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ABSTRACT Aims/Introduction PIONEER REAL Japan was a non‐interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice. Materials and Methods Adults naïve to injectable glucose‐lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34–44 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study; the co‐primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged

ABSTRACT Aims/Introduction Sodium–glucose cotransporter 2 (SGLT2) inhibitors effectively and safely reduce fasting and postprandial hyperglycemia while promoting weight loss. However, their unique mechanism of action contributes to concerns regarding their safety. We therefore carried out a large‐scale, non‐commercial, investigator‐initiated study on the safety and effectiveness of the SGLT2 inhibitor tofogliflozin. Materials and Methods This multicenter, open‐label, uncontrolled, prospective observational study was carried out at hospitals and clinics across Japan in participants aged ≥20 years who were SGLT2 inhibitor‐naïve and had an established diagnosis of type 2 diabetes. The primary endpoint was adverse drug reactions (ADRs) of special interest. Secondary endpoints included all other ADRs and adverse events, glycated hemoglobin (HbA1c), and weight loss. Results The study, carried out from June 2014 through February 2020, enrolled 11,480 participants from 1,103 medical institutions; 6,967 participants completed the 104‐week follow up. The most common ADRs of special interest were urinary and genital tract infections (1.53%), followed by volume depletion (1.25%). Hypoglycemia occurred in 27 participants (0.24%), adverse events in 1,054 (9.18%) and ADRs in 645 (5.62%). HbA1c decreased by 0.85% (95% confidence interval 0.82%–0.88%) and bodyweight decreased by 3.05 kg (95% confidence interval 2.94–3.17 kg). The HbA1c target was achieved by 51.70% of participants for target HbA1c

ABSTRACT Aims/Introduction PIONEER REAL Japan was a non‐interventional, multicenter, prospective study investigating oral semaglutide in adults with type 2 diabetes in routine clinical practice. We report baseline characteristics of participants enrolled in this study. Materials and Methods Adults aged ≥20 years with type 2 diabetes but no previous treatment with injectable glucose‐lowering medication were enrolled. Participants initiated oral semaglutide at their treating physician's discretion and were followed for 34–44 weeks. Participants were stratified into

Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by 18F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989–8.482; ΔPAC: OR, 2.344; 95% CI, 1.149–4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694–6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk. Registration Number in UMIN-CTR is UMIN000032525.

Sodium‐glucose cotransporter 2 inhibitors (SGLT2is) have been shown in cardiovascular outcome trials to reduce the risk of heart failure and major adverse cardiovascular as well as renal events in individuals with type 2 diabetes. Moreover, clinical evidence indicates that SGLT2i use reduces heart failure and chronic kidney disease (CKD) in east Asian patients with type 2 diabetes. Thus, SGLT2is might seem to be the preferred treatment for older patients with type 2 diabetes even in the presence of multiple comorbidities. However, older patients with type 2 diabetes may well have impaired physiological function, making the risk of certain adverse events higher than that in the general population. While a randomized clinical trial has been conducted to evaluate changes in skeletal muscle mass and function as well as those in cognitive function with SGLT2i use in older Japanese individuals with type 2 diabetes who are otherwise healthy, the safety of SGLT2is remains to be established among older individuals with type 2 diabetes also having impaired activity of daily living and/or cognitive impairment. Even so, international and domestic consensus reports recommend SGLT2is for patients with type 2 diabetes and heart failure, CKD, and/or cardiovascular diseases, and SGLT2is are being widely prescribed by general practitioners to older individuals with type 2 diabetes with little regard to the patient's comorbidities. We maintain that SGLT2i use in older patients with type 2 diabetes should be prescribed cautiously in consideration of the pathophysiology of the disease and the presence of complications and comorbidities as well as the individual's lifestyle.

Abstract Background Intramuscular adipose tissue (IMAT) formation derived from muscle fibro‐adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice. Methods Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross‐sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)‐knockout (Gipr−/−) and wild‐type (Gipr+/+) mice. FAPs isolated from lower limb muscles of 12‐week‐old Gipr+/+ mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr−/− mice and GIP receptor antagonist‐treated Gipr+/+ mice after glycerol injection into the TA muscles. Results Body composition analysis revealed that 104‐week‐old Gipr−/− mice had a greater proportion of lean tissue mass (73.7 ± 1.2% vs. 66.5 ± 2.7%, P

