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To describe glucose-lowering treatment regimens and glycated haemoglobin (HbA1c) trajectories in individuals with type 2 diabetes (T2D) over 36 months of follow-up from the start of second-line therapy.This data analysis from the 3-year, observational DISCOVER study programme included 14 687 participants from 37 countries with T2D initiating second-line glucose-lowering therapy. Treatment and HbA1c data were collected at baseline (start of second-line therapy) and at 6, 12, 24 and 36 months. Treatment regimen changes over follow-up were analysed using the McNemar test, with carry-forward imputation for intermediate missing values.A total of 11 592 participants had treatment data at baseline and 36 months, and 11 882 had HbA1c data at baseline. At baseline and 36 months, respectively, rates of oral monotherapy use were 12.1% and 12.4% (P = 0.22), rates of dual oral therapy use were 63.4% and 47.6% (P 0.0001), rates of ≥ triple oral therapy use were 17.5% and 25.4% (P 0.0001), and rates of injectable treatment use were 7.0% and 13.7% (P 0.0001). Use of injectable drugs was most common among participants with an HbA1c level ≥64 mmol/mol (≥8.0%). Overall, 42.9% of participants changed treatment during follow-up. Mean HbA1c levels at baseline and 6 months were 67 mmol/mol (8.3%) and 55 mmol/mol (7.2%), respectively, remaining stable thereafter.Dual oral therapy was the most common treatment regimen at the start of second-line treatment, and over half of the participants remained on the same treatment during follow-up.

Sarcopenia is a major cause of disability in the elderly. Although type 2 diabetes is a risk factor for increased sarcopenia, the relationship between prediabetes and sarcopenia has not been elucidated. We aimed to examine the relationship between sarcopenia and prediabetes.The design of this study is a cross-sectional study. We evaluated glucose metabolism using the 75-g oral glucose tolerance test and glycated haemoglobin, appendicular skeletal muscle mass, and hand grip strength in 1629 older adults living in an urban area of Tokyo, Japan. We investigated the frequency of sarcopenia in participants with normal glucose tolerance (NGT), prediabetes and diabetes. A multivariable logistic regression model was used to analyse the association between glucose tolerance and the prevalence of sarcopenia.The mean age of participants was 73.1 ± 5.4 years. In men, 44.3% had NGT, 26.6% had prediabetes, and 29.1% had diabetes. In women, the distribution was 56.1%, 28.8% and 15.2%. The prevalence of sarcopenia was 12.7% in men and 11.9% in women. Logistic regression revealed that prediabetes and diabetes are independent risk factors for sarcopenia in men (prediabetes, odds ratio [OR] = 2.081 [95% confidence interval {CI}: 1.031-4.199]; diabetes, OR = 2.614 [95% CI: 1.362-5.018]) and diabetes, but not prediabetes, is an independent risk factor for sarcopenia in women (prediabetes, OR = 1.036 [95% CI: 0.611-1.757]; diabetes, OR = 2.099 [95% CI: 1.146-3.844]). In both sexes, higher age (men, OR = 1.086 [95% CI: 1.028-1.146]; women, OR = 1.195 [95% CI: 1.142-1.251]), higher body fat percentage (men, OR = 1.346 [95% CI: 1.240-1.461]; women, OR = 1.218 [95% CI: 1.138-1.303]) and lower body mass index (men, OR = 0.371 [95% CI: 0.299-0.461]; women, OR = 0.498 [95% CI: 0.419-0.593]) were independent risk factors for sarcopenia.Although we confirmed that diabetes mellitus is associated with sarcopenia in both sexes, prediabetes is associated with sarcopenia in men, but not in women.

We sought to describe global patterns in achievement of risk factor control for primary prevention in patients with T2D and explore the association of country's GNI/capita with risk factor control.The DISCOVER study is a prospective, observational study of patients with T2D from 38 countries enrolled at initiation of second-line glucose-lowering therapy. We examined achievement of risk factor control (glycosylated hemoglobin7%, blood pressure140/90 mmHg, prescription of a statin) at 3 years among those without optimal control at baseline. Countries were stratified by gross national income (GNI)/capita, from 2017). We examined the impact of country GNI/capita with achievement of risk factor control.Our cohort included 9613 patients with T2D and without baseline cardiovascular disease (mean age 57.2 ± 8.7 years, 47.9% women). At baseline, 6354/7646 patients (83.1%) had suboptimal glucose control, 3449/9200 patients (37.5%) had suboptimal BP control, and 2800/4221 patients (66.7%) were not on an appropriate statin (sample sizes differed due to missing covariate data). Optimal control at 3 years of follow-up was achieved in 41% (glucose), 56% (blood pressure), and 29% (statins) of patients. There was significant variability in achievement of risk factor control across countries but no association between country GNI/capita with achievement of risk factor control (p 0.08 for all).In a global, prospective study of patients with T2D, we found that cardiovascular risk factor control achievement was suboptimal despite 3 years of follow-up in specialized health care systems. Neither country-level nor patient-level socioeconomic factors fully explained this finding.

