Search for Dark Photon Dark Matter in the Mass Range 74-110 µeV with a Cryogenic Millimeter-Wave Receiver.

We search for the dark photon dark matter (DPDM) using a cryogenic millimeter-wave receiver. DPDM has a kinetic coupling with electromagnetic fields with a coupling constant of χ and is converted into ordinary photons at the surface of a metal plate. We search for signal of this conversion in the frequency range 18-26.5 GHz, which corresponds to the mass range 74-110 µeV/c^{2}. We observed no significant signal excess, allowing us to set an upper bound of χ<(0.3-2.0)×10^{-10} at 95% confidence level. This is the most stringent constraint to date and tighter than cosmological constraints. Improvements from previous studies are obtained by employing a cryogenic optical path and a fast spectrometer.

The effect of laryngeal elevation training on swallowing function in patients with dysphagia.

OBJECTIVE: To investigate the effect of laryngeal elevation training without highly loaded head lifting on swallowing function in patients with dysphagia. METHODS: Fifty-seven patients with dysphagia (36 men; mean age, 78.5 ± 11.4 years) were included. All participants performed the swallowing forehead exercise and the chin push-pull manoeuvre for two months. Videoendoscopy to assess swallowing function, the peak expiratory flow test and the hand grip strength test were performed at the initial visit (time 1) and two months after the start of the intervention (time 2). We used the Hyodo score, a scoring method for videoendoscopic assessment, for evaluation of swallowing function. RESULTS: The linear mixed model showed a significant main effect of time (the Hyodo score at time 1 was greater than the score at time 2). The effects of the co-variates were not significant. CONCLUSION: The present study demonstrated the significant effect of laryngeal elevation training without head lifting on the Hyodo score.

Efficacy and Safety of Lixisenatide in Japanese Patients with Type 2 Diabetes Insufficiently Controlled with Basal Insulin±Sulfonylurea: A Subanalysis of the GetGoal-L-Asia Study.

The aim of the study was to evaluate the efficacy and safety of once-daily lixisenatide 20 µg as add-on to basal insulin with or without sulfonylurea in Asian patients with type 2 diabetes mellitus. The study as a subanalysis of the 159 Japanese patients from the 24-week double-blind GetGoal-L-Asia study (NCT00866658) who received once-daily lixisenatide or placebo. The primary endpoint was change from baseline in HbA1c evaluated using analysis of covariance. Once-daily lixisenatide significantly reduced mean HbA1c [least squares mean difference vs. placebo - 1.1% (- 12 mmol/mol); p<0.0001]. Significantly more patients in the lixisenatide group reached HbA1c targets of < 7% (53 mmol/mol; 31.4 vs. 2.3% for placebo; p<0.0001) and ≤ 6.5% (48 mmol/mol; 12.9 vs. 1.2% for placebo; p=0.0028). Lixisenatide significantly reduced 2-h postprandial plasma glucose (least squares mean difference vs. placebo-8.64 mmol/l; p<0.0001), glucose excursion (least squares mean difference vs. placebo - 7.80 mmol/l; p<0.0001) and fasting plasma glucose (least squares mean difference vs. placebo - 0.96 mmol/l; p=0.0126). Body weight was reduced with lixisenatide but with no significant difference vs. placebo. Gastrointestinal adverse events were more frequent with lixisenatide (61.1 vs. 11.5% for placebo) but were generally transient and mild-to-moderate in intensity. The incidence of symptomatic hypoglycemia was 39.0 vs. 13.5% in patients receiving sulfonylureas and 32.3 vs. 22.9% in those not receiving sulfonylureas, for lixisenatide and placebo, respectively. In Japanese patients with type 2 diabetes mellitus, once-daily lixisenatide was well tolerated and led to significant and clinically relevant improvement in glycemic control, with a pronounced effect on postprandial plasma glucose.

Use of the Japanese health insurance claims database to assess the risk of acute pancreatitis in patients with diabetes: comparison of DPP-4 inhibitors with other oral antidiabetic drugs.

