EXPERIMENTAL PHYSIOLOGY, Issue 3 2001
W. G. Ding
The present investigation was designed to examine whether calmodulin is involved in the inhibition of the ATP-sensitive K+ (KATP) channel by glucagon-like peptide 1(7-36) amide (GLP-1) in mouse pancreatic ,-cells. Membrane potential, single channel and whole-cell currents through the KATP channels, and intracellular free Ca2+ concentration ([Ca2+]i) were measured in single mouse pancreatic ,-cells. Whole-cell patch-clamp experiments with amphotericin-perforated patches revealed that membrane conductance at around the resting potential is predominantly supplied by the KATP channels in mouse pancreatic ,-cells. The addition of 20 nM GLP-1 in the presence of 5 mM glucose significantly reduced the membrane KATP conductance, accompanied by membrane depolarization and the generation of electrical activity. A calmodulin inhibitor N -(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W-7, 20 ,M) completely reversed the inhibitory actions of GLP-1 on the membrane KATP conductance and resultant membrane depolarization. Cell-attached patch recordings confirmed the inhibition of the KATP channel activity by 20 nM GLP-1 and its restoration by 20 ,M W-7 or 10 ,M calmidazolium at the single channel level. Bath application of 20 ,M W-7 also consistently abolished the GLP-1-evoked increase in [Ca2+]i in the presence of 5 mM glucose. These results strongly suggest that the mechanisms by which GLP-1 inhibits the KATP channel activity accompanied by the initiation of electrical activity in mouse pancreatic ,-cells include a calmodulin-dependent mechanism in addition to the well-documented activation of the cyclic AMP-protein kinase A system. [source]

Functional Characterisation of the Volume-Sensitive Anion Channel in Rat Pancreatic ,-Cells

EXPERIMENTAL PHYSIOLOGY, Issue 2 2001
L. Best
The whole-cell and perforated patch configurations of the patch-clamp technique were used to characterise the volume-sensitive anion channel in rat pancreatic ,-cells. The channel showed high permeability (P) relative to Cl, to extracellular monovalent organic anions (PSCN/PCll= 1.73, Pacetate/PCll= 0.39, Plactate/PCll= 0.38, Pacetoacetate/PCll= 0.32, Pglutamate/PCll= 0.28) but was less permeable to the divalent anion malate (Pmalate/PCll= 0.14). Channel activity was inhibited by a number of putative anion channel inhibitors, including extracellular ATP (10 mM), 1,9-dideoxyforskolin (100 ,M) and 4-OH tamoxifen (10 ,M). Inclusion of the catalytic subunit of protein kinase A in the pipette solution did not activate the volume-sensitive anion channel in non-swollen cells. Furthermore, addition of 8-bromoadenosine 3,,5,-cyclic monophosphate (8-BrcAMP) or forskolin failed to activate the channel in intact cells under perforated patch conditions. Addition of phorbol 12,13-dibutyrate (200 nM), either before or after cell swelling, also failed to affect channel activation. Our findings do not support the suggestion that the volume-sensitive anion channel in pancreatic ,-cells can be activated by protein kinase A. Furthermore, the ,-cell channel does not appear to be subject to regulation via protein kinase C. [source]

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2005
Jackie A Clowes MB
First page of article [source]

Hepatobiliary and Pancreatic: Sclerosing cholangitis associated with critical illness

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2010
M Tian
No abstract is available for this article. [source]

Hepatobiliary and Pancreatic: Multiple sexually transmitted infections

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2010
Y Nakanishi
No abstract is available for this article. [source]