Insights from epidemiological, clinical and basic research are illuminating the interplay between metabolic disorders, cardiovascular disease (CVD) and kidney dysfunction, termed cardio-renal-metabolic (CRM) disease. Broadly defined, CRM disease involves multidirectional interactions between metabolic diseases such as type 2 diabetes (T2D), various types of CVD and chronic kidney disease (CKD). T2D confers increased risk for heart failure, which-although well known-has only recently come into focus for treatment, and may differ by ethnicity, whereas atherosclerotic heart disease is a well-established complication of T2D. Many people with T2D also have CKD, with a higher risk in Asians than their Western counterparts. Furthermore, CVD increases the risk of CKD and vice versa, with heart failure, notably, present in approximately half of CKD patients. Molecular mechanisms involved in CRM disease include hyperglycaemia, insulin resistance, hyperactivity of the renin-angiotensin-aldosterone system, production of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, calcium-handling abnormalities, mitochondrial malfunction and deficient energy production, and chronic inflammation. Pathophysiological manifestations of these processes include diabetic cardiomyopathy, vascular endothelial dysfunction, cardiac and renal fibrosis, glomerular hyperfiltration, renal hypoperfusion and venous congestion, reduced exercise tolerance leading to metabolic dysfunction, and calcification of atherosclerotic plaque. Importantly, recognition of the interaction between CRM diseases would enable a more holistic approach to CRM care, rather than isolated treatment of individual conditions, which may improve patient outcomes. Finally, aspects of CRM diseases may differ between Western and East Asian countries such as Japan, a super-ageing country, with potential differences in epidemiology, complications and prognosis that represent an important avenue for future research.

Background Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients. Methods This randomized, double-blind, placebo-controlled multicentre phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR ≥15.0– Results The mean age of the 1013 patients is 65.9 years, 21.5% are female, the mean eGFR is 37.84 ml/min/1.73 m2 and the median UACR is 351.80 mg/g. Conclusions Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of eGFR (≥15.0–

Context J-DISCOVER is a prospective observational cohort study aiming to understand the current management of patients with early-stage type 2 diabetes mellitus (T2DM) in Japan, enrolling patients initiating second-line treatment. Objective The current analysis examined the change in treatment satisfaction during the study period and factors affecting this change among patients in J-DISCOVER. Methods We used data from the J-DISCOVER study, in which 1798 patients with T2DM aged ≥ 20 years were enrolled from 142 sites across Japan. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Results The mean DTSQ treatment satisfaction score increased from 25.9 points at baseline to 27.3 points at 6 months, which was maintained through 36 months. Among the baseline characteristics examined, higher baseline DTSQ treatment satisfaction scores (P Conclusion Changes in DTSQ treatment satisfaction scores were related to HbA1c improvement, suggesting that the management strategy was appropriately planned for each patient. The results also suggest that the availability of social support for patients with T2DM who are elderly or living alone may be an important factor affecting treatment satisfaction, adherence, and clinical outcomes.

Autophagy is known to play an essential role in intracellular quality control through the degradation of damaged organelles and components. We previously demonstrated that β-cell-specific autophagy deficient mice, which lack Atg7, exhibited impaired glucose tolerance, accompanied by the accumulation of sequestosome 1/p62 (hereafter referred to as p62). Whereas p62 has been reported to play essential roles in regulating cellular homeostasis in the liver and adipose tissue, we previously showed that β-cell-specific p62 deficiency does not cause any apparent impairment in glucose metabolism. In the present study, we investigated the roles of p62 in β cells under autophagy-deficient conditions, by simultaneously inactivating both Atg7 and p62 in a β-cell specific manner. Whereas p62 accumulation was substantially reduced in the islets of Atg7 and p62 double-deficient mice, glucose tolerance and insulin secretion were comparable to Atg7 single-deficient mice. Taken together, these findings suggest that the p62 accumulation appears to have little effect on β-cell function under conditions of autophagy inhibition.

Autophagy is known to play a pivotal role in β-cell function. While the lifelong inhibition of autophagy through Atg7 deletion in β cells has been demonstrated to lead to impaired glucose tolerance together with β-cell dysfunction, the temporal association between autophagy inhibition and β-cell dysfunction remains unclear. To address such questions, inducible β-cell-specific Atg7-knockout (iβAtg7

Metal homeostasis is tightly regulated in cells and organisms, and its disturbance is frequently observed in some diseases such as neurodegenerative diseases and metabolic disorders. Previous studies suggest that zinc and iron are necessary for the normal functions of pancreatic β cells. However, the distribution of elements in normal conditions and the pathophysiological significance of dysregulated elements in the islet in diabetic conditions have remained unclear. In this study, to investigate the dynamics of elements in the pancreatic islets of a diabetic mouse model expressing human islet amyloid polypeptide (hIAPP): hIAPP transgenic (hIAPP-Tg) mice, we performed imaging analysis of elements using synchrotron scanning X-ray fluorescence microscopy and quantitative analysis of elements using inductively coupled plasma mass spectrometry. We found that in the islets, zinc significantly decreased in the early stage of diabetes, while iron gradually decreased concurrently with the increase in blood glucose levels of hIAPP-Tg mice. Notably, when zinc and/or iron were decreased in the islets of hIAPP-Tg mice, dysregulation of glucose-stimulated mitochondrial respiration was observed. Our findings may contribute to clarifying the roles of zinc and iron in islet functions under pathophysiological diabetic conditions.

