Human adipose tissue glucose uptake determined using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET in combination with microdialysis

Aims/hypothesis: To determine the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [¹⁸F]-2-fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) and glucose, for [¹⁸F]FDG in human adipose tissue. Methods: [¹⁸F]FDG-PET was combined with microdialysis. Seven non-obese (29 ± 2 years of age, BMI 24 ± 1 kg/m²) and seven obese (age 32 ± 2 years of age, BMI 31 ± 1 kg/m²) men were studied during euglycaemic hyperinsulinaemia (1 mU/kg · min^–1 for 130 min). Abdominal adipose tissue [¹⁸F]FDG uptake (rGU_FDG) and femoral muscle glucose uptake were measured using [¹⁸F]FDG-PET. Adipose tissue perfusion was measured using [¹⁵O]-labelled water and PET, and interstitial glucose concentration using microdialysis. Glucose uptake (by microdialysis, rGU_MD) was calculated by multiplying glucose extraction by regional blood flow. The LC was determined as the ratio of rGU_FDG to rGU_MD. Results: Rates of adipose tissue glucose uptake (rGU_MD) were 36 % higher in the non-obese than in the obese patients (11.8 ± 1.7 vs 7.6 ± 0.8 μmol/kg · min^–1, p < 0.05, respectively) and a correlation between rGU_MD and rGU_FDG was found (r = 0.82, p < 0.01). The LC averaged 1.14 ± 0.11, being similar in the obese and the non-obese subjects (1.01 ± 0.15 vs 1.26 ± 0.15, respectively, NS). Muscle glucose uptake was fourfold to fivefold higher than adipose tissue glucose uptake in both groups. Conclusion/interpretation: [¹⁸F]FDG-PET seems a feasible tool to investigate adipose tissue glucose metabolism in human beings. Direct measurements with [¹⁸F]FDG-PET and microdialysis suggest a LC value of 1.14 for [¹⁸F]FDG in human adipose tissue during insulin stimulation and the LC does not appear to be altered in insulin resistance. Furthermore, the obese patients show insulin resistance in both adipose tissue and skeletal muscle. [Diabetologia (2001) 44: 2171–2179] Received: 10 May 2001 and in revised form: 29 August 2001     

Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice

Objective

We recently discovered that leucine deprivation increases hepatic insulin sensitivity via general control nondepressible (GCN) 2/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways. The goal of the present study was to investigate whether the above effects were leucine specific or were also induced by deficiency of other branched chain amino acids including valine and isoleucine.

Methods

Following depletion of BCAAs, changes in metabolic parameters and the expression of genes and proteins involved in regulation of insulin sensitivity and glucose metabolism were analyzed in mice and cell lines including human HepG2 cells, primary mouse hepatocytes and a mouse myoblast cell line C2C12.

Results

Valine or isoleucine deprivation for 7 days has similar effect on improving insulin sensitivity as leucine, in wild type and insulin-resistant mice models. These effects are possibly mediated by decreased mTOR/S6K1 and increased AMPK signaling pathways, in a GCN2-dependent manner. Similar observations were obtained in in vitro studies. In contrast to leucine withdrawal, valine or isoleucine deprivation for 7 days significantly decreased fed blood glucose levels, possibly due to reduced expression of a key gluconeogenesis gene, glucose-6-phosphatase. Finally, insulin sensitivity was rapidly improved in mice 1 day following maintenance on a diet deficient for any individual BCAAs.

Conclusions

Our results show that while improvement on insulin sensitivity is a general feature of BCAAs depletion, individual BCAAs have specific effects on metabolic pathways, including those that regulate glucose level. These observations provide a conceptual framework for delineating the molecular mechanisms that underlie amino acid regulation of insulin sensitivity.     