Review article: pain and chronic pancreatitis

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2009
J. G. LIEB II
Summary Background, Pain in chronic pancreatitis chronic pancreatitis is a frustrating and challenging symptom for both the patient and clinician. It is the most frequent and most significant symptom. Many patients fail the currently available conservative options and require opiates or endoscopic/surgical therapy. Aim, To highlight the pathophysiology and management of chronic pancreatitis pain, with an emphasis on recent developments and future directions. Methods, Expert review, utilizing in addition a comprehensive search of PubMed utilizing the search terms chronic pancreatitis and pain, treatment or management and a manual search of recent conference abstracts for articles describing pain and chronic pancreatitis. Results, Pancreatic pain is heterogenous in its manifestations and pathophysiology. First-line medical options include abstinence from alcohol and tobacco, pancreatic enzymes, adjunctive agents, antioxidants, and non-opiate or low potency opiate analgesics. Failure of these options is not unusual. More potent opiates, neurolysis and endoscopic and surgical options can be considered in selected patients, but this requires appropriate expertise. New and better options are needed. Future options could include new types of pancreatic enzymes, novel antinociceptive agents nerve growth factors, mast cell-directed therapy, treatments to limit fibrinogenesis and therapies directed at the central component of pain. Conclusions, Chronic pancreatitis pain remains difficult to treat. An approach utilizing conservative medical therapies is appropriate, with more invasive therapies reserved for failure of this conservative approach. Treatment options will continue to improve with new and novel therapies on the horizon. [source]

Insulin resistance/,-cell function and serum ferritin level in non-diabetic patients with hepatitis C virus infection

LIVER INTERNATIONAL, Issue 4 2003
Masanori Furutani
Abstract Background/Aims: Since impaired glucose tolerance and iron overload are frequently demonstrated in hepatitis C virus (HCV)-related liver diseases, in this study we investigated insulin resistance, pancreatic ,-cell function, i.e., insulin secretion, and serum ferritin levels in patients with HCV infection, especially non-diabetic patients. Methods: Homeostasis model assessments for insulin resistance (HOMA-IR) and ,-cell function (HOMA-,) were performed in 92 HCV-infected patients. Results: The levels of plasma immunoreactive insulin (IRI), HOMA-IR, and HOMA-, were significantly correlated with fasting plasma glucose (FPG) levels. Among the 86 non-diabetics (with an FPG of <126 mg/dl), IRI, HOMA-IR, and HOMA-, were significantly higher in patients with liver cirrhosis than in patients with persistently normal alanine aminotransferase levels. The IRI and HOMA-IR values, but not the HOMA-, values, were correlated with both serum transaminase and ferritin levels in the 65 non-diabetic chronic hepatitis patients. Conclusion: Insulin resistance was connected with impaired glucose tolerance and the severity of liver diseases in non-diabetic patients with HCV infection. Iron overload may be responsible for insulin resistance, or vice versa. Pancreatic ,-cell function was unrelated to the patients' serum ferritin levels. [source]

Effect of Helicobacter pylori infection and its eradication on nutrition

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2002
T. Furuta
Aims: To investigate the effects of Helicobacter pylori infection and eradication on nutrition. Methods: The body weight, height, blood pressure, gastric juice pH and fasting serum levels of glucose, total protein, albumin, total cholesterol and triglyceride were measured in H. pylori -positive and H. pylori -negative subjects, and the effect of eradication of H. pylori on these parameters was determined. The development of gastro-oesophageal reflux disease after treatment was also examined. Eight patients underwent a pancreatic function test before and after H. pylori eradication therapy. Results: The incidence of hypoproteinaemia in H. pylori -positive subjects was significantly higher than that in H. pylori -negative subjects. After eradication of H. pylori, the gastric juice pH values were significantly decreased, and the body weight and serum levels of total cholesterol, total protein and albumin were significantly increased. The incidence of hyperlipidaemia significantly increased and that of hypoproteinaemia significantly decreased in the group with eradication. Pancreatic function improved significantly after eradication of H. pylori. No significant changes in these parameters were observed in the group without eradication. Obese patients had a higher risk of the development of gastro-oesophageal reflux disease after eradication of H. pylori infection. Conclusions: The eradication of H. pylori appears to improve some nutritional parameters. [source]