Chronic inflammation caused by gut dysbiosis is associated with the pathophysiology of metabolic disease. Synbiotics are useful for ameliorating gut dysbiosis; however, it remains unclear what types of bacteria act as key markers for synbiotic-driven improvement of chronic inflammation. Here, we performed a post hoc analysis of a 24-week randomized controlled study using synbiotics to investigate the association between gut microbiota and inflammatory markers. We characterized the responders who showed lower interleukin-6 (IL-6) levels in response to synbiotic supplementation among 86 obese patients with type 2 diabetes mellitus. In our baseline analysis, the relative abundances of

The volumes of intracranial tissues of 40 healthy volunteers acquired from 0.3- and 3-T scanners were compared using intraclass correlation coefficients, correlation analyses, and Bland-Altman analyses. We found high intraclass correlation coefficients, high Pearson's correlation coefficients, and low percentage biases in all tissues and most of the brain regions, although small differences were observed in some areas. These findings may support the validity of brain volumetry with low-field magnetic resonance imaging.

Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization (HCI) to mice with normal or high-fat diet (HFD) and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. Although 2-wk HFD alone did not alter intramyocellular diacylglycerol (IMDG) accumulation, HCI alone increased it by 1.9-fold and HCI after HFD further increased it by 3.3-fold. Parallel to this, we found increased protein kinase C ε (PKCε) activity, reduced insulin-induced 2-deoxyglucose (2-DOG) uptake, and reduced phosphorylation of insulin receptor β (IRβ) and Akt, key molecules for insulin signaling pathway. Lipin1, which converts phosphatidic acid to diacylglycerol, showed increase of its activity by HCI, and dominant-negative lipin1 expression in muscle prevented HCI-induced IMDG accumulation and impaired insulin-induced 2-DOG uptake. Furthermore, 24-h leg cast immobilization in human increased lipin1 expression. Thus, even short-term immobilization increases IMDG and impairs insulin sensitivity in muscle via enhanced lipin1 activity.

The main molecular mechanism underlying acute suppression of iodine organification in normal thyroids after an excessive iodine load, i.e., the Wolff-Chaikoff effect, is assumed to be suppression of iodine oxidation and iodothyronine synthesis. However, the mechanism underlying chronic anti-thyroid action of inorganic iodine in Graves' disease is not fully understood. Using a mouse model of Graves' hyperthyroidism, we examined changes in iodothyronine content and gene expression profiles in the thyroid glands after inorganic iodine loading.Graves' hyperthyroidism was induced and maintained in BALB/c mice by repeated immunizations of recombinant adenovirus expressing the human TSH receptor A-subunit. Hyperthyroid mice were left untreated (GD-C; n=8) or treated with inorganic iodine for 12 weeks (GD-NaI; n=8). We used unimmunized BALB/c mice as a control group (n=10). In each mouse, serum T4 levels were measured with ELISA at 4-week intervals. The intrathyroidal iodothyronine content and gene expression levels were respectively evaluated by mass spectrometry and RNA sequencing (RNA-seq) at the end of the experimental period.Serum T4 levels in the GD-C group remained higher than the control group, whereas those in the GD-NaI group declined to normal levels during the experimental period. Intrathyroidal T3, reverse (r) T3 and T4 contents in the GD-C group were higher than the control group, and rT3 and T4 were further increased in the GD-NaI group. The observed alterations in iodothyronine levels in the thyroid and sera may be explained by altered expression levels of genes for iodothyronine biosynthetic molecules, their transporter and deiodinases.In this mouse model of hyperthyroidism, higher intrathyroidal accumulation of T4 and reduced gene expression data of iodothyronine transporters in the GD-NaI group suggest that chronic anti-thyroid action of iodine in Graves' disease involves suppression of hormone secretion.

As diabetes results from the absolute or relative deficiency of insulin secretion from pancreatic β cells, possible methods to efficiently generate surrogate β cells have attracted a lot of efforts. To date, insulin-producing cells have been generated from various differentiated cell types in the pancreas, such as acinar cells and α cells, by inducing defined transcription factors, such as PDX1 and MAFA, yet it is still challenging as to how surrogate β cells can be efficiently generated for establishing future regenerative therapies for diabetes. In this study, we demonstrated that the exogenous expression of PDX1 activated STAT3 in α cells in vitro, and STAT3-null PDX1-expressing α cells in vivo resulted in efficient induction of α-to-β reprogramming, accompanied by the emergence of α-cell-derived insulin-producing cells with silenced glucagon expression. Whereas β-cell ablation by alloxan administration significantly increased the number of α-cell-derived insulin-producing cells by PDX1, STAT3 suppression resulted in no further increase in β-cell neogenesis after β-cell ablation. Thus, STAT3 modulation and β-cell ablation nonadditively enhance α-to-β reprogramming induced by PDX1, which may lead to the establishment of cell therapies for curing diabetes.

Obesity and aging reduce muscle mass and leads to deficits in muscle maintenance, but it is unknown whether obesity additively accelerates muscle wasting in the setting of aging. The present study investigated morphological characteristics in fast-twitch dominant muscle of mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 mo. The fast-twitch extensor digitorum longus muscle was isolated, and the composition of muscle fiber type, individual muscle cross-sectional area (CSA), and myotube diameter were measured. Increased the percentage of type IIa myosin heavy chain (MHC) fibers, whereas decreased type IIB MHC in both HFD protocols. The CSA and myofiber diameter were lower in both 20 mo LFD and HFD fed mice compared to 4 mo mice, but there were no differences between 20-mo LFD and HFD-fed mice. These data suggest that long term of HFD feeding does not aggravated muscle wasting in fast-twitch dominant muscle of aged mice.