Positive association of branched-chain amino acids with triglyceride and glycated haemoglobin in Indian patients with type 2 diabetes mellitus

Background and aimsOver the past few years, branched-chain amino acids (BCAAs) are increasingly being linked to insulin resistance and type 2 diabetes mellitus (T2DM), but their relevance for metabolic dyslipidaemia in T2DM is unclear. This study aims to determine the plasma and urinary BCAAs and their association with insulin resistance, lipid profile and glycated haemoglobin in patients with T2DM among Indian adults.MethodsIn this analytical cross-sectional study, a total of eighty subjects were recruited, 40 T2DM cases and 40 healthy controls. Blood samples collected were subjected to fasting blood sugar (FBS), lipid profile, HbA1c, insulin and BCAAs analysis and urine samples were assessed for BCAAs. All associations were assessed using Spearman Rank Correlation.ResultsThe plasma levels of BCAAs were significantly higher (p < 0.05) in subjects with T2DM than in control subjects. Spearman Rank Correlation analyses revealed a non-significant (p = 0.21) but positive association between BCAAs and homeostasis model assessment of insulin resistance (HOMA-IR) in patients with T2DM (Rho: 0.27). Among lipid profile parameters, only triglycerides had a significant positive correlation to plasma BCAAs in cases (Rho: 0.5971) but not in control subjects. Findings also revealed a significant positive (p < 0.05) association between plasma BCAAs and HbA1c in patients with T2DM (Rho: 0.5325). Urinary BCAAs levels had a non-significant increase in T2DM subjects and did not show any significant correlation with other parameters assessed.ConclusionElevated levels of plasma BCAAs are positively associated with triglyceride and HbA1c. They could serve as an effective marker for the assessment of metabolic dyslipidaemia in subjects with T2DM. Further, large scale studies are needed for confirmation of the same.     

Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes

ContextGestational diabetes is commonly linked to development of type 2 diabetes mellitus (T2DM). There is a need to characterize metabolic changes associated with gestational diabetes in order to find novel biomarkers for T2DM.ObjectiveTo find potential pathophysiological mechanisms and markers for progression from gestational diabetes mellitus to T2DM by studying the metabolic transition from pregnancy to postpartum.DesignThe metabolic transition profile from pregnancy to postpartum was characterized in 56 women by mass spectrometry-based metabolomics; 11 women had gestational diabetes mellitus, 24 had normal glucose tolerance, and 21 were normoglycaemic but at increased risk for gestational diabetes mellitus. Fasting serum samples collected during trimester 3 (gestational week 32 ± 0.6) and postpartum (10.5 ± 0.4 months) were compared in diagnosis-specific multivariate models (orthogonal partial least squares analysis). Clinical measurements (e.g., insulin, glucose, lipid levels) were compared and models of insulin sensitivity and resistance were calculated for the same time period.ResultsWomen with gestational diabetes had significantly increased postpartum levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and their circulating lipids did not return to normal levels after pregnancy. The increase in BCAAs occurred postpartum since the BCAAs did not differ during pregnancy, as compared to normoglycemic women.ConclusionsPostpartum levels of specific BCAAs, notably valine, are related to gestational diabetes during pregnancy.     

Clinical characteristics of collagenous and lymphocytic colitis

Background: Microscopic colitides (MC), collagenous colitis (CC) and lymphocytic colitis (LC) share clinical features, but their mutual relationship is unclear, and clinical comparative studies are rare. We aimed to examine the clinical features in CC and LC by focusing on concomitant diseases. Methods: Patients with MC (30 with CC, 54 with LC) were identified in the pathology databases and by reviewing biopsies. Controls included 84 age‐ and sex‐matched persons. The clinical data collected from patient records were prospectively completed by interviews. Results: The female:male ratio was 2:1 in CC and 5.75:1 in LC. Mean age at diagnosis was 53 in CC and 55.4 years in LC. There were no differences in the pattern of symptoms. Concomitant autoimmune diseases were more common in CC (53.3%) than in LC (25.9%; P?=?0.017). Celiac disease was common in both CC (20%) and LC (14.8%). Bronchial asthma was associated with LC (25.9%), but not with CC (6.7%; P?=?0.042). Colon diverticulosis was rare in MC (16%) compared with the controls (39%; P?=?0.001). Hypolactasia was common in MC (45%; 76% in CC, 54% in LC) compared to its prevalence in the Finnish general population (17%). Conclusions: CC and LC are largely similar clinically, but the differences in the occurrence of autoimmune conditions and bronchial asthma suggest that they differ in immunopathogenesis. MC is associated with reduced lactose tolerance and shows a negative association with diverticular disease, possibly related to the small intestinal pathology and abnormal stool consistency.     

