Feed characteristics of dried corn grain and corn grain silage produced in Japan compared with imported corn grain.

We compared the in situ dry matter degradability (ISDMD) and crude protein degradability (ISCPD) of high-moisture corn grain silage and dried corn grains produced in Japan (JHC and JDC, respectively) with corn grains imported from the United States (USC), Brazil (BRC), and South Africa (SAC). The ISDMD values of USC, BAC, and SAC were between those of JHC and JDC, but ISDMD did not differ significantly between USC and SAC. In contrast, ISDMD was lower for BAC than USC and SAC. Overall, our results indicate that ISDMD and ISCPD in the rumen differ between corn grains sources (domestic compared with imported and between production locations), primarily due to differences between the corn varieties represented. In particular, the ISDMD and ISCPD of JHC were greater than those of JDC, and this difference in degradability needs to be considered when using high-moisture corn grain silage as a substitute for dried corn grain as a feed for dairy cattle.

SGLT2 inhibitor versus carbohydrate-restricted isocaloric diet: reprogramming substrate oxidation in type 2 diabetes.

OBJECTIVE: Based on the whole-body energy metabolism and insulin action, the difference between increased excretion of carbohydrate in urine by SGLT2i and reduced same amount of oral carbohydrate intake are scarce. This study aimed to compare the effect of carbohydrate availability with reduced oral intake (carbohydrate-restricted isocaloric diet: CRIC diet) or lost in urine, as urinary glucosuria on sodium/glucose cotransporter-2 inhibitor (SGLT2i) treatment, focus on the insulin requirement and the macronutrient oxidation within insulin treated type 2 diabetes. METHODS: This is randomized 3-arm open-label prospective study. Subjects treated with titrated basal-bolus insulin regimen subsequent to three diet regimens, control diet (CON), administration of canagliflozin 100 mg/day to CON (SGLT2i), or CRIC diet, with a week admission to the endocrinology ward followed by 12 weeks outpatients' management. The main outcome measures including the total insulin dose (TID) required to achieve euglycemia, fasting and postprandial energy expenditure (EE) and respiratory quotient (RQ) at 1-week and 12-week. RESULTS: We enrolled 23 patients with type 2 diabetes (male/female: 14/9, age: 53.6 ± 14.2 years, body mass index: 26.9 ± 4.8 kg/m2, HbA1c: 12.5 ± 1.6%). The TID was similar with CON and SGLT2i at both 1 and 12-weeks. Although comparable net carbohydrate availability in SGLT2i and CRIC groups, the TID was significantly higher in the CRIC (p = 0.02) compare to the SGLT2i at both 1 and 12-weeks. Fasting EE was similar in all groups, postprandial EE was significantly elevated in the SGLT2i and CRIC groups compared to the CON group (p = 0.03 and 0.04). Compare to the CON, lower basal fasting RQ (p = 0.049) and decreased delta-RQ (postprandial RQ/fasting RQ) indicated continuous lipid substrate utilization in the SGLT2i (p = 0.04) and CRIC (p = 0.03) groups. CONCLUSION: The CRIC diet resulted in a similar fasting and postprandial EE and substrate oxidation compared to the SGLT2i. The increased insulin requirement in the CRIC diet indicates that a relatively highly lipid and protein consumption, compared to the SGLT2i and CON, may influence insulin requirement.

Quantitative evaluation of insulin-induced abdominal subcutaneous dystrophic tissue using shear wave elastography.