Introduction Treatment-related quality of life (QOL) is an important aspect of diabetes management. We evaluated the influence of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, on treatment-related QOL in Japanese patients with type 2 diabetes mellitus (T2DM). Methods This is the prespecified subanalysis study of the “Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)” trial. Treatment-related QOL was evaluated at baseline, week 26, week 52, and week 104 after the initiation of the study using the Diabetes Therapy-Related QOL questionnaire (DTR-QOL). Among the 340 patients in the original UTOPIA study, a total of 252 patients (127, tofogliflozin group; 125, conventional treatment group) who completed the DTR-QOL questionnaire at baseline were the study subjects of the current subanalysis. Results The tofogliflozin and conventional treatment groups exhibited almost comparable baseline clinical characteristics, while the use of antihypertensive drugs and lipid-lowering agents was significantly lower in the tofogliflozin treatment group than in the conventional treatment group. Tofogliflozin treatment increased the total score of DTR-QOL7 from baseline (P

AIMS Glycaemic control is a cornerstone of type 2 diabetes (T2D) management. We assessed factors associated with good long-term glycaemic control in patients with glycated haemoglobin (HbA1c) ≥7.0% at initiation of second-line glucose-lowering therapy, using data from DISCOVER, a global, prospective, 3-year observational study of patients with T2D. MATERIALS AND METHODS This analysis included patients with HbA1c ≥7.0% at baseline (initiation of second-line therapy). Multivariable regression models assessed factors associated with having HbA1c

Background: Estimating the nutritional content of food is essential for self-management in people with type 2 diabetes mellitus, but it is a difficult skill to learn. The aim of this study was to investigate how diabetes management was impacted by the ability of patients to search for items they ate from a database of 26,300 different foods, and to visualize nutritional intake using the Japanese mobile application (app) "Calomeal." Methods: This was a single-arm, single-center, pilot study. Eighteen outpatients with type 2 diabetes mellitus used the "Calomeal" app for 3 months. The primary endpoint was change in hemoglobin A1c (HbA1c). Secondary endpoints were changes in body weight (BW), lipid parameters, and quality of life scores. Results: The baseline characteristics of the study subjects were as follows: age: 53.4 ± 7.8 years; male/female ratio: 11/7; HbA1c: 7.9 (7.58 - 8.23)%; and body mass index (BMI): 25.17 (21.63 - 28.59) kg/m 2 . Significant reductions in HbA1c and BMI were observed over 3 months (HbA1c: 7.9 (7.58 - 8.23)% to 7.6 (7.3 - 8.23)%, P = 0.0410; BMI: 25.17 (21.63 - 28.59) to 24.54 (21.57 - 27.81) kg/m 2 , P = 0.0057). Reductions in HbA1c and BMI both correlated with decreased carbohydrate intake estimated by the mobile app. Conclusions: Japanese patients who used their smartphones to visualize their nutritional intake using the "Calomeal" app demonstrated improved short-term glycemic control and BMI. Although the validity of the results should be tested in future randomized controlled trials, this approach may be a clinical option for improving self-management in Japanese patients with type 2 diabetes mellitus. J Clin Med Res. 2021;13(8):425-433 doi: https://doi.org/10.14740/jocmr4558

Dietary habits are associated with various diseases and assessed by dietary patterns (DPs). Since the

We reported that full-length width of medial tibial osteophyte composed of cartilage and bone parts is directly correlated with medial meniscus extrusion (MME) in early-stage knee osteoarthritis (OA). However, no data are available for MME prevalence and its relationship to osteophyte in elderlies. 1,191 elderlies (females 57%; 72.9 years old on average) in the Bunkyo Health Study underwent standing plain radiograph and proton density-weighted MRI on knee joints. MRI-detected OA changes were evaluated according to the Whole Organ Magnetic Resonance Imaging Score. A new method to assess cartilage and bone parts of osteophyte was developed by pseudo-coloring images of proton density-weighted fat-suppressed MRI. Most of the subjects showed the Kellgren-Lawrence grade 1 or 2 of radiographic medial knee OA (88.1%), MME (98.7%, 3.90 ± 2.01 mm) and medial tibial osteophyte (99.3%, 3.27 ± 1.50 mm). Among the OA changes, MME was most closely associated with full-length width of medial tibial osteophyte (β = 1.114; 95%CI, 1.069–1.159; p

Type 2 diabetes mellitus (T2DM) is characterized by reduced exercise tolerance due to increased fatigability in skeletal muscle. In this study, we investigated muscle fatigue resistance of soleus (SOL) muscle in obese type 2 diabetic model mice (db/db). No differences in muscle volume, absolute force, or specific force in SOL muscle were observed between db/db mice and control mice (db/+), while fatigue resistance evaluated by repeated tetanic contractions was significantly lower in db/db mice (30th tetani, db/+: 63.7 ± 4.7%, db/db: 51.3 ± 4.8%). The protein abundance related to Ca