This study was initiated to evaluate the association of acute pancreatitis (AP) with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with diabetes in Japan. A retrospective cohort study of a large medical and pharmacy claims database was performed to compare the incidence of AP among those receiving DPP-4 inhibitors and those receiving other oral antidiabetic drugs. The incidence of all AP and hospitalizations for AP was similar between the two groups. Previous exposure to DPP-4 inhibitors did not affect occurrence of AP in patients on other oral antidiabetic drugs. The Kaplan-Meier curve for time to AP was similar between the two groups, and was not affected by previous exposure to DPP-4 inhibitors. The Cox proportional hazard models showed the incidence of AP was not significantly higher in those receiving DPP-4 inhibitors. Despite numerous, important limitations related to claims database-based analyses, our results indicate that there is no increased risk of AP with use of DPP-4 inhibitors among patients with diabetes in Japan.

Pharmacodynamics of the glucagon-like peptide-1 receptor agonist lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus poorly controlled on sulphonylureas with/without metformin.

AIMS: The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin. METHODS: This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 µg, and a 5- to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 µg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29-4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events. RESULTS: Change from baseline in PPG AUC[0:29-4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29-4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 µg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated. CONCLUSIONS: Lixisenatide significantly reduced PPG AUC[0:29-4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions.

Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study.

AIMS: To evaluate the efficacy and safety of alogliptin added to metformin versus metformin monotherapy in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on metformin (500 or 750 mg/day) + diet/exercise. METHODS: In a randomized, double-blind trial, 288 patients with type 2 diabetes mellitus T2DM received either 12.5 or 25 mg alogliptin once daily + metformin or placebo + metformin for 12 weeks. Thereafter, 276 patients continued on one of the two alogliptin dosages + metformin in an open-label extension for 40 weeks. The primary efficacy endpoint in the randomized, double-blind phase was the change in HbA1c from baseline (week 0) to the end of treatment (week 12). The primary endpoint during the long-term extension phase was adverse events. RESULTS: After 12 weeks both dosages of alogliptin + metformin produced significantly greater changes from baseline in HbA1c than placebo (metformin monotherapy: with changes in LS means - 0.55 and - 0.64% vs. 0.22%, respectively; p < 0.0001). Incidences of adverse effects were comparable between groups, with no increases in hypoglycaemia. Over 52 weeks, there were no safety or tolerability concerns with alogliptin when added to metformin. CONCLUSIONS: Alogliptin 12.5 and 25 mg once daily was safe and effective when added to metformin (500 or 750 mg/day) in Japanese patients with inadequately controlled type 2 diabetes on metformin alone.

Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia).

AIMS: To assess the efficacy and safety of once-daily lixisenatide versus placebo in Asian patients with type 2 diabetes insufficiently controlled on basal insulin ± sulfonylurea. METHODS: In this 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicentre study, participants (mean baseline HbA(1c) 8.53%) from Japan, Republic of Korea, Taiwan and the Philippines received lixisenatide (n = 154) or placebo (n = 157) in a stepwise dose increase to 20 µg once daily. The primary endpoint was HbA(1c) change from baseline to week 24. RESULTS: Once-daily lixisenatide significantly improved HbA(1c) versus placebo (LS mean difference vs. placebo = -0.88% [95%CI= -1.116, -0.650]; p < 0.0001), and allowed more patients to achieve HbA(1c) <7.0% (35.6 vs. 5.2%) and ≤ 6.5% (17.8 vs. 1.3%). Lixisenatide also significantly improved 2-h postprandial plasma glucose and glucose excursion, average 7-point self-monitored blood glucose and fasting plasma glucose. Lixisenatide was well tolerated; 86% of patients on lixisenatide completed the study versus 92% on placebo. Ten (6.5%) lixisenatide and 9 (5.7%) placebo patients experienced serious adverse events. More lixisenatide patients [14 (9.1%)] discontinued for adverse events versus placebo [5 (3.2%)], mainly with gastrointestinal causes. Nausea and vomiting were reported in 39.6 and 18.2% of patients on lixisenatide versus 4.5 and 1.9% on placebo. Symptomatic hypoglycaemia was more frequent with lixisenatide (42.9%) versus placebo (23.6%), but was similar between groups (32.6 vs. 28.3%, respectively), in those not receiving sulfonylureas. No severe hypoglycaemia was reported. CONCLUSIONS: In an Asian type 2 diabetes population insufficiently controlled by basal insulin ± sulfonylurea, once-daily lixisenatide significantly improved glycaemic control, with a pronounced postprandial effect, and was well tolerated.