AIMS/INTRODUCTION: Subcutaneous dystrophic tissue (DT) produced by insulin injection causes dysglycemia owing to inadequate absorption of insulin. However, precise techniques for measuring DT have not been established. Shear wave elastography (SWE) is an imaging technology that can quantify tissue stiffness. In this study, insulin injection-induced DT was quantified using SWE to generate whole-abdominal wall subcutaneous tissue by three-dimensional (3D) imaging in patients with type 2 diabetes who were treated with multiple insulin injections. MATERIALS AND METHODS: Seven patients with type 2 diabetes were recruited who received long-standing multiple insulin injections. Using SWE, the shear wave velocity (SWV) of DT and control (normal subcutaneous tissue) was measured. Furthermore, two of seven patients underwent whole-abdominal SWE examination to calculate the proportion of DT. A subcutaneous insulin tolerance test was also performed in both the DT and control tissues. RESULTS: The SWV in DT was significantly higher than that in the control tissue (2.87 [2.66-2.98] vs 1.29 [1.23-1.44] m/s, P < 0.01). The proportion of the DT volume was 0.67% and 5.21% for two individuals from the entire abdominal subcutaneous tissue volume. The area under the curve for the subcutaneously injected insulin aspart concentration at the DT sites was lower than that of the control tissue (75.0 [52.1-111] vs 116 [86.9-152.5] h*mU/L, P = 0.1). CONCLUSIONS: SWE can be useful in quantifying abdominal subcutaneous insulin-induced DT, especially the 3D volume of insulin injection-induced DT from the entire abdominal subcutaneous tissue. This study is the first to examine the volume and distribution of abdominal subcutaneous DT using SWE.

Dipeptidyl peptidase-4 inhibitor improves glycemic variability in multiple daily insulin-treated type 2 diabetes: a prospective randomized-controlled trial.

AIMS: To improve glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) treatment in diabetes. To evaluate the GV improvement in MDI treated type 2 diabetes (T2D) with low-dose metformin 750 mg/day (LMET), which was popular in the clinical practice in Japan, we compared the effect of adding vildagliptin 100 mg/day (LMET + DPP4i treatment) or increased metformin dose to 1500 mg/day (HMET treatment), in the setting of continuous glucose monitoring (CGM) analysis. MATERIALS AND METHODS: Single-center, open-label, 12 weeks-two period cross-over design. Twenty T2D with inadequately controlled (7.0% < HbA1c ≤ 9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM indices, performed after each 12 week treatment periods. RESULTS: There was no significant difference in both LMET + DPP4i treatment and HMET treatment, in terms of HbA1c, body weight changes, and total daily dose of insulin to achieve the targeted glycemia. LMET + DPP4i treatment compared to HMET treatment, significantly reduced the calculated GV value, mean (7.15 ± 1.30 vs 7.82 ± 1.60, p = 0.04), standard deviation (1.78 ± 0.55 vs 2.27 ± 1.11, p = 0.03), continuous overlapping net glycemic action (6.44 ± 1.28 vs 7.12 ± 1.69, p < 0.05), J-Index (26.7 ± 11.0 vs 34.9 ± 19.8, p < 0.05), high blood glucose index (3.01 ± 1.96 vs 6.73 ± 4.85, p = 0.02), and mean amplitude of glycemic excursions (4.53 ± 1.35 vs 5.50 ± 2.34, p = 0.03). CONCLUSION: The GV metrics regarding daily and nocturnal hypoglycemia were not significantly different between LMET + DPP4i treatment and HMET treatment. LMET + DPP4i treatment decreased GV associated with hyperglycemia. Adding DPP-4-inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI compared to additional high-dose metformin. National Clinical Trial registration in Japan, number is JPRN-UMIN000024663. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00513-6.

Changes in subjective sleep quality in patients with type 2 diabetes who did not use Sleep agents: a cross-sectional study according to age and clinical background.

AIM: Diabetes and aging are both well-established risk factors for insomnia. Therefore, we investigated the changes in subjective sleep quality in relation to clinical backgrounds and age in patients with type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 380 participants with T2DM who were between 18 and 79 years of age from our outpatient clinics. Individuals with any symptoms and medical histories associated with obstructive sleep apnea (OSA) were excluded from the interview and analyses. Data were collected using self-administered questionnaires, namely the Pittsburgh Sleep Quality Index (PSQI) and the Morning-Evening Questionnaire (MEQ), as well as medical records and blood samples. We performed stratified analyses according to age decades. RESULTS: The number of patients in the age groups (in years) was as follows: < 50 (n = 69), 50-60 (n = 52), 60-70 (n = 138), and 70-80 (n = 121). PSQI score was highest in the < 50 group (4.99 ± 2.40), and significantly decreased with age (p < 0.05). Body mass index (BMI) was also highest in the < 50 group (25.5 ± 4.8 kg/m2), and markedly decreased with age (p < 0.01). Interestingly, BMI was significantly correlated with the PSQI score (rs = 0.157, p < 0.05). We also found that younger patients had shorter sleep duration, stronger daytime sleepiness, and a tendency for the evening type. CONCLUSION: Younger T2DM patients had poorer sleep quality and higher BMI. Our findings suggest that insomnia should be accounted for as a potential comorbidity when examining or treating patients with T2DM and obesity even in the younger population.