Introduction This study aimed to investigate the relationships between timing of the first physician visit after detection of an abnormal glycated hemoglobin (HbA1c) value at routine annual check and the time to antidiabetic treatment prescription; and understand treatment patterns in patients newly diagnosed with type 2 diabetes mellitus (T2DM). Methods This retrospective, longitudinal, observational cohort study examined data from JMDC Inc., an administrative claims database. Patients with HbA1c value of at least 6.5% at routine annual check, aged 20 years or older, and prescribed at least one antidiabetic drug were included. This cohort was classified into early physician visit and delayed physician visit groups based on the timing of the first physician visit relative to the median. Patients were monitored from the date of first HbA1c checkup of at least 6.5% to the date of first physician visit with an HbA1c test, and from the date of the first physician visit to the date of prescription of first-line and second-line T2DM treatments. The time to first prescription of antidiabetic treatment for the two groups was then compared. Results Of 4798 eligible patients, 54.8% were prescribed first-line T2DM therapy less than 2 months from the first physician visit for T2DM diagnosis. A lower percentage of the early group compared with the delayed group required T2DM pharmacological therapy in less than 2 months (46.1% vs. 63.4%). The early group had a longer median time to prescription of first-line therapy [92 days vs. 15 days, p

AIMS: Using data from DISCOVER, a 3-year, prospective, global observational study of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we sought to explore the effects of second-line dual combinations therapies plus metformin on body weight, glycated haemoglobin (HbA1c ), health-related quality of life, and risks of hypoglycaemia and further treatment intensification. MATERIALS AND METHODS: Adjusted changes from baseline in weight, HbA1c , and 36-item Short Form Health Survey version 2 (SF-36v2) summary scores at 6, 12, 24, and 36 months were assessed using linear mixed models. Risk of hypoglycaemia and further intensification were assessed using interval censored analyses. RESULTS: At baseline, 7613 patients received metformin in combination with a sulphonylurea (SU; 40.9%), a dipeptidyl peptidase-4 (DPP-4) inhibitor (48.3%), a sodium-glucose co-transporter 2 (SGLT-2) inhibitor (8.3%), or a glucagon-like peptide-1 (GLP-1) receptor agonist (2.4%). After 36 months, all combinations showed similar reductions in HbA1c (0.8-|1.0%), however, metformin plus a DPP-4 inhibitor, an SGLT-2 inhibitor, or a GLP-1 receptor agonist were associated with greater weight loss (1.9, 2.9, and 5.0 kg, respectively) than metformin plus an SU (1.3 kg, P < 0.0001). Proportions of further treatment intensification were similar across combinations (19.9-26.2%). Patients prescribed metformin plus an SU more often reported one or more hypoglycaemic events (11.9%) than other combinations (3.9-|6.4%, P < 0.0001). SF-36v2 summary scores were typically lowest among patients prescribed metformin and an SU. CONCLUSIONS: Combinations of metformin with an SU were associated with the lowest weight reduction, highest risk of hypoglycaemia, and lower SF-36v2 scores. This article is protected by copyright. All rights reserved.

Context Adipose tissue dysfunction is characterized by decreased adiponectin (AN) levels and impaired adipose tissue insulin sensitivity (ATIS) and is associated with metabolic disorders. While Asians readily develop metabolic disease without obesity, it remains unclear how decreased AN level and impaired ATIS affect metabolic abnormalities in nonobese Asians. Design and Setting To investigate the relationships between decreased AN level, impaired ATIS, and metabolic abnormalities, we studied 94 Japanese men whose body mass index was less than 25 kg/m2. We divided the subjects into 4 groups based on their median AN level and ATIS, the latter calculated as the degree of insulin-mediated suppression of free fatty acids during hyperinsulinemic euglycemic clamp, and compared the metabolic parameters in the 4 groups. Results The High-ATIS/High-AN group (n = 29) showed similar anthropometric data to the High-ATIS/Low-AN group (n = 18). In contrast, both the Low-ATIS/High-AN (n = 18) and Low-ATIS/Low-AN (n = 29) groups showed significantly lower muscle insulin sensitivity than the High-ATIS groups. The intrahepatic lipid level in the Low-ATIS/Low-AN group was significantly higher than that in the High-ATIS groups. In addition, the Low-ATIS/Low-AN group had a significantly higher fasting serum triglyceride level and significantly lower high-density lipoprotein cholesterol level than the other 3 groups. Conclusions In nonobese Japanese men with high ATIS, the AN level was not associated with metabolic characteristics. On the other hand, subjects with low ATIS showed reduced muscle insulin sensitivity, and those with a decreased AN level demonstrated multiple metabolic abnormalities, represented by fatty liver and dyslipidemia.

Aim To investigate whether changes in endogenous glucose production (EGP) and insulin and glucagon levels are elicited by the decrease in plasma glucose (PG) levels induced by the sodium-glucose co-transporter-2 (SGLT2) inhibitor tofogliflozin. Materials and methods We evaluated EGP in 12 Japanese patients with type 2 diabetes under the conditions of no drugs administered (CON), single administration of the SGLT2 inhibitor tofogliflozin (TOF), and single administration of TOF with adjustment of PG levels with exogenous glucose infusion to mimic changes in PG levels observed with CON (TOF + G). We evaluated changes in EGP and levels of C-peptide and glucagon from baseline to 180 minutes after drug administration. Results Endogenous glucose production decreased in the CON (-0.22 ± 0.11 mg/kg·min) and TOF + G experiments (-0.31 ± 0.24 mg/kg·min), but not in the TOF experiment (+0.08 ± 0.19 mg/kg·min). The decrease in C-peptide was significantly greater in the TOF experiment (-0.11 ± 0.06 nmol/L) than in the CON (-0.03 ± 0.06 nmol/L) and the TOF + G experiments (-0.01 ± 0.11 nmol/L), while the increase in glucagon was significantly greater in the TOF experiment (+11.1 ± 6.3 pmol/L), but not in the TOF + G experiment (+8.6 ± 7.6 pmol/L) compared to the CON experiment (+5.1 ± 4.3 pmol/L). Conclusions These results indicate that the decrease in PG levels induced by SGLT2 inhibitor administration is required for the increase in EGP and decrease in insulin secretion.