ABSTRACT Aims/Introduction Polypharmacy in diabetes patients is related to worse clinical outcomes. The aim of this study was to evaluate the usefulness of our countermeasure for polypharmacy, which combines a pharmacist check followed by a multidisciplinary team review in diabetic patients with polypharmacy. Methods A single‐center, retrospective observational study was conducted at Gifu University Hospital. Study participants included diabetic patients taking six or more drugs on admission to the diabetes ward between July 2021 and June 2022. Drugs which were discontinued by the present countermeasure were examined, and the number of drugs being taken by each patient was compared between admission and discharge. Results 102 of 308 patients were taking six or more drugs on admission. The drugs being taken by these patients were evaluated by pharmacists using a checklist for polypharmacy. Eighty‐four drugs which were evaluated as inappropriate or potentially inappropriate medications by pharmacists were discontinued following the multidisciplinary team review. The median and mean number of drugs taken by the 102 patients significantly decreased from 9.0 (IQR: 8–12) and 9.26 ± 2.64 on admission to 9.0 (IQR: 6–10) and 8.42 ± 2.95 on discharge (P = 0.0002). We followed up with these patients after discontinuation of the drugs and confirmed that their clinical status had not deteriorated. Conclusion The present countermeasure for polypharmacy, which combines a pharmacist check based on a checklist for evaluating polypharmacy followed by a multidisciplinary team review, was useful for reducing the number of inappropriate or potentially inappropriate medications taken by diabetes patients with polypharmacy.

ABSTRACT Aims/Introduction Glucagon is secreted from pancreatic α‐cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show hyper‐amino acidemia and α‐cell hyperplasia, indicating that glucagon contributes to feedback regulation between the liver and the α‐cells. In addition, both insulin and various amino acids, including branched‐chain amino acids and alanine, participate in protein synthesis in skeletal muscle. However, the effect of hyperaminoacidemia on skeletal muscle has not been investigated. In the present study, we examined the effect of blockade of glucagon action on skeletal muscle using mice deficient in proglucagon‐derived peptides (GCGKO mice). Materials and Methods Muscles isolated from GCGKO and control mice were analyzed for their morphology, gene expression and metabolites. Results GCGKO mice showed muscle fiber hypertrophy, and a decreased ratio of type IIA and an increased ratio of type IIB fibers in the tibialis anterior. The expression levels of myosin heavy chain (Myh) 7, 2, 1 and myoglobin messenger ribonucleic acid were significantly lower in GCGKO mice than those in control mice in the tibialis anterior. GCGKO mice showed a significantly higher concentration of arginine, asparagine, serine and threonine in the quadriceps femoris muscles, and also alanine, aspartic acid, cysteine, glutamine, glycine and lysine, as well as four amino acids in gastrocnemius muscles. Conclusions These results show that hyperaminoacidemia induced by blockade of glucagon action in mice increases skeletal muscle weight and stimulates slow‐to‐fast transition in type II fibers of skeletal muscle, mimicking the phenotype of a high‐protein diet.

Abstract Background Studies that have reported lower risk for cardiovascular outcomes in users of Sodium–Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). Methods and results Adults initiating empagliflozin and DPP-4i in 2014–2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64–0.86), CVM (HR 0.55; 95% CI 0.38–0.80), HHF or CVM (HR 0.57; 95% CI 0.48–0.67) and stroke (HR 0.79; 95% CI 0.67–0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. Conclusion These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

Abstract Background Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. Case presentation Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. Conclusions Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia.

Abstract The objective of this study was to provide recommendations regarding effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins (glargine U‐300, degludec U‐100, glargine U‐100, detemir, and insulin protamine Hagedorn) in insulin‐naïve adult patients with type 2 diabetes in the Asia‐Pacific region. Based on evidence from a systematic review, we developed an Asia‐Pacific clinical practice guideline through comprehensive internal review and external review processes. We set up and used clinical thresholds of trivial, small, moderate, and large effects for different critical and important outcomes in the overall certainty of evidence assessment and balancing the magnitude of intervention effects when making recommendations, following GRADE methods (Grading of Recommendations, Assessment, Development, and Evaluation). The AGREE (Appraisal of Guidelines, Research and Evaluation) and RIGHT (Reporting Items for practice Guidelines in HealThcare) guideline reporting checklists were complied with. After the second‐round vote by the working group members, all the recommendations and qualifying statements reached over 75% agreement rates. Among 44 contacted external reviewers, we received 33 clinicians' and one patient's comments. The overall response rate was 77%. To solve the four research questions, we made two strong recommendations, six conditional recommendations, and two qualifying statements. Although the intended users of this guideline focused on clinicians in the Asia‐Pacific region, the eligible evidence was based on recent English publications. We believe that the recommendations and the clinical thresholds set up in the guideline can be references for clinicians who take care of patients with type 2 diabetes worldwide.