Pre-Existing Diabetes Limits Survival Rate After Immune Checkpoint Inhibitor Treatment for Advanced Lung Cancer: A Retrospective Study in Japan.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) are promising in the treatment of advanced cancer, their use is associated with immune-related adverse events (irAEs) that affect endocrine organ systems. Although development of irAEs was associated with improved cancer-specific survival, the risk of irAEs is unclear. We investigated the association of pre-ICI comorbidities-including diabetes-with irAEs, overall survival (OS), and progression-free survival (PFS) in advanced lung cancer. METHODS: Patients with lung cancer who were treated with ICIs during the period from September 1, 2015 through July 31, 2018 were retrospectively enrolled. All data were collected from the NEPTUNE database of university patients. Hazard ratios were estimated by using Cox regression weighted for propensity scores. Odds ratios were calculated by logistic regression and adjusted for unbalanced variables. The Kaplan-Meier method was used to compare OS, and the generalized Wilcoxon test was used to compare median survival. RESULTS: Among the 88 patients identified, 22 (25.0%) had diabetes (DM) before ICI treatment and 57 (75.0%) did not (non-DM); irAEs developed in 12.2% of patients with DM and in 9.1% of patients in non-DM (p=0.87). Diabetes status was not associated with irAE risk in relation to baseline characteristics (age, sex, TNM staging, thyroid and renal function) or in propensity score-matched analysis (age, TNM staging). During a mean follow-up of 30 months, OS and cancer-specific PFS were significantly higher in patients who developed irAEs (Kaplan-Meier estimates, p=0·04 and 0·03, respectively). In propensity score-matched analysis, diabetes was significantly associated with lower OS (multivariate hazard ratio, 0·36; 95% CI, 0·13-0·98) unrelated to irAEs. Irrespective of irAEs, PFS was also lower among patients with DM than among non-DM patients (Kaplan-Meier estimate, p=0·04). CONCLUSION: Pre-existing diabetes was associated with higher mortality in advanced lung cancer, regardless of irAE development during treatment with ICI.

Chronotherapeutic efficacy of suvorexant on sleep quality and metabolic parameters in patients with type 2 diabetes and insomnia.

AIMS: This study aimed to assess the chronotherapeutic efficacy of suvorexant on subjective sleep parameters and metabolic parameters in patients with type 2 diabetes and insomnia. METHODS: Thirteen patients with type 2 diabetes who met the Pittsburg Sleep Quality index criteria for primary insomnia took suvorexant 20 mg/day (15 mg/day for ≥65 years) for 14 ± 2 weeks. The following parameters were assessed before and after the treatment: sleep diary for sleep duration and quality (i.e., sleep onset latency, waking after sleep onset, and sleep efficiency [sSE]), Insomnia Severity Index, clinical and biochemical data, continuous glucose monitoring (CGM), and validated self-administered questionnaire on food intake. RESULTS: Suvorexant significantly improved sSE, abdominal circumference, and sucrose intake (all p < 0.05), but did not change HbA1c, CGM parameters, or body weight. Correlation analysis revealed that changes in sSE were associated with those in HbA1c and body weight (r = -0.61 and r = -0.66, respectively; both p < 0.05). CONCLUSIONS: Suvorexant significantly improved sleep quality and obesity-associated parameters in patients with type 2 diabetes in 14 weeks. Improvements in sleep quality were associated with improvements in glycemic control. Sleep disorder treatment using suvorexant may provide metabolic benefits for patients with type 2 diabetes.

Successful Treatment of Amiodarone-induced Thyrotoxicosis Type 1 in Combination with Methimazole and Potassium Iodide in a Patient with Hashimoto's Thyroiditis.