Male patients with acromegaly frequently have hypogonadism. However, whether excess GH affects gonadal function remains unclear. We retrospectively compared clinical features affecting total testosterone (TT) and free testosterone (FT) levels between 112 male patients with acromegaly and 100 male patients with non-functioning pituitary adenoma (NFPA) without hyperprolactinemia. Median maximum tumor diameter (14.4 vs. 26.5 mm) and suprasellar extension rate (33 vs. 100%) were lower in acromegaly, but LH, FSH, TT, and FT were not significantly different. In acromegaly, TT was less than 300 ng/dL in 57%, and FT was below the age-specific reference range in 77%. TT and FT were negatively correlated with GH, IGF-1, and the tumor size, and positively correlated with LH. In NFPA, they were positively correlated with IGF-1, LH, FSH, ACTH, cortisol, and free T4, reflecting hypopituitarism. Multiple regression analysis showed that TT and FT had the strongest correlation with GH in acromegaly, and with LH in NFPA. Surgical remission was achieved in 87.5% of 56 follow-up patients with acromegaly. TT and FT increased in 80.4 and 87.5%, respectively, with a significant increase in LH. In acromegaly, the degree of postoperative increase in TT(FT) correlated with the fold increase of TT(FT)/LH ratio, a potential parameter of LH responsiveness, but not with fold increase of LH, whereas in NFPA it correlated with both. These results suggest that excessive GH is the most relevant factor for hypogonadism in male acromegaly, and may cause impaired LH responsiveness as well as the suppression of LH secretion.

Background Subclinical diastolic dysfunction in patients with type 1 diabetes mellitus (T1DM) caused by myocardial injury due to diabetic cardiomyopathy leads to a high risk of death and heart failure. This myocardial injury extends not only to the left ventricle (LV) but also to the left atrium (LA). However, LA function in children and young adults with T1DM has not been extensively studied. Objective Therefore, the aim of this study was to assess LA dysfunction in pediatric and adult patients with T1DM usingLA strain analysis withechocardiography. Subjects Fifty-three patients (median age: 23 [range: 5-41] years) with T1DM. Methods We dividedthe patients into three age groups (D1: 5-14 years, D2: 15-24 years, D3: 25-41 years);53 age- and sex-matched controls were divided into three corresponding groups (C1, C2, and C3). LA and LV functions were evaluated usingechocardiography. Results LA reservoir strain was lower in the D2 and D3 groups than in the C2 and C3 groups (p = 0.001, p = 0.004, respectively). LA conduit strain was lower in the D2 group thanin the C2 group (p = 0.002). LA stiffness wassignificantlygreater in the D3 groupthan in the C3 group (p Conclusions In patients with T1DM, LA phasic function decreased in adolescents and young adults, and LA stiffness increased in adult patients aged>30 years. LA phasic function and LA stiffness can be potentially used as early markers for diastolic dysfunction. This article is protected by copyright. All rights reserved.

Aims/Introduction As a low‐carbohydrate diet and the use of sodium–glucose transporter‐2 inhibitors are both known to increase D‐beta‐hydroxybutyrate levels, the effect of these levels on glucose metabolism has attracted attention. We investigated the acute effects of ketone monoester (KM) ingestion on blood glucose levels during the 75‐g oral glucose tolerance test (OGTT) in participants with impaired glucose tolerance. Materials and Methods Nine Japanese adults aged 48–62 years (4 men, 5 women) with impaired glucose tolerance participated in this study. After participants fasted overnight, we carried out OGTT for 180 min with and without KM ingestion on two separate days in a randomized cross‐over design. We compared the area under the curve (AUC) of D‐beta‐hydroxybutyrate, glucose, insulin, C‐peptide, glucagon and free fatty acids during OGTT. Results The AUC of D‐beta‐hydroxybutyrate during OGTT was significantly higher with KM than without KM (KM 5995.3 ± 1257.1 mmol/L·h; without KM 116.1 ± 33.9 mmol/L·h, P, Ketone monoester lowers glucose level during the oral glucose tolerance test in individuals with impaired glucose tolerance. This improvement was associated with decreased insulin clearance and elevated early phase insulin level.

AIMS To explore the impact of baseline characteristics on clinical outcomes in the phase 3 LixiLan JP trials which evaluated the efficacy and safety of iGlarLixi, a titratable fixed-ratio combination of insulin glargine 100 units/mL (iGlar) and GLP-1 RA lixisenatide (Lixi), vs Lixi (JP-O1, NCT02749890) or iGlar (LixiLan JP-O2, NCT02752828; JP-L, NCT02752412) in Japanese people with type 2 diabetes uncontrolled on oral antidiabetes drugs (OADs; JP-O1, JP-O2) or OADs and basal insulin (JP-L). MATERIALS AND METHODS Glycated haemoglobin (HbA1c) change from baseline to week 26 was assessed within patient subgroups. Subgroups were defined by dipeptidyl peptidase-4 inhibitor use at screening (JP-O1, JP-O2 only), baseline HbA1c (