Clinical characteristics and patterns and predictors of response to therapy in collagenous and lymphocytic colitis

Abstract

Background. Collagenous colitis (CC) and lymphocytic colitis (LC) are chronic inflammatory disorders of the colon. There is a paucity of data on differences in etiology, natural history, and treatment response between CC and LC. Methods. Between 2002 and 2013, we identified new diagnoses of CC and LC using the Research Patient Data Registry in a tertiary referral center. We used chi square or Fischer’s exact test and Wilcoxon rank-sum tests to compare the differences in clinical characteristics, treatment types, and response rates between LC and CC. Results: Through 2013, we confirmed 131 patients with a new diagnosis of microscopic colitis (MC) (55 LC, 76 CC). Compared to cases of LC, patients with a diagnosis of CC were more likely to be women (86% vs. 69%, p = 0.03), have elevated erythrocyte sedimentation rate (mean 28 vs. 13 mm/h, p = 0.04), and less likely to be diabetic (5% vs. 18%, p = 0.02). Budesonide was the most effective treatment for both CC and LC (94% and 80%, respectively). However, there were no statistically significant differences in response to various treatments according to the type of MC (all p > 0.10). Older age at the time of diagnosis was associated with better response to bismuth subsalicylate (odds ratio: 1.76; 95% confidence interval: 1.21–2.56 for every 5-year increase) for both CC and LC. Conclusion. Despite differences in the clinical characteristics, response rates to available treatments appeared to be similar in both LC and CC. Older patients may have a better response to bismuth subsalicylate therapy.     

The plasma 8-OHdG levels and oxidative stress following cholecystectomy: a randomised multicentre study of patients with minilaparotomy cholecystectomy versus laparoscopic cholecystectomy

Objective: The aim of the study was to evaluate the role of 8-OHdG (8-hydroxy-2′-deoxyguanosine) detecting oxidative stress response following cholecystectomy in a randomised multicentre study of patients with minilaparotomy cholecystectomy (MC) versus laparoscopic cholecystectomy (LC).

Methods: Initially, 106 patients with non-complicated symptomatic gallstone disease were randomised into MC (n?=?56) or LC (n?=?50) groups. Plasma levels of the oxidative stress marker 8-OHdG measured at three time points; before (PRE), immediately after (POP1) and 6?h after operation (POP2).

Results: The demographic variables and the surgical data were similar in the study groups. The plasma oxidative stress marker 8-OHdG concentrations following surgery in the MC versus LC patients were quite similar. There was no significant correlation between the individual values of the11-point numeric rating pain scale (NRS) versus the plasma 8-OHdG post-operatively in the MC and LC patients. However, there was a statistically significant correlation between the individual values of the plasma 8-OHdG (PRE) versus IL-10 (PRE) for the MC and LC patients (r?=?0.214, p?=?0.037). There was also a statistically significant correlation between the individual values of the plasma 8-OHdG (POP2) versus IL-1β (POP2) for the MC and LC patients (r?=?0.25, p?=?0.01).

Conclusion: Our results suggest that the oxidative stress marker 8-OHdG concentrations following surgery in MC versus LC patients were quite similar. A new finding with possible clinical relevance is a correlation between the individual plasma values of the 8-OHdG versus anti-inflammatory interleukin IL-10 and 8-OHdG versus IL-1β (proinflammatory) in the MC and LC patients suggesting that inflammation and oxidative stress are related.     

Sevalamer Hydrochloride,Sevelamer Carbonate and Lanthanum Carbonate: In Vitro and In Vivo Effects on Gastric Environment

Hyperphosphatemia is common in patients with chronic renal failure. Phosphate binders are associated with gastric intolerance, representing the main reason of drug discontinuation. The aim of this study was to compare the effects in vitro and in vivo of sevelamer hydrochloride (SH), sevelamer carbonate (SC) and lanthanum carbonate (LC) on gastric microenvironment. We have also evaluated the efficacy and tolerability of these drugs in hemodialysis (HD) patients. In vitro analysis: Dissolution time, ability to uptake phosphorus, changes in pH starting from gastric milieu and the amount of carbon dioxide (CO₂) produced were the variables analyzed. In vivo analysis: 24‐h esophago‐gastric pH measurement was evaluated in 24 HD patients treated with phosphate binders and proton pump inhibitor (PPI). In vitro: LC dissolved over a longer time compared with SC (58 ± 2.4 vs. 12 ± 0.6 min; P < 0.001) and SH (58 ± 2.4 vs. 10.3 ± 0.8 min; P < 0.001), determining the most alkaline pH. SC had the highest chelation power, binding 4.00 × 10^?9 mol/L of phosphoric acid. CO₂ volume released was increased in LC solution (53.2 ± 7.8) compared to SC (33.9 ± 6.2; P < 0.001) and SH (2.3 ± 1.8; P < 0.001). In vivo: gastric pH increased after administration of phosphate binder. The most alkaline pH was recorded in patients treated with SC. The alkalinization of the gastric environment was not prevented by PPI therapy. 424 episodes of esophageal reflux were registered, 74% of them were alkaline. The LC group was characterized by the highest number of episodes. Sevelamer carbonate had a greater capacity and rapidity to chelate phosphorus, with a mild tolerability, due to its low CO₂ production. Sevelamer HCl was the most tolerated chelator because it did not produce CO₂, while lanthanum carbonate was the least soluble.     

Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries

OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history. DESIGN A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls. PATIENTS AND METHODS We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11). RESULTS Results are expressed as mean ± SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 ± 0.7 vs LP 35.2 ± 1.2, P < 0.01; OC 34.7 ± l.8 vs OP 37.8 ± 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 ± 9 vs LP 179 ± 9, NS; OC 168 ± 12 vs OP 133 ± 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL₂-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38–0.62), LP 0.31 (0.26–0.44), P < 0.05; OC 0.34 (0.21–0.47), OP 0.21 (0.12–0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL₂-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries. CONCLUSION Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.     

Elevated plasma resistin concentrations in patients with liver cirrhosis

Background: Resistin, an adipose‐derived polypeptide hormone, has been proposed to be a candidate in insulin resistance, although its role in humans remains controversial. Liver cirrhosis (LC) is characterized by an elevated number of circulating proinflammatory cytokines, hyperinsulinemia and insulin resistance. The aim of this study was to determine the plasma resistin levels in patients with LC. Methods: Resistin levels were determined in 79 patients with LC and in 31 healthy controls. Patients included 34 with Child–Pugh grade A, 30 with Child's B and 15 with Child's C LC. Fasting plasma glucose, fasting plasma insulin, adiponectin, the homeostatic model assessment insulin resistance (HOMA‐IR) index, quantitative insulin sensitivity check index (QUICKI) and biochemical parameters were also determined. Results: Plasma resistin levels were 7.61 ± 6.70 ng/mL in the LC patients and 3.38 ± 1.68 ng/mL in the controls, respectively. The plasma resistin levels were significantly elevated in patients with LC in comparison to the controls (P < 0.01). The plasma resistin levels increased in a stepwise fashion in line with a higher grade according to Child–Pugh classification. Fasting plasma insulin, adiponectin and HOMA‐IR index were also significantly elevated in patients with LC in comparison to controls. Inversely, QUICKI significantly decreased in patients with LC. According to Spearman's rank correlation, log resistin showed significantly positive correlation with fasting plasma insulin, log adiponectin, HOMA‐IR index, and a negative correlation with QUICKI (P < 0.01). The plasma resistin levels did not correlate with sex, body mass index and fasting plasma glucose levels. Conclusion: The plasma resistin levels increased in patients with LC, thus showing a positive correlation with fasting plasma insulin, adiponectin, HOMA‐IR index, and a negative correlation with QUICKI. Although a decreased extraction of resistin due to reduced liver function cannot be ruled out, resistin may contribute to insulin resistance in patients with LC. The pathophysiological roles of resistin in LC still require further investigation.     

Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals

Background & aims

3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB.

Microscopic colitis: a descriptive clinical cohort study of 795 patients with collagenous and lymphocytic colitis

Objective Microscopic colitis is a common cause of chronic diarrhoea in the Scandinavian countries. This report comprises demographic data, clinical and endoscopic features, and occurrence of coeliac and inflammatory bowel disease (IBD) in a large urban cohort of patients with lymphocytic colitis (LC) and collagenous colitis (CC). Materials and methods A total of 795 patients with microscopic colitis from two hospitals in Stockholm were included. Medical records were reviewed and clinical data, including endoscopic and histological findings, were compiled. Results Forty-three percent had CC (female:male ratio 3.7:1) and 57% had LC (female:male ratio 2.7:1). The mean age at diagnosis of CC was 63 years and of LC was 59 years (p?=?0.005). Clinical features were similar in both entities, but the intensity of symptoms differed. Watery diarrhoea was reported in 55% in CC patients versus in 43% in LC patients (p?=?0.0014), and nocturnal diarrhoea in 28% versus 18% (p?=?0.002). Subtle endoscopic mucosal findings were reported in 37% of the CC patients and in 25% of the LC patients (p?=?0.0011). Colorectal adenomatous polyps were found in 5.3% of all patients. Coeliac disease occurred in 6% and IBD occurred in 2.1% of all patients. Conclusions Clinical features of LC and CC are similar but not identical. CC seems to be a more severe type of bowel inflammation and LC tends to occur earlier in life. Both forms might indeed feature endoscopic findings despite the designation ‘microscopic’. Our study confirms the strong association with coeliac disease.     