ABSTRACT Aims/Introduction We aimed to clarify the effectiveness of the Diabetic Nephropathy Aggravation Prevention Program in Japan by comparing the diabetes‐related medical visit behavior of individuals under the municipal national health insurance according to insurers' effort levels. Materials and Methods We assessed changes in medical visit behavior according to insurers' effort levels, “Full Efforts,” “Some Efforts” and “No Effort,” using longitudinal data from the National Database of Health Insurance Claims and Specific Health Checkups before 2015 and after 2018 regarding the national health insurance programs in Japan. We analyzed the effect of the Diabetic Nephropathy Aggravation Prevention Program using a generalized linear mixed model for 208,388 participants with diabetes. Results The additive effect on medical visit behavior was significantly higher for insurers with “Full Efforts” than for those with “No Effort;” the coefficient (log odds ratio) was 0.159 (95% confidence interval 0.063–0.256). The additive effects on medical visit behavior sizes for the people with hemoglobin A1c ≥7.0%, positive urinary protein and systolic blood pressure ≥140 mmHg were 0.508, 0.402 and 0.232, respectively, which were larger than the overall effect size (0.159) for insurers with “Full Efforts.” Conclusions Our findings showed that insurer efforts had an additive effect on the increase in the number of medical visits, suggesting that this national program could reduce the number of end‐stage renal failures or dialysis in Japan.

Abstract Aims To investigate the effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins in insulin‐naïve patients with type 2 diabetes mellitus. Methods MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched from January 2000 to February 2022. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines were followed and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was adopted. The registration ID is CRD42022319078 in PROSPERO. Results Among 11 163 citations retrieved, 35 publications met the planned criteria. From meta‐analyses and network meta‐analyses, we found that when injecting basal insulin regimens at bedtime, the optimal choice in order of most to least effective might be glargine U‐300 or degludec U‐100, glargine U‐100 or detemir, followed by neutral protamine hagedorn (NPH). Injecting glargine U‐100 in the morning may be more effective (ie, more patients archiving glycated hemoglobin

Abstract Aims/Introduction The EMPA‐REG OUTCOME® trial demonstrated benefits of empagliflozin, a sodium‐glucose cotransporter‐2 inhibitor (SGLT2i), on cardiovascular, renal outcomes and all‐cause mortality in patients with type 2 diabetes and established cardiovascular disease. The EMPRISE study program evaluates how these effects translate in a broad population of patients with type 2 diabetes in routine clinical care across countries. Materials and Methods The study included patients ≥18 years with type 2 diabetes initiating empagliflozin or any dipeptidyl peptidase‐4 inhibitors (DPP‐4i) from large administrative databases in Japan, South Korea, and Taiwan. Propensity score‐matched (1:1) ‘as‐treated’ analyses comparing the risk of cardiovascular outcomes and all‐cause mortality between empagliflozin and DPP‐4i use were performed in each country. Pooled hazard ratios (pHR) with 95% confidence intervals (CI) were computed using random effects meta‐analysis models comparing both empagliflozin and SGLT2i with DPP‐4i use, respectively. Intention‐to‐treat and subgroup analyses in patients with/without cardiovascular disease and in patients receiving 10 mg empagliflozin were performed. Results The study included 28,712 and 70,233 matched patient pairs for empagliflozin/DPP‐4i and SGLT2i/DPP‐4i analyses, respectively. The risk of composite outcomes including (i) hospitalization for heart failure (HHF) and all‐cause mortality was lower with empagliflozin (pHR 0.76, 95% CI 0.67–0.86) and SGLT2i (0.71, 0.65–0.77); (ii) combined myocardial infarction, stroke, and all‐cause mortality was also lower with empagliflozin (0.74, 0.61–0.88) and SGLT2i (0.69, 0.60–0.78) compared to DPP‐4i. The intention‐to‐treat and three subgroup analyses were consistent with results of the main analyses. Conclusions The results suggest that both empagliflozin and SGLT2i compared with DPP‐4i are associated with a lower risk of cardiovascular events and all‐cause mortality in routine clinical care in East Asia.