Supplemental digital content is available in the text., Objectives Quantitative synthetic magnetic resonance imaging (MRI) enables the determination of fundamental tissue properties, namely, T1 and T2 relaxation times and proton density (PD), in a single scan. Myelin estimation and brain segmentation based on these quantitative values can also be performed automatically. This study aimed to reveal the changes in tissue characteristics and volumes of the brain according to age and provide age-specific reference values obtained by quantitative synthetic MRI. Materials and Methods This was a prospective study of healthy subjects with no history of brain diseases scanned with a multidynamic multiecho sequence for simultaneous measurement of relaxometry of T1, T2, and PD. We performed myelin estimation and brain volumetry based on these values. We performed volume-of-interest analysis on both gray matter (GM) and white matter (WM) regions for T1, T2, PD, and myelin volume fraction maps. Tissue volumes were calculated in the whole brain, producing brain parenchymal volume, GM volume, WM volume, and myelin volume. These volumes were normalized by intracranial volume to a brain parenchymal fraction, GM fraction, WM fraction, and myelin fraction (MyF). We examined the changes in the mean regional quantitative values and segmented tissue volumes according to age. Results We analyzed data of 114 adults (53 men and 61 women; median age, 66.5 years; range, 21–86 years). T1, T2, and PD values showed quadratic changes according to age and stayed stable or decreased until around 60 years of age and increased thereafter. Myelin volume fraction showed a reversed trend. Brain parenchymal fraction and GM fraction decreased throughout all ages. The approximation curves showed that WM fraction and MyF gradually increased until around the 40s to 50s and decreased thereafter. A significant decline in MyF was first noted in the 60s age group (Tukey test, P < 0.001). Conclusions Our study showed changes according to age in tissue characteristic values and brain volumes using quantitative synthetic MRI. The reference values for age demonstrated in this study may be useful to discriminate brain disorders from healthy brains.

Obesity is a health problem worldwide, and brown adipose tissue (BAT) is important for energy expenditure. Here, we explored the role of leukotriene A4 hydrolase (LTA4 H), a key enzyme in the synthesis of the lipid mediator leukotriene B4 (LTB4 ), in diet-induced obesity. LTA4 H-deficient (LTA4 H-KO) mice fed a high-fat diet (HFD) showed a lean phenotype, and bone-marrow transplantation studies revealed that LTA4 H-deficiency in non-hematopoietic cells was responsible for this lean phenotype. LTA4 H-KO mice exhibited greater energy expenditure, but similar food intake and fecal energy loss. LTA4 H-KO BAT showed higher expression of thermogenesis-related genes. In addition, the plasma thyroid-stimulating hormone and thyroid hormone concentrations, as well as HFD-induced catecholamine secretion, were higher in LTA4 H-KO mice. In contrast, LTB4 receptor (BLT1)-deficient mice did not show a lean phenotype, implying that the phenotype of LTA4 H-KO mice is independent of the LTB4 /BLT1 axis. These results indicate that LTA4 H mediates the diet-induced obesity by reducing catecholamine and thyroid hormone secretion.

Introduction Reduced muscle strength is a high risk factor for type 2 diabetes mellitus, and this association is especially strong in non-obese male individuals. However, it remains unclear how reduced muscle strength affects susceptibility to diabetes. We have examined whether lower limb muscle strength is associated with insulin resistance in non-obese Japanese male subjects. Methods Measurements from 64 non-diabetic, non-obese, middle-aged Japanese men were analyzed. Insulin sensitivity in muscle was measured using the hyperinsulinemic-euglycemic clamp. Isometric muscle strength of the knee extensor and flexor muscles was evaluated using a dynameter. Results Lower muscle strength of knee flexors, but not knee extensors, was associated with impaired muscle insulin sensitivity (knee flexor muscles: low, medium, and high strength was 6.6 ± 2.2, 7.3 ± 2.0, and 8.8 ± 2.2 mg/kg per minute, respectively, p for trend

Triglyceride (TG) is a tri-ester composed of a glycerol and 3 fatty acids. Degradation of TG in adipose tissue is increased in the fasting state but inhibited in the postprandial state. Although insulin suppresses adipose TG degradation, patients with insulin resistance have high concentrations of insulin and free glycerol (FG) in the fasting state.We examined whether the fasting FG concentration reflects visceral obesity and insulin sensitivity in middle-aged Japanese men.We measured the fasting serum FG concentration in 72 males aged 30 to 50 years using a simple enzymatic method. The subjects were divided into tertiles according to their homeostasis model assessment of insulin resistance (HOMA-IR). Besides routine glucose- and lipid-related parameters, we determined insulin sensitivity as the rate of glucose disappearance in a 2-step hyperinsulinemic-euglycemic clamp and the abdominal visceral fat area (VFA) by magnetic resonance imaging.The highest HOMA-IR tertile group had a higher fasting FG concentration than the middle- and lowest-tertile groups (0.077 ± 0.024 vs 0.063 ± 0.017 and 0.061 ± 0.016 mmol/L, P .05 and P .01). The FG concentration was positively correlated with VFA (rs = 0.36; P .01) and the HOMA-IR score (rs = 0.26, P .05) but negatively correlated with insulin sensitivity (rs = -0.26, P .05). Multivariate regression analysis revealed that the FG concentration is independently associated with VFA and insulin sensitivity.The fasting FG concentration reflects VFA and insulin sensitivity in middle-aged Japanese men. The fasting FG concentration may be a potential surrogate marker of visceral obesity and insulin resistance in outpatients.