A patient with underlying Hashimoto's thyroiditis developed amiodarone-induced thyrotoxicosis type 1 that was successfully treated using methimazole in combination with potassium iodide. A 35-year-old woman admitted for perinatal care of twin-to-twin transfusion syndrome was given amiodarone for 7 days for paroxysmal ventricular contraction following pulseless ventricular tachycardia 1 day after delivery. She developed thyrotoxicosis one month after the discontinuation of amiodarone therapy and was negative for thyroid-stimulating hormone receptor antibody. An increased peak velocity of the superior thyroid artery suggested amiodarone-induced thyrotoxicosis type 1. Her thyroid function recovered after combination therapy with methimazole and potassium iodide.

Sustained fasting glucose oxidation and postprandial lipid oxidation associated with reduced insulin dose in type 2 diabetes with sodium-glucose cotransporter 2 inhibitor: A randomized, open-label, prospective study.

AIMS/INTRODUCTION: Hyperglycemia impairs energy substrate oxidation as a result of glucotoxicity. We examined whether the reduction of plasma glucose using a sodium-glucose cotransporter 2 inhibitor, in inpatient diabetes management, has any effect on: (i) treatment period and basal-bolus dosage of insulin that achieve euglycemia; (ii) fasting/postprandial energy expenditure (EE); and (iii) energy substrate oxidation. MATERIALS AND METHODS: This was a randomized, open-label, 7-day prospective study. Participants were type 2 diabetes patients with hyperglycemia, aged >20 years, with glycated hemoglobin >10%, daily mean preprandial blood glucose >11 mmol/L (200 mg/dL) and no previous antidiabetic medication. A total of 18 type 2 diabetes patients were randomized (1:1) to basal-bolus insulin titration algorithm (INS) alone or INS + dapagliflozin 5 mg/day (INS/DAPA). The main outcome measures were total daily insulin dose to achieve euglycemia, as well as EE and respiratory quotient during fasting and postprandial states, measured by indirect calorimetry. RESULTS: The rate of euglycemia was higher in the INS/DAPA compared with INS group (100 vs 55.6%, P = 0.04), whereas the total daily dose of insulin was 19% lower and was accompanied by a decreased basal-bolus ratio (P = 0.02). Fasting and postprandial EE elevation were similar in both groups. The post-treatment fasting respiratory quotient significantly increased in the INS/DAPA group (0.72 ± 0.05 vs 0.79 ± 0.08, P = 0.04), and the postprandial respiratory quotient elevation was abolished; the opposite trend was observed in the INS group (P < 0.02). CONCLUSIONS: INS/DAPA sustained fasting carbohydrate oxidation, postprandial lipid-derived EE (failed to increase carbohydrate-derived EE) and reduced basal insulin requirement might be related to further bodyweight loss. CLINICAL TRIAL REGISTRY: National University Hospital Medical Information Network UMIN000018997.

Efficacy of intermittent empagliflozin supplementation on dietary self-management and glycaemic control in patients with poorly controlled type 2 diabetes: A 24-week randomized controlled trial.

AIMS: To explore the effects of intermittent use of empagliflozin, a sodium-glucose co-transporter-2 inhibitor, on dietary self-management and glycaemic control in patients with inadequately controlled type 2 diabetes. MATERIALS AND METHODS: We conducted a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial of 50 patients with type 2 diabetes, treated with no more than three oral antidiabetic drugs (glycated haemoglobin [HbA1c] ≥52 mmol/mol but <86 mmol/mol). The participants were randomized to take 10 mg/d empagliflozin either every day (regular group, n = 25) or on the day on which they considered they had overeaten (intermittent group, n = 25) for 24 weeks. We limited empagliflozin prescription to half of the required period in the intermittent group. The primary endpoint was change in HbA1c at the end of the 24-week treatment period relative to baseline. The secondary outcomes included changes in body weight, daily energy intake and diabetes treatment-related quality of life (QoL). Energy intake was assessed using a diet-specific validated questionnaire rather than actual assessments of food intake. RESULTS: The intake rate of empagliflozin was 96.7 ± 7.2% for the regular group and 45.7 ± 7.0% for the intermittent group. Interestingly, ΔHbA1c was identical in the two groups (-0.64 ± 0.19% and - 0.65 ± 0.17%, respectively). Body weight decreased (-2.72 ± 0.52 and - 1.50 ± 0.45 kg, respectively) and diabetes treatment-related QoL increased significantly from baseline in both groups. Energy intake, however, decreased significantly only in the intermittent group (-221.0 ± 108.3 kcal/d). CONCLUSIONS: Intermittent empagliflozin supplementation is a useful therapeutic option that empowers dietary self-management, improves glycaemic control and is accompanied by body weight loss and an increase in diabetes treatment-related QoL in patients with inadequately controlled type 2 diabetes.