From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic ,-cell KATP channels

PEDIATRIC DIABETES, Issue 2 2005
Khalid Hussain
Abstract:, Pancreatic ,-cell adenosine triphosphate (ATP)-sensitive potassium (KATP) channels play a pivotal role in linking glucose metabolism to regulated insulin secretion. KATP channels are hetero- octameric complexes comprising two subunits Kir6.2 and sulfonylurea receptor 1 (SUR1). Changes in the intracellular concentration of nucleotides (ATP) cause alterations in the resting and opening state of the KATP channels. Loss-of-function mutations in the genes encoding the two subunits of KATP channels lead to the most common form of congenital hyperinsulinism (CHI). This causes persistent and severe hypoglycemia in the neonatal and infancy period. CHI can cause mental retardation and epilepsy if not treated properly. On the other hand, now there is evidence of an association between polymorphisms in the Kir6.2 gene and type 2 diabetes mellitus, mutations in the Kir6.2 gene and neonatal diabetes mellitus, and mutations in the SUR1 gene and diabetes mellitus. Interestingly, for reasons that are unclear at present, mice knockout models of KATP channels are different from the human phenotype of CHI. This article is a review focusing on how abnormalities in the pancreatic ,-cell KATP channels can lead to severe hypoglycemia on the one hand and diabetes mellitus on the other. [source]

Glycaemic goals in patients with type 2 diabetes: current status, challenges and recent advances

DIABETES OBESITY & METABOLISM, Issue 6 2010
K. Khunti
Recommendations for the management of type 2 diabetes include rigorous control of blood glucose levels and other risk factors, such as hypertension and dyslipidaemia. In clinical practice, many patients do not reach goals for glycaemic control. Causes of failure to control blood glucose include progression of underlying pancreatic , -cell dysfunction, incomplete adherence to treatment (often because of adverse effects of weight gain and hypoglycaemia) and reluctance of clinicians to intensify therapy. There is increasing focus on strategies that offer potential to improve glycaemic control. Structured patient education has been shown to improve glycaemic control and other cardiovascular risk factors in people with type 2 diabetes. Payment of general practitioners by results has been shown to improve glycaemic control. New classes of glucose-lowering agents have expanded the treatment options available to clinicians and patients and include the dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These new classes of therapy and other strategies outlined above could help clinicians to individualize treatment and help a greater proportion of patients to achieve long-term control of blood glucose. [source]

Role and therapeutic potential of microRNAs in diabetes

DIABETES OBESITY & METABOLISM, Issue 2009
I. G. M. Kolfschoten
The discovery in mammalian cells of hundreds of small RNA molecules, called microRNAs, with the potential to modulate the expression of the majority of the protein-coding genes has revolutionized many areas of biomedical research, including the diabetes field. MicroRNAs function as translational repressors and are emerging as key regulators of most, if not all, physiological processes. Moreover, alterations in the level or function of microRNAs are associated with an increasing number of diseases. Here, we describe the mechanisms governing the biogenesis and activities of microRNAs. We present evidence for the involvement of microRNAs in diabetes mellitus, by outlining the contribution of these small RNA molecules in the control of pancreatic ,-cell functions and by reviewing recent studies reporting changes in microRNA expression in tissues isolated from diabetes animal models. MicroRNAs hold great potential as therapeutic targets. We describe the strategies developed for the delivery of molecules mimicking or blocking the function of these tiny regulators of gene expression in living animals. In addition, because changes in serum microRNA profiles have been shown to occur in association with different human diseases, we also discuss the potential use of microRNAs as blood biomarkers for prevention and management of diabetes. [source]

Zinc, a regulator of islet function and glucose homeostasis

DIABETES OBESITY & METABOLISM, Issue 2009
N. Wijesekara
It is well known that zinc is required in pancreatic ,-cells in the process of insulin biosynthesis and the maturation of insulin secretory granules. In fact, the zinc level in pancreatic islets is amongst the highest in the body and reduction in its levels in the pancreas has been associated with diabetes. High concentrations of zinc can also be toxic because of enhanced oxidative damage. The link between zinc, diabetes and islet dysfunction has recently been reiterated by genomewide association studies that identified an islet cell membrane zinc transporter, SLC30A8 (ZnT8), as one of the risk loci for type 2 diabetes. Here we explore the importance of both zinc and ZnT8 to islet biology and whole body glucose homeostasis. [source]

Thiazolidinediones and the preservation of ,-cell function, cellular proliferation and apoptosis