The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study

Aims. To define the prevalence and clinical characteristics of glucose metabolism disorders (GMD) in patients with compensated liver cirrhosis (LC).Material and methods. Fasting plasma glucose (FPG) levels were measured to 130 patients with clinically stable LC. Oral glucose tolerance tests (OGTT) and fasting plasma insulin determinations were performed to patients with normal FPG. Insulin resistance (IR) was calculated with HOMA2-IR index. GMD were classified according to FPG and OGTT tests results and to the chronologic relation between diagnosis of diabetes mellitus (DM) and LC as follows: type-2 DM (T2DM), hepatogenous diabetes (HD) and impaired glucose tolerance. Patients from all groups were compared.Results. The prevalence of GMD were as follows: T2DM in 25 patients (19.2%, 95% CI 12.5-25.9), HD in 28 (21.5%, 95% CI 14.5-28.5) and IGT in 36 (38.5%, 95% CI 30.1-46.7). The total of patients with GMD was 79.2% (95% CI 72.3-86.1). In 41% of cases GMD were subclinical and 48.7% of patients had IR. Patients with T2DM had a higher number of variables with significant differences compared with the other groups (more marked compared to the patients without GMD). The only differences between the patients with T2DM and HD were hypercreatininemia: 1.14 ± 0.53 vs. 0.84 ± 0.22 mg/dL (p = 0.005) and family history of DM: 8 (32%) vs. 2 (7%) (p = 0.02).Conclusion. Almost 80% of patients with compensated LC had GMD. Half of them were subclinical. The patients with T2DM had marked clinical differences compared to patients from the other groups, particularly renal impairment.     

A randomized multicenter study of minilaparotomy cholecystectomy versus laparoscopic cholecystectomy with ultrasonic dissection in both groups

Objective: Ultrasonic dissection (UsD) has been used in laparoscopic cholecystectomy (LC), though it is not the golden standard technique. Applying UsD to cholecystectomy by minilaparotomy (MC) is less common and there are no prospective randomized trials comparing these two techniques. Therefore, we conducted the present study to investigate the use of the UsD in the MC versus the LC procedure. Material and methods: Initially 104 patients with non-complicated symptomatic gallstone disease were randomized into MC (n?=?53) or LC (n?=?51) groups, both groups using UsD, over a period of 2 years (2013–2015). The study groups were similar in terms of age and American Society of Anesthesiologists (ASA) physical status score. Results: The demographic variables and the surgical data were similar in the study groups. Similar low postoperative pain scores were reported in the two study groups during the first four hours after surgery. The incidence of nausea/vomiting was similar between the two study groups, 47% in the MC group versus 42% in the LC group. However, the patients in the MC group were treated more frequently with antiemetics, the incidence being 39% in the MC group versus 21% in the LC group (p?=?0.02). The pain at rest at 24h after the surgery was similar in the two study groups, but the LC patients reported less pain at the normal activity, the mean of numerical rating scale (NRS) of 0–10 score being 3.9 in the MC group versus 2.9 in the LC group (p?=?0.05), and the pain at the quick movement/coughing, the mean NRS being 4.9 in the MC group versus 3.2 in the LC group (p?=?0.005). The length of sick leave was 17.4 days in the MC group and 14.4 days in the LC group (p?=?0.05). Conclusion: Our results suggest that both MC and LC are feasible and safe options for mini-invasive cholecystectomy. A new finding with clinical relevance in the present work is a relatively similar short-term outcome in the MC and LC althought the LC patients reported significantly lower pain score 24 hours postoperatively and a shorter convalescence.     

Ultrathin choledochoscope improves outcomes in the treatment of gallstones and suspected choledocholithiasis

Background: We aimed to compare laparoscopic cholecystectomy (LC) and simultaneous laparoscopic transcystic common bile duct exploration (LTCBDE) using an ultrathin choledochoscope with LC followed by endoscopic retrograde cholangiopancreatography (ERC) and endoscopic sphincterotomy (ES) when indicated.