Up-Titration Strategy After DPP-4 Inhibitor-Based Oral Therapy for Type 2 Diabetes: A Randomized Controlled Trial Shifting to a Single-Dose GLP-1 Enhancer Versus Adding a Variable Basal Insulin Algorithm.

INTRODUCTION: It is unclear whether adding basal insulin or enhancing incretin signaling with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is more effective as an up-titration strategy after dipeptidyl peptidase-4 inhibitor (DPP-4i)-based oral antidiabetic drug (OAD) therapy. GLP-1RAs can be injected without dose adjustment, unlike basal insulin. Our objective was to examine the efficacy of changing patients inadequately controlled with oral DPP-4i-based OAD therapy to injectable GLP-1RA and discontinuing the DPP4i versus adding basal insulin glargine (IGlar) with the continuation of the oral DPP4i. METHODS: Sixty patients with type 2 diabetes (T2DM) and glycated hemoglobin (HbA1c) between 7.0% and 10.0% on DPP-4i-based OAD therapy were randomized to either adding IGlar and remaining on the DPP-4i or liraglutide and discontinuing the DPP-4i for 24 weeks. Patients in the IGlar group started with 0.1 unit/kg and were titrated according to the algorithm. In the liraglutide group, the DPP-4i was replaced with liraglutide 0.9 mg/day, the maximum dose in Japan. We evaluated HbA1c, glycated albumin (GA), and anthropometrics. RESULTS: HbA1c was significantly lower at week 24 (- 1.0 ± 0.9% in the IGlar group and - 0.6 ± 0.8% in the liraglutide group), but the difference between groups was not significant. Changes in GA were similar (- 2.9 ± 3.2% vs. - 2.6 ± 3.2%) in both groups. Body weight (BW) was significantly lower only in the liraglutide group (+ 0.5 ± 2.6 kg vs. - 2.2 ± 2.0 kg). The rate of minor hypoglycemic episodes was similar for both groups. CONCLUSION: For poorly controlled T2DM on DPP-4i-based OAD therapy, switching to single-dose liraglutide to enhance incretin signaling is as effective as dose-titrated basal IGlar, but significant BW reduction was only seen in the liraglutide group. These results suggest that enhancing incretin signaling with a single-dose injectable GLP-1 RA might be an alternative to dose-titrated basal insulin therapy in patients with T2DM poorly controlled with DPP-4i-based OAD therapy. These findings should be confirmed in a longer and larger trial. TRIAL REGISTRATION: Trial Registry (UMIN-CTR) as UMIN000012224.

Analgesic effects of ASP3662, a novel 11ß-hydroxysteroid dehydrogenase 1 inhibitor, in rat models of neuropathic and dysfunctional pain.

BACKGROUND AND PURPOSE: Glucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11ß-HSD1 inhibitor, on neuropathic and dysfunctional pain. EXPERIMENTAL APPROACH: The enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague-Dawley rats. KEY RESULTS: ASP3662 inhibited human, mouse and rat 11ß-HSD1 but not human 11ß-HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague-Dawley rats showed that ASP3662 has CNS-penetrability and long-lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine-induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant-induced arthritis rats. CONCLUSIONS AND IMPLICATIONS: ASP3662 is a potent, selective and CNS-penetrable inhibitor of 11ß-HSD1. The effects of ASP3662 suggest that selective inhibition of 11ß-HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.

Giant Cavernous Hemangioma of the Adrenal Gland in an Elderly Patient.

Cavernous hemangioma is a rare, non-functional, benign adrenal tumor. Adrenal cavernous hemangioma is often diagnosed after surgery with a histologic examination. A 70-year-old man complaining of appetite loss was admitted to our hospital. An incidental large left adrenal mass was found by computed tomography (CT). There were no clinical signs of adrenogenital syndrome, Cushing's syndrome or primary aldosteronism. Total resection was carried out. The pathological diagnosis was cavernous hemangioma. The differentiation of adrenal tumor is necessary in cases of large tumors, and resection is desirable given the risks of hemorrhaging and rupture.