ABSTRACT Aims/Introduction This study was designed and carried out to investigate the association of dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. Materials and Methods The JMDC Claims Database, which contains the medical and prescription information of Japanese employment‐based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP‐4is or other oral glucose‐lowering agents (GLAs). Results Individuals with diabetes who received DPP‐4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow‐up periods (median [interquartile range]) were 17 months (8–33) for DPP‐4is and 14 months (7–28) for other oral GLAs. Kaplan–Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log‐rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP‐4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8–1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8–1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. Conclusion This database study shows that there is not a significant PC risk due to DPP‐4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings.

Abstract Tissue optical clearing permits detailed evaluation of organ three-dimensional (3-D) structure as well as that of individual cells by tissue staining and autofluorescence. In this study, we evaluated intestinal morphology, intestinal epithelial cells (IECs), and enteroendocrine cells, such as incretin-producing cells, in reporter mice by intestinal 3-D imaging. 3-D intestinal imaging of reporter mice using optical tissue clearing enabled us to evaluate both detailed intestinal morphologies and cell numbers, villus length and crypt depth in the same samples. In disease mouse model of lipopolysaccharide (LPS)-injected mice, the results of 3-D imaging using tissue optical clearing in this study was consistent with those of 2-D imaging in previous reports and could added the new data of intestinal morphology. In analysis of incretin-producing cells of reporter mice, we could elucidate the number, the percentage, and the localization of incretin-producing cells in intestine and the difference of those between L cells and K cells. Thus, we established a novel method of intestinal analysis using tissue optical clearing and 3-D imaging. 3-D evaluation of intestine enabled us to clarify not only detailed intestinal morphology but also the precise number and localization of IECs and incretin-producing cells in the same samples.

Abstract Aims/Introduction Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super‐aged' populations, such as Japan. This post‐hoc analysis assessed once‐weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. Materials and Methods Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once‐weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (

Abstract Background Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. Case presentation A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). Conclusion We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

Abstract Aims/Introduction To assess the impact of baseline characteristics on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. Materials and Methods In the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 9 and 10 trials, Japanese patients were randomized to once‐daily oral semaglutide (3, 7, or 14 mg) or a comparator (placebo or once‐daily subcutaneous liraglutide 0.9 mg in PIONEER 9; once‐weekly subcutaneous dulaglutide 0.75 mg in PIONEER 10) for 52 weeks, with 5 weeks of follow up. An exploratory analysis grouped patients in each trial according to baseline glycated hemoglobin (HbA1c; ≤8.0, >8.0–≤9.0, or >9.0%), body mass index (

ABSTRACT Aims/Introduction We investigated the utilization of healthcare resources in patients with type 2 diabetes treated with empagliflozin, a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor, versus dipeptidyl peptidase‐4 (DPP‐4) inhibitors in clinical practice in Japan, South Korea, and Taiwan. Materials and Methods We analyzed the Japanese Medical Data Vision database (December 2014–April 2018), the South Korean National Health Information Database, and the Taiwanese National Health Insurance claims database (both May 2016–December 2017). Patients with type 2 diabetes starting empagliflozin, 10 or 25 mg, or a DPP‐4 inhibitor were matched 1:1 via propensity scores (PS). We compared inpatient care needs, emergency room (ER) visits, and outpatient visits between the treatment groups using Poisson regression and Cox proportional hazards models, pooled across countries by random‐effects meta‐analysis. Results We identified 28,712 pairs of PS‐matched patients; the mean follow‐up was 5.7–6.8 months. Empagliflozin‐treated patients had a 27% lower risk of all‐cause hospitalization compared with DPP‐4 inhibitor–treated patients (rate ratio [RR] 0.73, 95% CI 0.67–0.79), and 23% reduced risk for first hospitalization (hazard ratio 0.77, 95% CI 0.73–0.81). The risk for an ER visit was 12% lower with empagliflozin than with DPP‐4 inhibitors (RR 0.88, 95% CI 0.83–0.94) while the risk for outpatient visit was 4% lower (RR 0.96, 95% CI 0.96–0.97). These findings were generally consistent across countries, regardless of baseline cardiovascular disease, and in the subgroup starting empagliflozin with the 10 mg dose. Conclusions Empagliflozin treatment was associated with lower inpatient care needs and other healthcare resource utilization than DPP‐4 inhibitors in routine clinical practice in East Asia in this study.