Reduction of insulin signaling upregulates angiopoietin-like protein 4 through elevated free fatty acids in diabetic mice.

BACKGROUND: Angiopoietin-like protein 4 (Angptl4) is thought to cause an increase in serum triglyceride levels. In the present study, we elucidated Angptl4 expression in the mouse models of type 1 and type 2 diabetes mellitus, and investigated the possible mechanisms involved. METHODS: Type 1 diabetes was induced in C57BL/6 J mice by treating them with streptozotocin (STZ). Type 2 diabetes was induced by feeding the mice a high-fat diet (HFD) for 18 weeks. RESULTS: The levels of Angptl4 mRNA expression in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) were found to increase in the STZ diabetic mice relative to control mice. This effect was attenuated by insulin administration. In the HFD diabetic mice, the Angptl4 mRNA expression levels were increased in liver, WAT, and BAT. Treatment with metformin for 4 weeks attenuated the increased levels of Angptl4 mRNA. Fatty acids (FAs) such as palmitate and linoleate induced Angptl4 mRNA expression in H4IIE hepatoma cells and 3T3-L1 adipocytes. Treatment with insulin but not metformin attenuated FA-induced Angptl4 mRNA expression in H4IIE. Both insulin and metformin did not influence the effect of FAs in 3T3-L1 cells. CONCLUSION: These observations demonstrated that Angptl4 mRNA expression was increased through the elevated free FAs in diabetic mice.

Three-dimensional computed tomography analysis of neoglottis after supracricoid laryngectomy with cricohyoidoepiglottopexy.

INTRODUCTION: Supracricoid laryngectomy with cricohyoidoepiglottopexy is an organ-preserving procedure used to treat laryngeal cancer. However, the post-operative neoglottis tends to be variable in form and difficult to predict. METHODS: We retrospectively analysed three-dimensional images reconstructed from multidetector-row computed tomography data for 21 patients, assessing arytenoid motion and minimum neoglottic gap cross-sectional area. RESULTS: While mean transverse and coronal motion was similar for bilateral and unilateral arytenoids, movement along the sagittal axis was greater for unilateral than bilateral arytenoids. The neoglottic gap during respiration was wider in patients with bilateral arytenoids, but both groups had a similar neoglottic gap during phonation. CONCLUSION: Anterior shifting of the unilateral arytenoid plays an important role in compensating for the inability to achieve neoglottic closure. These two results demonstrate that the unilateral arytenoid alone is capable of achieving sufficient neoglottic narrowing to compensate for the resected arytenoid. Three-dimensional analysis was useful to evaluate the physiological status of the neoglottis after supracricoid laryngectomy with cricohyoidoepiglottopexy.

'Flaccid neoglottis' following supracricoid partial laryngectomy: laryngoscopic revision assisted by navigation system.

OBJECTIVE: Supracricoid partial laryngectomy is a reliable laryngeal preservation procedure for tumour stage 2 and selected stage 3 to 4 laryngeal cancers. Of 70 patients thus treated, two (3 per cent) had 'flaccid neoglottis', i.e. redundant mucosa at the inner arytenoid edge which intermittently obstructed the neoglottis. We discuss the mechanism and management of this complication. METHOD: The two cases are presented. A navigation system was used to assist surgery. Neoglottal spatial alteration (specifically cross-sectional area) was assessed pre- and post-operatively using three-dimensional computed tomography. Voice was also evaluated. RESULTS: Inspiratory stridor and delayed stomal closure were the main symptoms. Minimum neoglottal cross-sectional area was smaller in case one than in non-affected patients. Both patients had relatively rougher and breathier voices, but had adapted well to this. CONCLUSION: Flaccid neoglottis is mainly due to excessive anterior retraction of residual laryngeal mucosa and to excessive mucosal pliability with age. A navigation system was useful for confirmation, but the potential for incorrect image recognition should be kept in mind. Flaccid neoglottis was treatable, with improved laryngeal function.

Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study.

AIM: To assess the efficacy and safety of alogliptin added to pioglitazone versus pioglitazone monotherapy, in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus diet/exercise. METHODS: Patients were stabilized on pioglitazone 15 or 30 mg/day plus diet/exercise during a 16-week screening period. Patients with HbA1c of 6.9-10.4% were randomized to 12 weeks' double-blind treatment with alogliptin 12.5 or 25 mg once daily or placebo, added to their stable pioglitazone regimen. The primary endpoint was the change in HbA1c from baseline to week 12. Patients had an option to continue in a 40-week, open-label extension study, with those originally randomized to alogliptin remaining on the same dosage regimen while patients treated with placebo were randomly allocated to alogliptin 12.5 or 25 mg (added to their stable pioglitazone). RESULTS: The change from baseline in HbA1c after 12 weeks was significantly greater with alogliptin 12.5 mg added to pioglitazone and alogliptin 25 mg added to pioglitazone than with placebo added to pioglitazone (-0.91 and -0.97% vs. -0.19%; p < 0.0001). Responder rates (HbA1c <6.9% and HbA1c <6.2%) and changes in fasting and postprandial blood glucose levels showed a similar positive trend in terms of glycaemic control. The benefits seen with alogliptin were sustained during the 40-week extension period. Alogliptin added to pioglitazone was generally well tolerated; hypoglycaemia was infrequent and increases in body weight were minor. CONCLUSIONS: Once-daily alogliptin was effective and generally well tolerated when given as add-on therapy to pioglitazone in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus lifestyle measures. Clinical benefits were maintained for 52 weeks.

Computer-based analysis with three-dimensional imaging constructed from fine-slice computed tomography scan of supracricoid laryngectomy with cricohyoidoepiglottopexy: report of two cases.

OBJECTIVE: Supracricoid laryngectomy with cricohyoidoepiglottopexy is an organ-preserving surgical technique used to treat laryngeal cancer. This procedure resects the vocal folds; however, it is unclear how the sound source and airway morphology are involved in phonation through the post-operative neoglottis. METHOD: Multidetector helical computed tomography scanning was performed on two patients who had undergone supracricoid laryngectomy with cricohyoidoepiglottopexy. The cricoid and arytenoid cartilages and the airway were visualised using three-dimensional images. RESULTS: The mobility of the arytenoid cartilages was well preserved in the one patient with bilateral arytenoids, and in the other patient with only one arytenoid remaining. Two types of airway configuration were observed during phonation: one patient had a single stream airway, while the other had a combination of several streams. CONCLUSION: In the patient with only one arytenoid remaining, the preserved arytenoid tended to be rotated excessively inward. Therefore, phonation may have also occurred in various airways followed by mucosal vibration, which may be a sound source.

High-speed digital imaging laryngoscopy of the neoglottis following supracricoid laryngectomy with cricohyoidoepiglottopexy.

OBJECTIVES: This study aimed to analyse vocal performance and to investigate the nature of the neoglottal sound source in patients who had undergone supracricoid laryngectomy with cricohyoidoepiglottopexy, using a high-speed digital imaging system. METHODS: High-speed digital imaging analysis of neoglottal kinetics was performed in two patients who had undergone supracricoid laryngectomy with cricohyoidoepiglottopexy; laryngotopography, inverse filtering analysis and multiline kymography were also undertaken. RESULTS: In case one, laryngotopography demonstrated two vibrating areas: one matched with the primary (i.e. fundamental) frequency (75 Hz) and the other with the secondary frequency (150 Hz) at the neoglottis. In case two, laryngotopography showed two vibrating areas matched with the fundamental frequency (172 Hz) at the neoglottis. The interaction between the two areas was considered to be the sound source in both patients. The waveform of the estimated volume flow at the neoglottis, obtained by inverse filtering analysis, corresponded well to the neoglottal vibration patterns derived by multiline kymography. These findings indicated that the specific sites identified at the neoglottis by the present method were likely to be the sound source in each patient. CONCLUSIONS: High-speed digital imaging analysis is effective in locating the sites responsible for voice production in patients who have undergone supracricoid laryngectomy with cricohyoidoepiglottopexy. This is the first study to clearly identify the neoglottal sound source in such patients, using a high-speed digital imaging system.