Usefulness of urinary biomarkers for nephrotoxicity in cynomolgus monkeys treated with gentamicin, cisplatin, and puromycin aminonucleoside.

The objective of this study was to investigate the availability of novel urinary biomarkers (BMs) such as total protein, albumin, ß2-microglobulin, clusterin, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL) for the detection of acute nephrotoxicity in cynomolgus monkeys. Animals (total 9 males/3 groups) were administered gentamicin (GM) subcutaneously at 40 mg/kg for 7 days, cisplatin (CDDP) intravenously at 3 mg/kg once and puromycin aminonucleoside (PAN) intravenously at 20 mg/kg for 7 days. Two-hr urine on Days 0, 3, and 6, and 16-hr urine and blood on Days 1, 4, and 7 were collected. Novel urinary BMs and conventional clinical pathology parameters were evaluated in parallel to histopathological and electron microscopic examinations on the kidneys at termination. Urinary BMs and enzymes increased earlier than serum creatinine and blood urea nitrogen, particularly in 2-hr urine after dosing on Day 0, urinary albumin was increased in all groups and urinary NGAL with the highest magnitude of change rate among urinary BMs was observed in the GM and CDDP groups. Degeneration/necrosis and hyaline droplet of renal tubule, cellular cast and dilatation of renal tubule, and hypertrophy of podocytes were observed in the GEN, CDDP, and PAN groups, respectively. These results showed that the increases of urinary BMs reflected the agent-specific renal damages and these urinary BMs could be useful for the detection of segment-specific nephrotoxicity. Urinary albumin and NGAL are the most useful BMs to estimate glomerular and distal tubular damages, respectively, as well as proximal tubular damage in cynomolgus monkeys.

Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study.

BACKGROUND: Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM. METHODS: DEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, n = 80) were enrolled and randomized to receive either 1500 mg/day metformin (the metformin group, n = 40), or 750 mg/day metformin supplemented with 5 mg/day dapagliflozin (the dapagliflozin group, n = 40), for 16 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation. RESULTS: Although FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P < 0.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2'-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16 weeks (P < 0.001). CONCLUSIONS: Dapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754).

Acute suppurative thyroiditis in infected thyroid cyst in an adult patient under hemodialysis.

Acute suppurative thyroiditis (AST) accompanied by an abscess is a rare clinical case. Hemodialysis patients are at risk for infections. Sepsis mortality was from 100 to 300 times higher for chronic dialysis patients than that for the general public. Thus, special care should be taken against infection in patients under hemodialysis.

Glycemic Variability in Type 1 Diabetes Compared with Degludec and Glargine on the Morning Injection: An Open-label Randomized Controlled Trial.

INTRODUCTION: Optimal adjustment of basal insulin to overcome hypoglycemia and glycemic variability (GV) depends on its duration of action and peak-less profile. Owing to the ability of long-acting basal insulin to avoid hypoglycemia, we titrated pre-meal glucose to normal fasting blood glucose, 80-110 mg/dL (4.5-6.1 mmol/L), and post-meal glucose to 80-140 mg/dL (4.5-7.8 mmol/L). The purpose of this study was to evaluate two basal insulin analogues degludec (IDeg) and glargine (IGlar), injected in the morning, for GV using continuous glucose monitoring (CGM) in type 1 diabetes (T1DM). METHODS: In this crossover study, 20 Japanese patients with T1DM (age 54 ± 16 years, disease duration 16 ± 8 years, BMI 24 ± 4 kg/m2, HbA1c 7.4 ± 0.8%) were randomized into one of two different starting regimens, and CGM was conducted on three consecutive days during the last week of each 12-week titration period. Treatment satisfaction was assessed at the end of each treatment period using the Diabetes Therapy-Related Quality of Life Questionnaire (DTR-QOL). RESULTS: There were no differences in HbA1c, total insulin dosage, body weight changes, and basal to bolus ratio between the IDeg and IGlar arms. The day-to-day variability in fasting interstitial GV on the CGM curves was significantly less in the IDeg than IGlar treatment period (25.9 ± 22.0 vs. 43.8 ± 30.1 mg/dl, p = 0.04). Other markers of GV, calculated by the EasyGV software, including mean amplitude of glycemic excursions (MAGE), J-index, total and nocturnal hypoglycemia were not different between the two treatment periods. The score of "satisfaction with treatment", a subdomain of the DTR-QOL system, was higher in the IDeg period. CONCLUSION: Thus, the morning injection of the two long-acting insulin analogues seemed similar with regard to the magnitude of hypoglycemia in T1DM, but treatment with IDeg was associated with lower day-to-day variation in glucose level. These results suggest that IDeg is safe with minimal morning GV in patients with T1DM. CLINICAL TRIAL REGISTRATION: Japanese Clinical Trials Registry, UMIN000012358.