Methods: We retrospectively reviewed the records of patients seen between 2004 and 2014 and treated with LC+LTCBDE or LC for gallstones and suspected choledocholithiasis. Postoperative complications and surgical outcomes were compared using t-test, Mann-Whitney U test, or chi-square test.

Results: 115 patients underwent successful LC+LTCBDE and 112 LC; follow-up data was available for 103 and 106 patients, respectively. Seventeen patients (16.5%) in the LC+LTCBDE group and 10 (28.6%) in the LC+ERC+ES group developed complications (P = 0.114). The LC+LTCBDE group had a significantly higher rate of satisfactory biliary function outcomes than the LC+ERC+ES group (98.1% vs. 85.7%, respectively) (P = 0.017).

Conclusions: Single-step LC+LTCBDE using an ultrathin choledochoscope may provide better outcomes in patients with gallstones and suspected choledocholithiasis.     

Neuropsychiatric dysfunction in patients with chronic hepatitis and liver cirrhosis

Aim: The aim of this study is to clarify the cerebral functions in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC). Methods: We studied 58 patients with CH (20 in fibrosis stage F1, 20 in F2, 18 in F3), 77 with LC (46 rated as Child–Pugh class A, 24 as B, 7 as C), and 20 healthy volunteers (HV). Computer‐aided quantitative neuropsychiatric function test systems, including eight neuropsychiatric tests were performed. Results: Subjects with results over the cut‐off value for healthy subjects ranged from 11.1–28.6% in CH and 19.5–36.4% in LC. The percentages with abnormality in at least one test in CH and LC were 72.4% and 80.6%, respectively, which were significantly higher than that in the HV group (35.0%) (P = 0.003, P = 0.0003, respectively). Among CH subjects, those with three or more abnormal results in the F1, F2 and F3 subgroups were 15.0%, 20.0% and 38.9%, respectively. Among LC subjects, those with three or more abnormal results in the Child–Pugh class A, B and C subgroups comprised 30.4%, 50.0% and 57.1%, respectively. The rate in the CH F3 subgroup (P = 0.011) and in all three LC subgroups (P = 0.023, P = 0.001, P = 0.002, respectively) were significantly higher than that in the HV group. Conclusion: The percentage of patients with neuropsychiatric function impairment was high in both LC and CH, especially in stage F3. Neuropsychiatric dysfunction may initiate in CH in a considerable number of patients.     

慢性充血性心力衰竭患者血浆BCAAs水平的临床研究

目的:探讨研究慢性充血性心力衰竭(CHF)患者血浆支链氨基酸(BCAAs)水平的变化,及其与氨基末端脑钠尿肽前体(NT-pro-BNP)和左室射血分数(LVEF)的相关性。方法:共纳入168例诊断为CHF患者作为病例组,同时随机选择同期体检的41例健康成年人作为对照组。采用ELISA方法测定空腹血浆BCAAs水平、NT-pro-BNP,超声心动图检测LVEF值。比较两组血浆BCAAs水平及其与NT-pro-BNP、LVEF的关系。结果:两组受试者基线资料无明显差异;CHF患者血浆BCAA水平、LVEF均低于对照组,血浆NT-pro-BNP高于对照组(P<0.01);随着NYHA分级增加,NT-pro-BNP逐渐升高,LVEF逐渐降低(P<0.01),而BCAAs水平无明显变化;Spearson偏相关分析显示经性别、年龄、收缩压、舒张压、体质量指数校正后,CHF组BCAAs水平与NT-pro-BNP呈负相关(r=-0.168,P<0.05),而与LVEF无关(r=0.069,P>0.05)。结论:CHF患者血浆BCAAs水平明显低于正常对照组,与NT-pro-BNP水平呈负相关。     

Effects of chronic administration of alogliptin on the development of diabetes and β-cell function in high fat diet/streptozotocin diabetic mice

