Shinsuke Oh-I

Identification of nesfatin-1 as a satiety molecule in the hypothalamus.

The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour. Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of α-melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus.

Fasting concentrations of nesfatin-1 are negatively correlated with body mass index in non-obese males

Background  We recently identified a novel anorexigenic protein, nesfatin‐1, which is processed from nesfatin/nucleobindin‐2 (NUCB2). However, the clinical importance of this protein has not been determined.

Relationship between hyperinsulinemia and pulse wave velocity in moderately hyperglycemic patients

AIM Arterial stiffness assessed by pulse wave velocity (PWV) reflects early stage arteriosclerosis. The influence of hyperinsulinemia on peripheral vascular disease (PVD) is still unknown. We determined the influences of hyperinsulinemia on PVD assessed by PWV in moderately hyperglycemic patients. METHODS Thirty-six moderately hyperglycemic, outcoming patients were recruited in this study. All subjects were divided into two groups by fasting immunoreactive insulin (F-IRI) concentrations; group A; F-IRI> or =5 microU/ml, group B; F-IRI<5 microU/ml. Both hbPWV (from heart to brachial artery) and baPWV (brachial to artery to ankle) were evaluated by using Form PWV/ABI, in addition to ankle-brachial pressure index (ABPI). RESULTS In group A, both hbPWV and baPWV showed significantly higher values than in group B. ABPIs were not different between two groups. Although age, FPG, plasma HbA1c, serum total-cholesterol, HDL-cholesterol concentrations, and systolic and diastolic blood pressure were at same levels in group A as group B, body mass index, HOMA-R, serum triglyceride concentrations were significantly higher in group A, indicating the existence of insulin resistance in group A. CONCLUSION Hyperinsulinemia may be involved in the development of PVD in moderately hyperglycemic patients.

Prolonged intrahepatic cholestasis after exposure to loxoprofen

OBJECTIVE The objective of this report was to describe a case of prolonged intrahepatic cholestasis likely associated with the use of loxoprofen, a phenylpropionate NSAID. METHODS A 36-year-old female patient was transferred to Gunma University Hospital, Maebashi, Japan, with progressive pruritus and jaundice that developed after 5-day treatment with 120 mg/d of loxoprofen (maximum recommended dose, 180 mg/d) for menstrual pain. Liver function tests found the following concentrations: total bilirubin, 27.5 mg/dL (normal [nl] range, 0.3-1.2 mg/dL); aspartate aminotransferase, 151 IU/L (nl, 13-33 IU/L); alkaine aminotransferase, 470 IU/L (nl, 8-42 IU/L); alkaline phosphatase, 1082 IU/L (n1, 115-359 IUAL); and gamma-glutamyl transpeptidase, 795 IU/L (nl, 10-47 IU/L) indicative of intrahepatic cholestasis. No use of alcohol or other drugs or herbal products was reported. The patient had a history of elevated hepatic enzymes of unknown origin following the use of mefenamic acid. The patient was prescribed ursodeoxycholic acid 3 weeks after the onset of symptoms of intrahepatic cholestasis. Thereafter, due to progressive cholestasis, an IV pulse of methylprednisolone (1000 mg/d) and the herbal product Inchin-ko-to (TJ-135) were administered. Plasma bilirubin adsorption (PA) and plasma exchange (PE) were performed. RESULTS Following treatment with PA and PE for 3 weeks with administration of methylprednisolone and Inchin-ko-to, signs and symptoms of intrahepatic cholestasis began to resolve (3.5 months after the onset); they were completely resolved 8 months after the initial episode. A Naranjo scale score of 6 suggested that loxoprofen was likely the cause of the prolonged cholestasis in this patient. CONCLUSION Based on the Naranjo score, this case of prolonged intrahepatic cholestasis in a young woman was likely associated with loxoprofen use.

Incidence of β3-adrenergic receptor polymorphism and prediction of successful weight reduction with mazindol therapy in severely obese Japanese subjects.

SUMMARY Mazindol, a centrally acting monoamine re-uptake inhibitor, enhances satiety and supports body weight loss, but response to this drug among obese patients is very variable. The possible involvement of the Trp64Arg polymorphism of the β3-adrenergic receptor (ADRB3) gene in the development of severe obesity and weight loss response to anorexigenic drugs has not been established. In the present study, the allelic frequency of the Trp64Arg ADRB3 gene polymorphism was determined in massively obese Japanese outpatients (BMI > 35 kg/m(2)), and we investigated whether allelic differences may determine the weight loss effect of mazindol. The allelic frequency of Trp64Arg heterozygotes and homozygotes did not differ in severely obese subjects compared to non-obese subjects. Trp64Arg heterozygotes experienced significantly increased weight loss and reduced blood pressure following mazindol administration for 12 weeks. Thus the ADRB3 gene polymorphism is predictive for difficulty in weight reduction with mazindol treatment, but is not related to the development of severe obesity in the Japanese population.:

Syntaxin4 Interacting Protein (Synip) Binds Phosphatidylinositol (3,4,5) Triphosphate