Predictive factors of late biochemical recurrence after radical prostatectomy.

OBJECTIVE: To assess the characteristics of biochemical recurrence in the late period (>5 years after radical prostatectomy) and the differences in the predictors of biochemical recurrence in different periods, we conducted a multicenter retrospective study. METHODS: We reviewed 478 men who underwent radical prostatectomy for clinically localized prostate cancer. All of the patients were followed up for at least 5 years. The cohort was then divided into three groups; no recurrence group, recurrence <5 years after surgery group and recurrence ≥5 years after surgery group. The background characteristics of each group were compared using the χ2 test. A Cox multivariate regression analysis was performed to determine the predictors of biochemical recurrence in each period. RESULTS: Biochemical recurrence occurred in 135 men. In 113 (84%) of the patients, biochemical recurrence occurred at <5 years after surgery; in 22 (16%), it occurred at ≥5 years after surgery. The proportion of men with a low preoperative prostate-specific antigen level was significantly larger in the latter group (P = 0.0023). A preoperative prostate-specific antigen level and a positive surgical margin were significant predictors of biochemical recurrence at <5 years after surgery (hazard ratio: 1.03 and 3.20). A positive surgical margin was also a significant predictor of biochemical recurrence at ≥5 years after surgery (hazard ratio: 3.03); however, a high preoperative prostate-specific antigen level was not. CONCLUSIONS: Biochemical recurrence occurred at ≥5 years after surgery in 16% of the patients. A positive surgical margin predicted biochemical recurrence in both the early and late periods.

Linagliptin improves endothelial function in patients with type 2 diabetes: A randomized study of linagliptin effectiveness on endothelial function.

AIMS/INTRODUCTION: The present multicenter, prospective, controlled, open and randomized three-arm parallel study was designed to compare the effects of linagliptin with those of metformin on endothelial function. MATERIALS AND METHODS: Type 2 diabetes patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0% and <8.0%, n = 96) were randomized to continue metformin 750 mg/day (control group, n = 29), metformin at 1,500 mg/day (metformin group, n = 26) and metformin 750 mg/day supplemented with linagliptin 5 mg/day (linagliptin add-on group, n = 29) and treated for 16 weeks. Vascular endothelial function was evaluated by flow-mediated dilation. The primary end-point was changes in flow-mediated dilation at 16 weeks relative to baseline. RESULTS: Linagliptin significantly improved flow-mediated dilation from baseline (4.9 ± 2.7%) to 16 weeks (6.3 ± 2.7%, P < 0.05), whereas the other groups did not show any changes. Hemoglobin A1c at 16 weeks was significantly lower in the metformin and linagliptin add-on groups compared with the control (6.6 ± 0.6%, 6.5 ± 0.5% and 7.0 ± 0.6%, respectively). Single and multiple regression analyses showed that apolipoprotein B correlated significantly with change in flow-mediated dilation, and apolipoprotein B was decreased only in the linagliptin add-on group (-6.0 ± 11.3 mg/dL, P < 0.01). CONCLUSIONS: Linagliptin for 16 weeks improved endothelial function with a modest improvement in glycemic control. This effect was mediated, at least in part, by reduction in apolipoprotein B. Linagliptin has a protective role on endothelial function in patients with type 2 diabetes with moderate hyperglycemia.

Characteristics of hepatic insulin-sensitive nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high-HIS, mid-HIS, low-HIS), as assessed by the hyperinsulinemic-euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high-HIS group was identical to that of the non-NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low-HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high-HIS and low-HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis-aconitic acid, were significantly higher in the high-HIS group compared to the low-HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin-sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634-647).