Abstract Aims/Introduction An efficient screening strategy for identification of cognitive dysfunction remains a clinical issue in the management of elderly adults with diabetes. A magnetic resonance imaging voxel‐based specific regional analysis system for Alzheimer’s disease (VSRAD) has been developed as an automated brain morphometry system that includes the hippocampus. We carried out a multicenter retrospective study to evaluate the utility of VSRAD for screening cognitive dysfunction in diabetes outpatient clinics. Materials and Methods We enrolled patients with diabetes aged >65 years who underwent brain magnetic resonance imaging scans for the purpose of a medical checkup between November 2018 and May 2019. Patients who were already suspected or diagnosed with mild cognitive impairment and/or dementia as well as those with a history of cerebrovascular disease were excluded. Results A total of 67 patients were enrolled. Five patients were diagnosed with mild cognitive impairment or dementia (clinical cognitive dysfunction). Patients with clinical cognitive dysfunction showed a significantly higher z‐score in VSRAD analysis (2.57 ± 0.47 vs 1.15 ± 0.55, P

Abstract Aims/Introduction This 6‐month, single‐center, prospective, open‐labeled, randomized trial was designed to investigate whether physicians’ diabetes self‐management education using an education tool developed by the Japan Association of Diabetes Education and Care and a self‐monitoring of blood glucose (SMBG) analyzer improves glycemic control in individuals with type 2 diabetes receiving insulin and SMBG. Materials and Methods Participants were randomized into intervention (I) and control (C) groups. Both groups received physicians’ diabetes self‐management education at each hospital visit, whereas the Japan Association of Diabetes Education and Care education tool and the SMBG readings analyzer was used in group I, but not group C. All participants filled out a diabetes treatment‐related quality of life form and an original questionnaire on SMBG use with five questions (Q1–Q5) before and after the study period. Results A total of 76 individuals were recruited and randomized. Glycated hemoglobin (HbA1c) was significantly improved during the study period in group I, whereas no significant change was observed in group C. The change in HbA1c was greater in group I, although it did not reach statistical significance. The diabetes treatment‐related quality of life total score was not changed in either group. Interestingly, the score of Q1 (“How important is SMBG to you?”) in the SMBG questionnaire was unchanged in group I, whereas it was significantly decreased in group C. HbA1c change was independently associated with changes in insulin dose and SMBG Q1 score. Conclusion Greater HbA1c‐lowering by physicians’ diabetes self‐management education using the Japan Association of Diabetes Education and Care education tool and SMBG analyzer in individuals with type 2 diabetes receiving insulin and SMBG was suggested, but not confirmed.

Abstract Aims/Introduction Differences in the glucose‐lowering mechanisms of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have been noted. Clarifying these differences could facilitate the choice of optimal drugs for individuals with type 2 diabetes and requires investigation in a clinical setting. Materials and Methods A single‐arm, prospective, observational study was conducted to evaluate the effects of various GLP‐1RAs on postprandial glucose excursion, secretions of insulin and glucagon as well as on the gastric emptying rate. Participants were subjected to meal tolerance tests before and 2 weeks and 12 weeks after GLP‐1RA initiation. Effects on postprandial secretions of glucose‐dependent insulinotropic polypeptide (GIP) and apolipoprotein B48 were also investigated. Results Eighteen subjects with type 2 diabetes received one of three GLP‐1RAs, i.e., lixisenatide, n = 7; liraglutide, n = 6; or dulaglutide, n = 5. While 12‐week administration of all of the GLP‐1RAs significantly reduced HbA1c, only lixisenatide and liraglutide, but not dulaglutide, significantly reduced body weight. Postprandial glucose elevation was improved by all of the GLP‐1RAs. Postprandial insulin levels were suppressed by lixisenatide, while insulin levels were enhanced by liraglutide. Postprandial glucagon levels were suppressed by lixisenatide. The gastric emptying rate was significantly delayed by lixisenatide, while liraglutide and dulaglutide had limited effects on gastric emptying. GIP secretion was suppressed by lixisenatide and liraglutide. Apolipoprotein B48 secretion was suppressed by all of the GLP‐1RAs. Conclusions All of the GLP‐1RAs were found to improve HbA1c in a 12‐week prospective observational study in Japanese individuals with type 2 diabetes. However, differences in the mechanisms of the glucose‐lowering effects and body weight reduction were observed.

