake. The pancreatic peptide amylin exerts similar actions, yet its physiological importance is uncertain. Objectives were to compare the dose-dependent effects of intravenous infusion of amylin and CCK-8 on gastric emptying and food intake in rats, and to assess whether physiological doses of amylin are effective. Amylin and CCK-8 inhibited gastric emptying with mean effective doses (ED(50)s) of 3 and 35 pmol x kg(-1) x min(-1) and maximal inhibitions of 60 and 65%, respectively. Amylin and CCK-8 inhibited food intake with ED(50)s of 8 and 14 pmol x kg(-1) x min(-1) and maximal inhibitions of 78 and 69%, respectively. The minimal effective amylin dose for each effect was 1 pmol x kg(-1) x min(-1). Our previous work suggests that this dose increases plasma amylin by an amount comparable to that produced by a meal. These results support the hypothesis that amylin acts as a hormonal signal to the brain to inhibit gastric emptying and food intake and that amylin produces satiety in part through inhibition of gastric emptying.

Gastrointestinal growth factors and pancreatic islet hormones during postoperative IGF-I supplementation in man.

Insulin-like growth factor-I (IGF-I) has been demonstrated to exert a nitrogen sparing effect, both experimentally and in patients after abdominal surgery. IGF-I is a major mediator for the anabolic effects of growth hormone (GH). Whether elevated circulating IGF-I levels are the sole mediator of the anabolic effects following GH has not been clarified. IGF-I influences glucose metabolism, both through its own specific receptor and by activating the insulin receptor, and has also been proposed to influence pancreatic islet secretion directly. In the present study, the postoperative effects of IGF-I on plasma levels of other gastrointestinal and pancreatic islet hormones and growth factors were measured in patients after abdominal surgery. Fifteen patients who were candidates for large bowel resection were randomly divided into two groups: IGF-I-treated (n=8) and placebo-treated (n=7). The IGF-I group received daily two s.c. injections of human recombinant IGF-I (80 microg/kg body weight) for five days, beginning on the morning of the first postoperative day. The other group received placebo injections. Fasting plasma levels of gastrointestinal growth factors (epidermal growth factor, transforming growth factor-alpha, IGF-II), gastrointestinal hormones (gastrin, enteroglucagon, peptide YY), and islet hormones (insulin, islet amyloid polypeptide (IAPP) and pancreatic glucagon) were determined by RIA preoperatively and after five days of treatment. No significant effects of IGF-I on other growth factors or gastrointestinal hormones were seen. A marked increase in plasma insulin postoperatively compared with the preoperative levels (42+/-3 vs 61+/-5 pM, P<0.05) was seen in the placebo group, whereas the postoperative levels in the IGF-I-treated patients remained unchanged (44+/-3 vs 45+/-4 pM). A similar pattern was observed for IAPP and cortisol concentrations. No differences in glucagon concentrations were seen. In conclusion, these results suggest that IGF-I does not influence production of other gastrointestinal hormones thought to be involved in alimentary growth or pancreatic glucagon. In contrast, IGF-I caused a marked reduction of insulin and IAPP secretion. The inhibition of beta-cell secretion could be direct or, alternatively, could involve an improvement in postoperative insulin resistance, perhaps by reducing serum cortisol.

Preoperative feeding does not reverse postoperative insulin resistance in skeletal muscle in the rat.

Metabolic studies on injured and postoperative patients have shown impaired glucose disposal in peripheral tissues after trauma. Using small-bowel resection as a model of surgical trauma, we investigated whether substrate availability could ameliorate the changes in muscle glucose uptake induced by trauma. We also studied the effect of preoperative feeding on postoperative insulin-stimulated insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity in both Wistar rats and genetically non-insulin-dependent diabetic Goto-Kakazaki rats (GK rats). Serum glucose, insulin, plasma epinephrine, lactate, and plasma nonesterified free fatty acids (NEFAs) were measured as indicators of the metabolic state and surgical stress. Insulin-stimulated glucose transport was significantly reduced in fed traumatized Wistar rats compared with fed nontraumatized rats (P < .05). Significant increases in in vivo insulin-stimulated IRS-1-associated PI 3-kinase activity were found in fed traumatized Wistar rats compared with fed nontraumatized Wistar rats and fasted traumatized Wistar rats, as well as fed traumatized GK rats compared with fed nontraumatized GK animals (all P < .017). Serum insulin concentrations were significantly reduced in fed traumatized Wistar and GK rats compared with the respective fed nontraumatized groups (both P < .01). Serum glucose levels were significantly elevated in fed traumatized GK rats compared with fed nontraumatized animals (P < .01). In the present study, preoperative feeding did not prevent a postoperative reduction in insulin-stimulated glucose transport in skeletal muscle. The finding that insulin-stimulated PI 3-kinase activity increased after trauma in both Wistar and GK rats indicates that postoperative insulin resistance is not caused by an impairment in the early steps of the insulin signaling pathway. The postoperative decreases in serum insulin despite high blood glucose suggest that trauma impairs the insulin response to hyperglycemia.

Effects of long-term infusion of anorexic concentrations of islet amyloid polypeptide on neurotransmitters and neuropeptides in rat brain.

Islet amyloid polypeptide (IAPP or amylin) potently reduces food intake in rats at or near physiological concentrations. Although the mechanisms of action of IAPP are not understood, the brain is a suggested site. Changes in hypothalamic and striatal neurotransmission have been reported following acute systemic administration of a pharmacological concentration of IAPP. In the current study, we evaluated the effects of chronic administration of low doses of IAPP on satiety-related neurotransmitters and neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and right cortex of the rat. Doses of 0, 5 and 25 pmol IAPP/kg-min were administered subcutaneously for 2 or 5 days. Food intake was reduced by 27 and 44% (both P<0.001) for the 5 and 25 pmol/kg-min groups, respectively, in the 2-day experiment and was decreased by 14% (P<0.01) and 24% (P<0.001), respectively, in the 5-day experiment. Body weight was significantly decreased in a dose-dependent fashion. In the 2-day experiment, norepinephrine increased in the hypothalamus in the 5 pmol IAPP/kg-min group, and neurotensin increased in the hippocampus in the 25 pmol/kg-min rats (both P<0.05). In the 5-day, 5 pmol/kg-min rats, 5-hydroxyindoleacetic acid (5-HIAA) increased in the hypothalmus and cholecystokinin (CCK) increased in the striatum (both P<0.05). In the 5-day, 25 pmol/kg-min group, neuropeptide Y (NPY) increased in the hypothalamus (P<0.01) and CCK increased in the hypothalmus and striatum (both P<0.05). The present study confirms that IAPP is a potent anorectic peptide at low doses and suggests that IAPP not only affects classical neurotransmitters in the brain but also alters concentrations of neuropeptides known to be involved in food intake.