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes.

AIM: Sulphonylureas (SUs) are often used as first-line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. METHODS: The efficacy and safety of the once-daily human glucagon-like peptide-1 (GLP-1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m(2); mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24-week, double-blind, parallel-group trial. RESULTS: The mean change in HBA1c from baseline to week 24 (LOCF) was -1.56 (s.d. 0.84) and -1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and -0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference -1.47 mmol/l and -1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: -0.37 kg), while mean body weight decreased in subjects receiving placebo (-1.12 kg). CONCLUSIONS: The addition of liraglutide to SU treatment for 24 weeks dose-dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.

Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice.

AIMS/HYPOTHESIS: Metformin, the major target of which is liver, is commonly used to treat type 2 diabetes. Although metformin activates AMP-activated protein kinase (AMPK) in hepatocytes, the mechanism of activation is still not well known. To investigate AMPK activation by metformin in liver, we examined the role of reactive nitrogen species (RNS) in suppression of hepatic gluconeogenesis. METHODS: To determine RNS, we performed fluorescence examination and immunocytochemical staining in mouse hepatocytes. Since metformin is a mild mitochondrial complex I inhibitor, we compared its effects on suppression of gluconeogenesis, AMPK activation and generation of the RNS peroxynitrite (ONOO(-)) with those of rotenone, a representative complex I inhibitor. To determine whether endogenous nitric oxide production is required for ONOO(-) generation and metformin action, we used mice lacking endothelial nitric oxide synthase (eNOS). RESULTS: Metformin and rotenone significantly decreased gluconeogenesis and increased phosphorylation of AMPK in wild-type mouse hepatocytes. However, unlike rotenone, metformin did not increase the AMP/ATP ratio. It did, however, increase ONOO(-) generation, whereas rotenone did not. Exposure of eNOS-deficient hepatocytes to metformin did not suppress gluconeogenesis, activate AMPK or increase ONOO(-) generation. Furthermore, metformin lowered fasting blood glucose levels in wild-type diabetic mice, but not in eNOS-deficient diabetic mice. CONCLUSIONS/INTERPRETATION: Activation of AMPK by metformin is dependent on ONOO(-). For metformin action in liver, intra-hepatocellular eNOS is required.

Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes.

OBJECTIVE: Liraglutide is a once-daily human glucagon-like peptide-1 (GLP-1) analogue developed for the treatment of type 2 diabetes mellitus (T2DM). In Phase 2 and Phase 3 trials, largely conducted in populations of European descent, liraglutide has been shown to lower HbA(1C), weight and systolic blood pressure with a low risk of hypoglycaemia. This Phase 3, 24-week, multi-centre, double-blind, double dummy, randomised parallel-group trial compared the efficacy and safety of liraglutide and glibenclamide monotherapy in Japanese subjects with T2DM, inadequately controlled with diet therapy or oral antidiabetic drug (OAD) monotherapy. RESEARCH DESIGN AND METHODS: A total of 411 Japanese subjects were randomised 2:1 to liraglutide (n = 272) or glibenclamide (n = 139). Liraglutide was administered at a maximum planned dose of 0.9 mg once daily. Glibenclamide was administered once or twice daily at a planned maximum dose of 2.5 mg/day, before or after meals. CLINICAL TRIAL REGISTRATION: NCT00393718. RESULTS: After 24 weeks, glycaemic control with liraglutide was non-inferior/superior to glibenclamide, with HbA(1C) at 24 weeks of 6.99% (SE +/- 0.07) with liraglutide and 7.50% (+/-0.09) with glibenclamide (difference, -0.5%; 95% CI -0.70 to 0.30; p < 0.0001). Mean fasting plasma glucose (FPG) levels at 24 weeks were significantly lower with liraglutide (7.6 mmol/l [SE +/- 0.1]) vs glibenclamide (8.3 mmol/l [+/-0.1]; difference, -0.72 mmol/l; 95% CI -1.0 to -0.4; p < 0.0001). Weight was reduced by -0.92 kg from a baseline of 65.2 kg in liraglutide-treated patients, compared with weight gain of +0.99 kg from a baseline of 64.8 kg with glibenclamide (difference, -1.91 kg; 95% CI -2.34 to -1.48; p < 0.0001). A significantly lower rate of minor hypoglycaemic episodes was achieved with liraglutide compared with glibenclamide (p < 0.0001), and no major hypoglycaemic episodes were reported in either treatment group. The most common gastrointestinal AEs were diarrhoea (liraglutide, 6.3%; glibenclamide, 3.8%) and constipation (liraglutide, 5.6%; glibenclamide, 3.8%). Nausea was infrequent (liraglutide, 4.5%; glibenclamide, 1.5%). CONCLUSIONS: Liraglutide monotherapy, administered once daily for 24 weeks in Japanese subjects with T2DM, was well tolerated. Compared with glibenclamide monotherapy, liraglutide achieved superior glycaemic control and weight outcome, and a significantly lower incidence of hypoglycaemia. Future studies, comprising a greater proportion of true therapy-naïve Japanese patients, will be beneficial in order to establish the true add-on efficacy of liraglutide monotherapy in patients with T2DM.