The insulin responsive Glut4 transport vesicles contain the v-SNARE protein Vamp2 that associate with the plasma membrane t-SNARE protein Syntaxin 4 to drive insulin-stimulated Glut4 translocation in skeletal muscle and adipocytes. The syntaxin 4 interacting protein (Synip) binds to syntaxin 4 in the basal state and dissociates in the insulin-stimulated state allowing for the subsequent binding of Vamp2 containing Glut4 vesicles and fusion with the plasma membrane. In this study, we have found that Synip binds phosphatidylinositol 3,4,5-triphosphate (PIP3), but not phosphatidylinositol 3 phosphate (PIP) or phosphatidylinositol 3,4-biphosphate (PIP2) through the Synip WW domain as deletion of this domain (Synip ΔWW) failed to bind PIP3. Over-expressed Synip ΔWW in 3T3L1 adipocytes reduced the basal levels of Glut4 at the plasma membrane with no effect on the binding to syntaxin 4 in vitro. Subcellular fractionation demonstrated that the amount of Synip ΔWW at the PM was decreased in response to insulin in 3T3L1 adipocytes whereas the amount of Synip WT increased. These data suggest that in the presence of insulin, the dissociated Synip remains anchored to the plasma membrane by binding to PIP3.

Glucagon plays an important role in the modification of insulin secretion by leptin.

Obese people show marked hyerinsulinemia, but the exact mechanism has not been clarified. Hyperleptinemia is one of possible candidates, although there is an obvious difference in the effect of leptin on insulin secretion between isolated pancreatic islets and β-cell line. Since glucagon may modulate the effect of leptin on insulin secretion, we determined the influences of glucagon in the leptin effect on insulin secretion. The influences of glucagon in the leptin effect on insulin secretion for 10 minutes were determined by using isolated mouse islets and HIT-T 15 cells. The influences of 3-isobutyl-1- methylxanthine (IBMX), forskolin, and dibutyryl cyclic AMP were investigated in the leptin effect on insulin secretion. Leptin-inhibited insulin and glucagon secretion in isolated mouse pancreatic islets. In contrast, leptin stimulated insulin secretion in isolated mouse islets previously incubated with monoclonal anti-glucagon antibodies for 18 hours. In HIT-T 15 cells, leptin dose-dependently increased insulin secretion, but this effect was attenuated by the addition of glucagon. The stimulatory effect of leptin on insulin secretion was attenuated by 48 hour pre-incubation with glucagon. In the presence of 100 mM IBMX, leptin decreased insulin secretion from HIT-T 15 cells. Leptin also reduced insulin secretion in the presence of 1mM forskolin or 1mM dibutyryl cyclic AMP. The leptin effects on insulin secretion were affected by the existence of glucagon. Intracellular cyclic AMP concentrations may determine the leptin effects on insulin secretion in pancreatic β-cells.

Hepatobiliary and pancreatic: Multifocal nodular hepatic steatosis associated with the metabolic syndrome

A 52-year-old woman was admitted to the Intensive Care Unit with hyperglycemic coma and aspiration pneumonia. She was known to have type 2 diabetes mellitus and, in addition, had other features of the metabolic syndrome including hypertension and dyslipidemia. She did not have a significant intake of alcohol. She was obese with a body mass index of 37.6 kg/m. While in the Intensive Care Unit, she had a non-contrast computed tomography (CT) scan that showed several unusual lesions in the liver (Fig. 1). The lesions had a spherical shape with a low-density margin and an isodense center. A subsequent contrast-enhanced CT scan showed similar lesions (arrows) but the central enhancement was similar to that of normal liver parenchyma (Fig. 2). A liver biopsy was performed using ultrasound guidance and showed macrovesicular fatty infiltration of the liver without significant inflammation or fibrosis. There were no features of liver metastases. Non-alcoholic fatty liver disease is the most common cause of a fatty liver in most populations. The diagnosis is suspected on the basis of changes in liver enzymes and can be supported by results from various imaging modalities including ultrasonography, CT and magnetic resonance imaging. In most patients, imaging shows diffuse fatty infiltration throughout the liver. However, a minority of patients with diffuse fatty infiltration can have ‘spared’ areas that receive blood from vessels other than the portal vein. Another variant is that of focal fatty infiltration that can take a variety of forms including lobar or segmental fan-shaped lesions, nodular lesions or lesions with geographic margins. In the patient described above, there was evidence of diffuse fatty change as the liver was of lower density than the spleen on a non-contrast CT scan. The presence of nodular or target lesions is unusual but needs to be included in the spectrum of changes that can occur in nonalcoholic fatty liver. These nodular lesions may be difficult to differentiate from liver metastases without liver biopsy.

Serious complications after a proximal gastrectomy with a jejunal pouch interposition for gastric cancer

Proximal gastrectomy with jejunal interposition is a common surgical method in Japan, because the procedure has been shown to give a better post-operative quality of life. Some complications are associated with it. However, esophageal candidiasis and linear marginal ulcer along the gastrojejunal anastomosis after the surgical method has never previously been reported. We herein report a case of a patient who developed serious complications after proximal gastrectomy with jejunal interposition. A 68-year-old man underwent proximal gastrectomy with a jejunal pouch interposition for reconstruction for type 1 gastric cancer. Twenty-three months after the procedure, he complained of dysphagia and epigastric pain. Esophagogastroduodenoscopy showed esophageal candidiasis. The patient improved symptomatically following antifungal medication with fluconazole. Eleven months later, the patient developed severe pneumonia. In subsequent days, a melena episode occurred. Esophagogastroduodenoscopy revealed a linear marginal ulcer along three-fourths of the gastrojejunal anastomosis. The ulcer was drug resistant. The patient died of respiratory failure. Jejunal pouch interposition after a proximal gastrectomy can be associated with significant complications. Further studies are required to identify the best condition of the procedure.