Introduction We evaluated the cost-effectiveness of linagliptin in Japan by estimating the lifetime outcome based on clinical event rates from the Asian subpopulation of the CARMELINA trial. In CARMELINA, linagliptin added to standard of care (SoC) versus SoC demonstrated noninferiority with regard to risk of composite cardiovascular (CV) outcome in patients with type 2 diabetes at high risk of CV and kidney events. Issues resulting from conducting a cost-effectiveness analysis using data from a clinical noninferiority study were also investigated. Methods A microsimulation model was used to evaluate linagliptin/SoC versus SoC in terms of direct costs and quality-adjusted life years (QALYs) from a Japanese public healthcare payer’s perspective. Cost data were obtained from recent Japanese publications. The time horizon was defined as lifetime, and the discount rate for costs and effectiveness was 2% per year. One-way and probabilistic sensitivity analyses were performed. Results In the base case analysis, and taking medical history into account, the incremental effectiveness of linagliptin/SoC versus SoC was 1.34 QALYs, and the incremental cost for linagliptin was − 545,319 yen. In the one-way sensitivity analysis, the parameter which most affected the results was the hazard ratio for renal failure of linagliptin/SoC compared with SoC. The probabilistic sensitivity analysis showed that the probability of reduced costs and increased effectiveness (dominant) was 48%. Assuming an incremental cost-effectiveness ratio (ICER) threshold of 5 million yen, the probability that the ICER was below the threshold was 89% for linagliptin/SoC compared with SoC. Conclusions This evaluation, using Asian subpopulation data from the CARMELINA trial, suggested that the cost-effectiveness of linagliptin for a lifetime outcome was favourable in Japan. However, the results must be interpreted cautiously because of the noninferiority trial data source, which might cause ICER variations for each parameter. Electronic Supplementary Material The online version of this article (10.1007/s13300-020-00852-8) contains supplementary material, which is available to authorized users.

Aims/Introduction In Japan, an insulin pump with predictive low‐glucose management (PLGM) was launched in 2018. It automatically suspends insulin delivery when the sensor detects or predicts low glucose values. The aim of this study was to analyze the safety and efficacy of PLGM in patients treated in a Japanese center. Materials and Methods We carried out a retrospective observational analysis of 16 patients with type 1 diabetes mellitus and one patient after pancreatectomy. They switched from the MiniMed 620G device to the 640G device with PLGM. The primary outcome was the change in the percentage of time in hypoglycemia. The secondary outcome was the change in HbA1c (%) over a period of 3 months. We also explored the presence of “post‐suspend hyperglycemia” with the 640G device. Results After changing to the 640G device, the percentage of time in hypoglycemia (glucose 180 mg/dL) significantly increased from 25.53% (15.78–44.14%) to 32.9% (24.71–45.49%; P = 0.0373). HbA1c significantly increased from 7.6 ± 1.0% to 7.8 ± 1.1% (P = 0.0161). From 1.5 to 4.5 h after the resumption of insulin delivery, the percentage of time in hyperglycemia was 32.23% (24.2–53.75%), but it was significantly lower, 2.78% (0–21.6%), when patients manually restarted the pump within 30 min compared with automatic resumption 31.2% (20–61.66%; P = 0.0063). Conclusions Predictive low‐glucose management is an effective tool for reducing hypoglycemia, but possibly elicits “post‐suspend hyperglycemia.” This information is useful for achieving better blood glucose control in the patients treated with PLGM., An insulin pump with predictive low‐glucose management was launched in 2018 in Japan. It automatically suspends insulin delivery when the sensor detects or predicts low glucose values. Predictive low‐glucose management is an effective tool for reducing hypoglycemia, but possibly elicits “post‐suspend hyperglycemia.”

Obesity and aging reduce skeletal muscle contractile function. However, it remains unclear whether obesity additively promotes muscle contractile dysfunction in the setting of aging. In this study, we investigated skeletal muscle contractile function ex vivo and intracellular Ca(2+) release in male C57BL/6J mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 mo. Tetanic force production in the extensor digitorum longus muscle was decreased by aging or HFD feeding, and the further reduction was observed in aged HFD mice. The 20-mo HFD-fed mice, not the 20-mo LFD-fed mice or 4-mo HFD-fed mice, showed reduced intracellular Ca(2+) peak levels by high concentration of caffeine (25 mM) compared with 4-mo LFD mice. Aging and HFD feeding additively increased intramyocellular lipid (IMCL) levels and were associated with the degree of impaired muscle contractile force and peak Ca(2+) level. These data suggest that impairment in the contractile force in aged muscle is aggravated by HFD, which may be due, at least in part, to dysfunction in intracellular Ca(2+) release. The IMCL level may be a marker for impaired muscle contractile force caused by aging and HFD. NEW & NOTEWORTHY The aim of this study was to examine the effect of high-fat diet (HFD)-induced obesity on contractile function and Ca(2+) release capacity in aged skeletal muscle. Not only were the force production and peak Ca(2+) levels decreased by aging and HFD feeding, respectively, but also, these interventions had an additive effect in aged HFD-fed mice. These data suggest that the impairment in the contractile force in aged muscle is aggravated by a HFD, which may be due to synergistic dysfunction in intracellular Ca(2+) release.