Aim: Alogliptin is a potent and highly selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor. The aim of this study was to determine its effects on glucose control and pancreas islet function and to identify the underlying molecular mechanisms after chronic administration, in a non‐genetic mouse model of type 2 diabetes. Methods: Alogliptin (5, 15 and 45 mg/kg) was orally administered to high fat diet/streptozotocin (HFD/STZ) diabetic mice daily for 10 weeks. Postprandial and 6‐h fasting blood glucose levels, blood A1C level, oral glucose tolerance and pancreas insulin content were measured during or after the treatment period. Alogliptin plasma concentration was determined by an LC/MS/MS method. Islet morphology and architectural changes were evaluated with immunohistochemical analysis. Islet endocrine secretion ability was assessed by measuring insulin release from isolated islets which were challenged with 16 mM glucose and 30 mM potassium chloride, respectively. Gene expression profiles of the pancreas were analysed using the mouse diabetes RT² Profiler PCR array which contains 84 genes related to the onset, development and progression of diabetes. Results: Alogliptin showed dose‐dependent reduction of postprandial and fasting blood glucose levels and blood A1C levels. Glucose clearance ability and pancreas insulin content were both increased. Alogliptin significantly restored the β‐cell mass and islet morphology, thus preserving islet function of insulin secretion. Expression of 10 genes including Ins1 was significantly changed in the pancreas of diabetic mice. Chronic alogliptin treatment completely or partially reversed the abnormalities in gene expression. Conclusions: Chronic treatment of alogliptin improved glucose control and facilitated restoration of islet architecture and function in HFD/STZ diabetic mice. The gene expression profiles suggest that the underlying molecular mechanisms of β‐cell protection by alogliptin may involve alleviating endoplasmic reticulum burden and mitochondria oxidative stress, increasing β‐cell differentiation and proliferation, enhancing islet architecture remodelling and preserving islet function.     

Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats

Background  Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). However, the possible mechanism is still obscure. The aim of the present study was to examine the effect of BCAAs, especially in conjunction with angiogenesis, on hepatocarcinogenesis under the condition of IR. Methods  The effect of BCAAs on the development of liver enzyme-altered preneoplastic lesions and angiogenesis was examined in obese diabetic Otsuka Long-Evans Tokushima Fatty rats. We also performed an in vitro study to elucidate the possible mechanisms involved. Results  Treatment with BCAAs markedly inhibited glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions along with suppression of neovascularization in the liver. The hepatic expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, was also attenuated. BCAA treatment significantly suppressed glucose- and insulin-induced in vitro angiogenesis in the presence of VEGF. Conclusions  In obese diabetic rats BCAAs exerted a chemopreventive effect against HCC, associated with the suppression of VEGF expression and hepatic neovascularization. Since BCAA preparations are widely used in clinical practice for patients with chronic liver diseases, this agent may represent a new strategy for chemoprevention against HCC in the future.     

Elevated fecal levels of eosinophil granule proteins predict collagenous colitis in patients referred to colonoscopy due to chronic non-bloody diarrhea

Objective: Colonoscopy with biopsy sampling is often performed to detect collagenous colitis (CC) and lymphocytic colitis (LC) in patients with chronic non-bloody diarrhea. However, the diagnostic yield is low and incurs high costs. Fecal calprotectin (FC) and myeloperoxidase (MPO) indicate intestinal inflammation in ulcerative colitis (UC) and Crohn’s disease (CD). In CC, elevated fecal levels of eosinophil protein X (EPX) and eosinophil cationic protein (ECP) have been reported. We aimed to evaluate if F-EPX, F-ECP, FC, and F-MPO could predict the diagnostic outcome in patients with chronic non-bloody diarrhea referred to colonoscopy. We also evaluated serum (S) EPX and ECP in this regard.

Methods: Of 67 included patients, 63 (94%) underwent colonoscopy with biopsy sampling. Fecal EPX, F-ECP, FC, F-MPO, S-EPX, and S-ECP were analyzed.

Results: Diagnostic outcome: normal: n?=?46 (73%), CC: n?=?9 (14%), LC: n?=?4 (6%), UC: n?=?2 (3%), CD: n?=?2 (3%). Higher levels of F-EPX and F-ECP were found in CC compared to a normal diagnostic outcome (p?=?0.01). No change was noted in any of the fecal markers in LC. When all of the fecal markers were normal the probability of a normal diagnostic outcome was 92%. We found no differences in S-EPX and S-ECP between the groups.

Conclusion: Elevated F-EPX and F-ECP could predict CC. None of the fecal markers predicted LC. Serum-EPX and S-ECP are not useful for the diagnosis of CC, LC, UC, or CD. With normal levels in all of the analyzed fecal markers, there is a low probability of a pathologic diagnostic outcome.