DIABETES OBESITY & METABOLISM, Issue 8 2008
Michael Decker
The thiazolidinediones (TZDs) or glitazones are pharmaceutical agents that have profound effects on energy expenditure and conservation. They also exert significant anti-inflammatory effects and influence cell proliferation and cell death. The drugs are primarily used in clinical practice in the treatment of patients with type 2 diabetes mellitus, a disorder of insulin resistance that occurs when the pancreatic ,-cells are unable to produce adequate amounts of insulin to maintain euglycaemia. Loss of pancreatic ,-cell function in type 2 diabetes is progressive and often precedes overt diabetes by 10 years or more, as was shown by the United Kingdom Prospective Diabetes Study. Any therapeutic or preventive approach that would limit or reverse loss of ,-cell function in diabetes would have profound effects on the morbidity associated with this widespread disease. Evidence suggesting a potential role of TZDs in preserving ,-cell function in type 2 diabetes as well as the ability of these agents to exert anti-inflammatory and proapoptotic anticancer effects, and their ability to promote cellular proliferation in various organs is reviewed. [source]

Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1

DIABETES OBESITY & METABOLISM, Issue 5 2005
B. D. Green
Glucagon-like peptide-1 (GLP-1) is an important insulinotropic hormone with potential in the treatment of type 2 diabetes. However, the short biological half-life of the peptide after cleavage by dipeptidylpeptidase IV (DPP IV) is a major limitation. Inhibition of DPP IV activity and the development of resistant GLP-1 analogues is the subject of ongoing research. In this study, we determined cell growth, insulin content, insulin accumulation and insulin secretory function of a insulin-secreting cell line cultured for 3 days with either GLP-1, GLP-1 plus the DPP IV inhibitor diprotin A (DPA) or stable N -acetyl-GLP-1. Native GLP-1 was rapidly degraded by DPP IV during culture with accumulation of the inactive metabolite GLP-1(9,36)amide. Inclusion of DPA or use of the DPP IV-resistant analogue, N -acetyl-GLP-1, improved cellular function compared to exposure to GLP-1 alone. Most notably, basal and accumulated insulin secretion was enhanced, and glucose responsiveness was improved. However, prolonged GLP-1 treatment resulted in GLP-1 receptor desensitization regardless of DPP IV status. The results indicate that prevention of DPP IV action is necessary for beneficial effects of GLP-1 on pancreatic , cells and that prolonged exposure to GLP-1(9,36)amide may be detrimental to insulin secretory function. These observations also support the ongoing development of DPP-IV-resistant forms of GLP-1, such as N -acetyl-GLP-1. [source]

Genetics of type 2 diabetes mellitus: status and perspectives

DIABETES OBESITY & METABOLISM, Issue 2 2005
Lars Hansen
Throughout the last decade, molecular genetic studies of non-autoimmune diabetes mellitus have contributed significantly to our present understanding of this disease's complex aetiopathogenesis. Monogenic forms of diabetes (maturity-onset diabetes of the young, MODY) have been identified and classified into MODY1,6 according to the mutated genes that by being expressed in the pancreatic ,-cells confirm at the molecular level the clinical presentation of MODY as a predominantly insulin secretory deficient form of diabetes mellitus. Genomewide linkage studies of presumed polygenic type 2 diabetic populations indicate that loci on chromosomes 1q, 5q, 8p, 10q, 12q and 20q contain susceptibility genes. Yet, so far, the only susceptibility gene, calpain-10 (CAPN10), which has been identified using genomewide linkage studies, is located on chromosome 2q37. Mutation analyses of selected ,candidate' susceptibility genes in various populations have also identified the widespread Pro12Ala variant of the peroxisome proliferator-activated receptor-, and the common Glu23Lys variant of the ATP-sensitive potassium channel, Kir6.2 (KCNJ11). These variants may contribute significantly to the risk type 2 diabetes conferring insulin resistance of liver, muscle and fat (Pro12Ala) and a relative insulin secretory deficiency (Glu23Lys). It is likely that, in the near future, the recent more detailed knowledge of the human genome and insights into its haploblocks together with the developments of high-throughput and cheap genotyping will facilitate the discovery of many more type 2 diabetes gene variants in study materials, which are statistically powered and phenotypically well characterized. The results of these efforts are likely to be the platform for major progress in the development of personalized antidiabetic drugs with higher efficacy and few side effects. [source]

Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channel

DIABETES OBESITY & METABOLISM, Issue 6 2001
D. K. Fuhrer
Summary Aim By focusing on the pancreatic , cell response to tacrolimus, cyclosporin A (CsA) and rapamycin we hoped to identify immunophilin, calcineurin and/or novel mechanism involvement and advance the understanding of immunosuppressant regulated insulin control. Methods A glucose responsive , cell model was established in which the glucose response was blocked by immunosuppressant treatment and this model was used to further characterise this effect. Quantification of insulin release to immunosuppressants and specific inhibitors was used to identify the mechanism involved. Results It was found that upon the addition of tacrolimus, rapamycin, or CsA, rapid and significant exocytosis of cellular insulin was seen. A dose response study of this effect revealed optimal concentration windows of 50, 80 nm for tacrolimus, 100,300 nm for rapamycin, and 7,12 mm for CsA in RIN-5F cells. Optimal insulin release for HIT-T15 cells was similar. Additional experiments demonstrate that immunosuppressant pretreatment blocked the subsequent immunosuppressant induced insulin release but not that of a thapsigargin control, suggesting that suppression and release are non-toxic, specific and in the same pathway. Further experiments showed that this insulin release was a calcium dependent process, which was blocked by inhibitors of l -type calcium channels. Continued studies showed that the specific ATP-sensitive potassium channel agonist diazoxide (150 mm) also blocked immunosuppressant-induced insulin release. Conclusions A model that fits this data is a novel calcineurin-independent immunophilin mediated partial closing of the ATP-sensitive potassium channel, which would lead to an initial insulin release but would reduce subsequent responses through this pathway. [source]

Recent developments and future prospects in pancreatic and islet transplantation

DIABETES OBESITY & METABOLISM, Issue 1 2001
Nadey S. Hakim
First page of article [source]

The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2009
Swapnil N. Rajpathak
Abstract This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic ,-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Rosiglitazone combined with insulin preserves islet , cell function in adult-onset latent autoimmune diabetes (LADA)

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2005
Zhiguang Zhou
Abstract Background LADA is thought to result from the chronic autoimmune destruction of the insulin-producing pancreatic , cells. In addition to antidiabetic effects, the newly developed insulin sensitizer-thiazolidinediones have the potential to increase the insulin content of islet cells by downregulating local inflammation and autoimmune response. Therefore, we hypothesized that LADA patients might benefit from thiazolidinediones treatment. Methods LADA patients, with a fasting C-peptide (FCP) of 0.3 nmol/L or more, were enrolled and randomly assigned to receive subcutaneous insulin alone (insulin group, n = 12) or rosiglitazone plus insulin (insulin + RSG group, n = 11) to compare the impacts on islet , cell function. Plasma glucose, HbA 1c, fasting C-peptide (FCP) and C-peptide after 2 h 75-g glucose load (PCP) were determined every 6 months. GAD-Ab and C-peptide were measured with radioimmune assays. Islet , cell function was evaluated by PCP and ,CP(,CP = PCP-FCP). Results All of the 23 patients have been followed up for 6 months, 17 cases for 12 months and 14 for 18 months. (1) During 6 months' follow-up, there were no significant changes for ,CP and PCP levels in both groups. (2) PCP and ,CP levels in insulin + RSG group patients stayed steady during the 12 months' observation (P = 0.161 for both PCP and ,CP), while in the insulin alone group, both FCP (P = 0.021) and PCP (P = 0.028) levels decreased significantly. Furthermore, PCP (P = 0.004) and ,CP(P = 0.015) differences between 12th month and baseline were higher in insulin + RSG group than those in the insulin group. (3) When observed up to 18 months, PCP and ,CP levels in insulin + RSG group patients still stayed steady, while PCP and ,CP levels decreased more in the insulin alone group. Conclusions This pilot study suggests that rosiglitazone combined with insulin may preserve islet , cell function in LADA patients. Copyright © 2004 John Wiley & Sons, Ltd. [source]

RD Lawrence Lecture 2008 Targeting GLP-1 release as a potential strategy for the therapy of Type 2 diabetes