Exendin-4 protects pancreatic beta cells from the cytotoxic effect of rapamycin by inhibiting JNK and p38 phosphorylation.

It has been reported that the immunosuppressant rapamycin decreases the viability of pancreatic beta cells. In contrast, exendin-4, an analogue of glucagon-like peptide-1, has been found to inhibit beta cell death and to increase beta cell mass. We investigated the effects of exendin-4 on the cytotoxic effect of rapamycin in beta cells. Incubation with 10 nM rapamycin induced cell death in 12 h in murine beta cell line MIN6 cells and Wistar rat islets, but not when coincubated with 10 nM exendin-4. Rapamycin was found to increase phosphorylation of c-Jun amino-terminal kinase (JNK) and p38 in 30 minutes in MIN6 cells and Wistar rat islets while exendin-4 decreased their phosphorylation. Akt and extracellular signal-regulated kinase (ERK) were not involved in the cytoprotective effect of exendin-4. These results indicate that exendin-4 may exert its protective effect against rapamycin-induced cell death in pancreatic beta cells by inhibiting JNK and p38 signaling.

Niflumic acid-sensitive ion channels play an important role in the induction of glucose-stimulated insulin secretion by cyclic AMP in mice.

AIMS/HYPOTHESIS: We have previously reported that glucose-stimulated insulin secretion (GSIS) is induced by glucagon-like peptide-1 (GLP-1) in mice lacking ATP-sensitive K(+) (K(ATP)) channels (Kir6.2(-/-) mice [up-to-date symbol for Kir6.2 gene is Kcnj11]), in which glucose alone does not trigger insulin secretion. This study aimed to clarify the mechanism involved in the induction of GSIS by GLP-1. METHODS: Pancreas perfusion experiments were performed using wild-type (Kir6.2(+/+)) or Kir6.2(-/-) mice. Glucose concentrations were either changed abruptly from 2.8 to 16.7 mmol/l or increased stepwise (1.4 mmol/l per step) from 2.8 to 12.5 mmol/l. Electrophysiological experiments were performed using pancreatic beta cells isolated from Kir6.2(-/-) mice or clonal pancreatic beta cells (MIN6 cells) after pharmacologically inhibiting their K(ATP) channels with glibenclamide. RESULTS: The combination of cyclic AMP plus 16.7 mmol/l glucose evoked insulin secretion in Kir6.2(-/-) pancreases where glucose alone was ineffective as a secretagogue. The secretion was blocked by the application of niflumic acid. In K(ATP) channel-inactivated MIN6 cells, niflumic acid similarly inhibited the membrane depolarisation caused by cAMP plus glucose. Surprisingly, stepwise increases of glucose concentration triggered insulin secretion only in the presence of cAMP or GLP-1 in Kir6.2(+/+), as in Kir6.2(-/-) pancreases. CONCLUSIONS/INTERPRETATION: Niflumic acid-sensitive ion channels participate in the induction of GSIS by cyclic AMP in Kir6.2(-/-) beta cells. Cyclic AMP thus not only acts as a potentiator of insulin secretion, but appears to be permissive for GSIS via novel, niflumic acid-sensitive ion channels. This mechanism may be physiologically important for triggering insulin secretion when the plasma glucose concentration increases gradually rather than abruptly.

Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: A double-blind, randomized, controlled trial in Japanese patients with type 2 diabetes.

AIMS: To evaluate dose-response efficacy and safety of once-daily human GLP-1 analog liraglutide in Japanese subjects with type 2 diabetes. METHODS: Patients (226, treated with diet with/without OADs, mean HbA(1c) 8.30%, mean BMI 23.9kg/m(2)) were randomized after OAD discontinuation and washout to receive liraglutide 0.1, 0.3, 0.6 or 0.9mg once daily, or placebo in double-blind, parallel-group design for 14 weeks. RESULTS: Liraglutide dose levels reduced HbA(1c) versus placebo (by 0.79%, 1.22%, 1.64% and 1.85%, respectively; p<0.0001 for linear contrast). Liraglutide 0.9mg/day resulted in 75% of patients achieving HbA(1c) <7.0% and 57% achieving HbA(1c) <6.5%. There were no major or minor hypoglycemic events. Liraglutide also reduced, with significant dose-response (each p<0.0001 for linear contrast) versus placebo: fasting plasma glucose (up to 2.5mmol/L), postprandial (0-3h) glucose excursion (up to 12.8mmol/(Lh)); and increased postprandial insulin secretion (up to 23.0microU/(mLh)) and beta-cell function as evaluated by HOMA-beta (up to around 20.0(microU/mL)/(mg/dL)). Body weight was unchanged; no development of liraglutide antibodies was detected. CONCLUSIONS: Liraglutide was highly effective and well tolerated at doses up to 0.9mg/day in Japanese patients with type 2 diabetes, allowing glycemic control without weight gain or hypoglycemia.

Src activation generates reactive oxygen species and impairs metabolism-secretion coupling in diabetic Goto-Kakizaki and ouabain-treated rat pancreatic islets.

AIMS/HYPOTHESIS: Na(+)/K(+)-ATPase inhibition by ouabain suppresses ATP production by generating reactive oxygen species (ROS) and impairs glucose-induced insulin secretion from pancreatic islets. To clarify the signal-transducing function of Na(+)/K(+)-ATPase in decreasing ATP production by the generation of ROS in pancreatic islets, the involvement of Src was examined. In addition, the significance of Src activation in diabetic islets was examined. METHODS: Isolated islets from Wistar rats and diabetic Goto-Kakizaki (GK) rats (a model for diabetes) were used. ROS was measured by 5-(and 6)-chloromethyl-2',7'-dichlorofluorescein fluorescence using dispersed islet cells. After lysates were immunoprecipitated by anti-Src antibody, immunoblotting was performed. RESULTS: Ouabain caused a rapid Tyr(418) phosphorylation, indicating activation of Src in the presence of high glucose. The specific Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) restored the ouabain-induced decrease in ATP content and the increase in ROS production. Both PP2 and ROS scavenger restored the impaired insulin release and impaired ATP elevation in GK islets, but had no such effect in control islets. PP2 reduced the high glucose-induced increase in ROS generation in GK islet cells but had no effect on that in control islet cells. Moreover, ouabain had no effect on ATP content and ROS production in the presence of high glucose in GK islets. CONCLUSIONS/INTERPRETATION: These results indicate that Src plays a role in the signal-transducing function of Na(+)/K(+)-ATPase, in which ROS generation decreases ATP production in control islets. Moreover, ROS generated by Src activation plays an important role in impaired glucose-induced insulin secretion in GK islets, in which Src is endogenously activated independently of ouabain.