DIABETIC MEDICINE, Issue 8 2008
F. M. Gribble
Abstract Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that play an important role in stimulating postprandial insulin release from pancreatic ,-cells. Agents that either mimic GLP-1 or prevent its degradation are now available for the treatment of Type 2 diabetes, and strategies to enhance endogenous GLP-1 release are under assessment. As intestinal peptides have a range of actions, including appetite regulation and coordination of fat metabolism, harnessing the enteric endocrine system is a promising new field for drug development. [source]

Age-related increase in haemoglobin A1c and fasting plasma glucose is accompanied by a decrease in , cell function without change in insulin sensitivity: evidence from a cross-sectional study of hospital personnel

DIABETIC MEDICINE, Issue 3 2002
A. P. Yates
Abstract Aims To examine the influence of age on glucose homeostasis in a population of healthy, non-diabetic hospital personnel. Methods One hundred and twenty female and 71 male non-diabetic individuals (fasting plasma glucose < 7.0 mmol/l) were fasted overnight prior to blood sampling. Glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and fasting plasma insulin (FPI) were measured using a BioRad Diamat automated HPLC, a Hitachi 747 analyser and a sensitive in-house radioimmunoassay, respectively. Mathematical modelling of the fasting glucose and insulin pairs (homeostasis model assessment (HOMA)) generated indices of pancreatic , cell function, HOMA-B and tissue insulin sensitivity HOMA-S. Results Spearman rank correlation analysis showed that in the whole group there was a significant negative correlation between age and HOMA-B (rs= ,0.218, P = 0.0022) and a significant positive correlation between age and both HbA1c (rs= 0.307, P = 0.0001) and FPG (rs= 0.26, P = 0.0003). There was no correlation between age and either FPI (rs= ,0.08, P = 0.266) or HOMA-S (rs= 0.024, P = 0.75). Analysis by gender showed the above associations to be present in the females (rs= ,0.243, P = 0.0076; rs= 0.304, P = 0.0007; rs= 0.32, P = 0.0004 for age vs. HOMA-B, HbA1c, and FPG, respectively). Again there was no correlation of age with FPI or insulin sensitivity. In the males there was a significant correlation of HbA1c with age (rs= 0.35, P = 0.002), but no significant correlation of age with any of the other parameters. Conclusions Glycaemic control deteriorates with age in healthy, non-diabetic individuals. Age-related rises in FPG and haemoglobin A1c result from a small but steady decline in pancreatic , cell function. Diabet. Med. 19, 254,258 (2002) [source]

ROLE OF ENDOSCOPY IN SCREENING OF EARLY PANCREATIC CANCER AND BILE DUCT CANCER

DIGESTIVE ENDOSCOPY, Issue 2009
Kiyohito Tanaka
In the screening of early pancreatic cancer and bile duct cancer, the first issue was ,what are the types of abnormality in laboratory data and symptoms in case of early pancreatic cancer and bile duct cancer?' Early cancer in the pancreaticobiliary region has almost no symptoms, however epigastralgia without abnormality in the gastrointestinal (GI) tract is a sign of early stage pancreaticobiliary cancer. Sudden onset and aggravation of diabetes mellitus is an important change in the case of pancreatic cancer. Extracorporeal ultrasonography is a very useful procedure of checking up changes of pancreatic and biliary lesions. As the role of endoscopy in screening, endoscopic ultrasonography (EUS) is the most effective means of cancer detection of the pancreas, and endoscopic retrograde cholangiopancreatography (ERCP) is most useful of diagnosis tool for abnormalities of the common bile duct. Endoscopic retrograde cholangiopancreatography is an important modality as the procedure of sampling of diagnostic materials. Endoscopic ultrasonography-fine needle aspiration (EUS-FNA) has the role of histological diagnosis of pancreatic mass lesion also. Especially, in the case of pancreas cancer without evidence of cancer by pancreatic juice cytology and brushing cytology, EUS-FNA is essential. Intra ductal ultrasonography (IUDS) and perotral cholangioscopy (POCS) are useful for determination of mucosal extent in extrahepatic bile duct cancer. Further improvements of endoscopical technology, endoscopic procedures are expected to be more useful modalities in detection and diagnosis of early pancreatic and bile duct cancers. [source]

The effect of metformin on measurements of insulin sensitivity and , cell response in 18 horses and ponies with insulin resistance

EQUINE VETERINARY JOURNAL, Issue 5 2008
A. E. Durham
Summary Reasons for performing study: Laminitis in equids is a very common debilitating disease, and insulin resistance (IR) and hyperinsulinaemia are increasingly recognised as important predisposing factors. Pharmacological modification of IR and hyperinsulinaemia might reduce the risk of laminitis. Hypothesis: Metformin, a drug commonly prescribed for treatment of human IR, may also decrease IR in equids. Methods: Eighteen horses and ponies with IR and recurrent laminitis were treated with 15 mg/kg bwt metformin per os q. 12 h. Each animal served as its own control by comparing pre- and post treatment proxies for IR, insulin sensitivity (IS) and pancreatic , cell function while controlling for possible dietary and managemental influences on IR. Results: Evidence of significantly improved IS and decreased pancreatic , cell secretion was found following metformin treatment. The magnitude of effect was greater at earlier resampling (6,14 days) than at later times (23,220 days). Apparent subjective clinical benefits were good but less favourable than effects on IR. Conclusions: Metformin is safe and appears to increase IS in equids. Potential relevance: Metformin may be indicated as a treatment for IR in equids. Further studies are required to define appropriate selection of subjects warranting therapy, dosing schedule and pharmacokinetics. [source]

Salmonella typhimurium infection halts development of type 1 diabetes in NOD mice

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2004
Paola Zaccone
Abstract Infectious disease has been proposed as an environmental modifier of autoimmunity in both human populations and the NOD mouse. We found that infection of NOD mice with attenuated, but not killed, Salmonella typhimurium can reduce the incidence of type 1 diabetes (T1D), even if infection occurs after the development of a peri-islet pancreatic infiltrate. Functional diabetogenic effector T,cells are still present, as demonstrated by the initiation of diabetes in NOD- scid recipients of transferred splenocytes. High levels of IFN-, are secreted by splenocytes of infected mice, but there is no evidence of involvement of IL-10 in the protective effect of the infection. Finally, prolonged changes in cell subsets are observed in infected mice involving invariant V,14J,281 NKT and dendritic cells. These data reinforce the idea that prevention of T1D in the NOD mouse cannot be reduced to the simple Th1/Th2 paradigm and that different infections may involve different protective mechanisms. [source]

Hypothalamic,endocrine aspects in Huntington's disease

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006
Åsa Petersén
Abstract Huntington's disease (HD) is a hereditary and fatal disorder caused by an expanded CAG triplet repeat in the HD gene, resulting in a mutant form of the protein huntingtin. Wild-type and mutant huntingtin are expressed in most tissues of the body but the normal function of huntingtin is not fully known. In HD, the neuropathology is characterized by intranuclear and cytoplasmic inclusions of huntingtin aggregates, and cell death primarily in striatum and cerebral cortex. However, hypothalamic atrophy occurs at early stages of HD with loss of orexin- and somatostatin-containing cell populations. Several symptoms of HD such as sleep disturbances, alterations in circadian rhythm, and weight loss may be due to hypothalamic dysfunction. Endocrine changes including increased cortisol levels, reduced testosterone levels and increased prevalence of diabetes are found in HD patients. In HD mice, alterations in the hypothalamic,pituitary,adrenal axis occurs as well as pancreatic ,-cell and adipocyte dysfunction. Increasing evidence points towards important pathology of the hypothalamus and the endocrine system in HD. As many neuroendocrine factors are secreted into the cerebrospinal fluid, blood and urine, it is possible that their levels may reflect the disease state in the central nervous system. Investigating neuroendocrine changes in HD opens up the possibility of finding biomarkers to evaluate future therapies for HD, as well as of identifying novel targets for therapeutic interventions. [source]

Inhibition of Rac1 decreases the severity of pancreatitis and pancreatitis-associated lung injury in mice

EXPERIMENTAL PHYSIOLOGY, Issue 10 2008
Marcelo G. Binker
Pancreatitis is a disease with high morbidity and mortality. In vitro experiments on pancreatic acini showed that supramaximal but not submaximal cholecystokinin (CCK) stimulation induces effects in the acinar cell that can be correlated with acinar morphological changes observed in the in vivo experimental model of cerulein-induced pancreatitis. The GTPase Rac1 was previously reported to be involved in CCK-evoked amylase release from pancreatic acinar cells. Here, we demonstrate that pretreatment with the Rac1 inhibitor NSC23766 (100 ,m, 2 h) effectively blocked Rac1 translocation and activation in CCK-stimulated pancreatic acini, without affecting activation of its closely related GTPase, RhoA. This specific Rac1 inhibition decreased supramaximal (10 nM) CCK-stimulated acinar amylase release (27.% reduction), which seems to be connected to the reduction observed in serum amylase (46.6% reduction) and lipase levels (46.1% reduction) from cerulein-treated mice receiving NSC23766 (100 nmol h,1). The lack of Rac1 activation also reduced formation of reactive oxygen species (ROS; 20.8% reduction) and lactate dehydrogenase release (LDH; 24.3% reduction), but did not alter calcium signaling or trypsinogen activation in 10 nM CCK-stimulated acini. In the in vivo model, the cerulein-treated mice receiving NSC23766 also presented a decrease in both pancreatic and lung histopathological scores (reduction in oedema, 32.4 and 66.4%; haemorrhage, 48.3 and 60.2%; and leukocyte infiltrate, 53.5 and 43.6%, respectively; reduction in pancreatic necrosis, 65.6%) and inflammatory parameters [reduction in myeloperoxidase, 52.2 and 38.9%; nuclear factor ,B (p65), 61.3 and 48.6%; and nuclear factor ,B (p50), 46.9 and 44.9%, respectively], together with lower serum levels for inflammatory (TNF-,, 40.4% reduction) and cellular damage metabolites (LDH, 52.7% reduction). Collectively, these results suggest that pharmacological Rac1 inhibition ameliorates the severity of pancreatitis and pancreatitis-associated lung injury through the reduction of pancreatic acinar damage induced by pathological digestive enzyme secretion and overproduction of ROS. [source]

Involvement of Calmodulin in Glucagon-Like Peptide 1(7-36) Amide-Induced Inhibition of the ATP-Sensitive K+ Channel in Mouse Pancreatic ,-Cells

Functional Characterisation of the Volume-Sensitive Anion Channel in Rat Pancreatic ,-Cells

Pituitary adenylate cyclase-activating polypeptide attenuates streptozotocin-induced apoptotic death of RIN-m5F cells through regulation of Bcl-2 family protein mRNA expression

FEBS JOURNAL, Issue 22 2008
Satomi Onoue
Oxidative stress, followed by the apoptotic death of pancreatic , cells, is considered to be one of causative agents in the evolution of the type 2 diabetic state; therefore, the protection of , cells can comprise an efficacious strategy for preventing type 2 diabetes. In the present study, RIN-m5F cells (i.e. the rat insulinoma , cell line) were stimulated with streptozotocin, resulting in a time- and concentration-dependent release of lactate dehydrogenase. There appeared to be significant apoptotic cell death after 2 h of treatment with streptozotocin at 10 mm, as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and 2.6-fold activation of cellular caspase-3, an apoptotic enzyme. By contrast, some neuropeptides of the glucagon-secretin family and coenzyme Q10, an endogenous mitochondrial antioxidant, could attenuate streptozotocin cytotoxicity, and especially pituitary adenylate cyclase-activating polypeptide (PACAP), at a concentration of 10,7 m, exhibited 34% attenuation of lactate dehydrogenase release from streptozotocin-treated RIN-m5F cells. Quantitative RT-PCR experiments indicated the inhibitory effect of PACAP on streptozotocin-evoked up-regulation of pro-apoptotic factor (Noxa and Bax) and a 2.3-fold enhancement of Bcl-2 mRNA expression, a pro-survival protein, was also observed after addition of PACAP. The data obtained suggest the anti-apoptotic role of PACAP in streptozotocin-treated RIN-m5F cells through the regulation of pro-apoptotic and pro-survival factors. [source]