Abstract Introduction Treatments for type 2 diabetes targeting baseline glucose levels but not postprandial glucose can result in normalized fasting blood glucose but suboptimal overall glycemic control (high glycated hemoglobin): residual hyperglycemia. In Japanese patients with type 2 diabetes the predominant pathophysiology is a lower insulin secretory capacity, and residual hyperglycemia is common with basal insulin treatment. Single‐injection, fixed‐ratio combinations of glucagon‐like peptide‐1 receptor agonists and basal insulin have been developed. iGlarLixi (insulin glargine 100 units/mL [iGlar]: lixisenatide ratio of 1 unit:1 µg) is for specific use in Japan. Post‐hoc analysis of the LixiLan JP‐L trial (NCT02752412) compared the effect of iGlarLixi with iGlar on this specific subpopulation with residual hyperglycemia. Materials and Methods Outcomes at week 26 (based on the last observation carried forward) were assessed in patients in the modified intent‐to‐treat population with baseline residual hyperglycemia. Results Overall, 83 (32.5%) patients in the iGlarLixi group and 79 (30.7%) patients in the iGlar group had baseline residual hyperglycemia. The proportion of patients with residual hyperglycemia at week 26 decreased to 15.7% in the iGlarLixi group, and increased to 36.9% in the iGlar group. Patients in the iGlarLixi group had significantly greater reductions in glycated hemoglobin compared with the iGlar group (−0.72% difference between groups; P

ABSTRACT Heterozygous RFX6 mutation has emerged as a potential cause of maturity‐onset diabetes mellitus of the young (MODY). A 16‐year‐old female was diagnosed with diabetes by her family doctor and was referred to our institution for genetic examination. Genetic testing revealed a novel RFX6 heterozygous mutation (NM_173560: exon17: c.1954C>T: p.R652X) in the patient and in her mother and brother. She had no islet‐specific autoantibodies and showed a reduced meal‐induced response of insulin, glucose‐dependent insulinotropic polypeptide, and glucagon‐like peptide‐1, which is consistent with the phenotype of MODY due to heterozygous RFX6 mutation. In conclusion, we report a case of MODY due to a novel heterozygous mutation, p.R652X.

Abstract Aims/Introduction The mechanisms underlying hypertriglyceridemia‐induced impaired glucose tolerance in Japanese individuals remain unclear. We aimed to evaluate the effect of hypertriglyceridemia on glucose metabolism in comparison with that of increased low‐density lipoprotein or decreased high‐density lipoprotein levels and to elucidate the sex differences in hypertriglyceridemia‐related dietary intake among Japanese individuals. Materials and Methods We randomly selected 898 (384 men and 514 women) participants aged 40–78 years in the Gifu Diabetes Study; those taking medication for dyslipidemia or diabetes mellitus were excluded. Serum levels of glucose metabolism parameters and the food frequency were measured cross‐sectionally. The glycated hemoglobin was measured again after 5 years. Results Glucose metabolism parameters and the percentage of individuals with impaired glucose tolerance were significantly higher in the high triglyceride group in men and women. Similar trends were observed in the low high‐density lipoprotein group, but only in men. Meanwhile, only the homeostasis model assessment of insulin resistance was higher in the high low‐density lipoprotein group. In non‐obese men, the percentage of energy intake from alcohol per total daily energy intake was significantly greater in the high triglyceride group. In obese women, the total energy intake was significantly greater in the high triglyceride group. At the 5‐year follow up, the risk of elevated glycated hemoglobin levels with hypertriglyceridemia was increased in men. Conclusions Hypertriglyceridemia is a stronger risk factor for impaired glucose tolerance than increased low‐density lipoprotein or decreased high‐density lipoprotein. For dietary habits, increased daily alcohol energy intake in non‐obese men and increased total energy intake in obese women were associated with hypertriglyceridemia.

Abstract Background Primary central nervous system lymphoma is a rare extra-nodal lymphoma of the central nervous system. Primary central nervous system lymphoma lesions usually appear in the vicinity of the ventricle, and there are few reports of primary central nervous system lymphoma with hypothalamic-pituitary lesions. Case presentation We treated a 56-year-old male with primary central nervous system lymphoma with the primary lesion in the hypothalamus, which was found by magnetic resonance imaging after sudden onset of endocrinological abnormalities. Initially, he was hospitalized to our department for hyponatremia. Endocrinological examination in conjunction with head magnetic resonance imaging and endoscopic biopsy revealed hypothalamic hypopituitarism and tertiary hypoadrenocorticism caused by a rapidly growing, diffuse large B-cell lymphoma in the hypothalamus. Remission of the tumor was achieved by high-dose methotrexate with whole brain radiotherapy, and some of the hormone responses were normalized. Conclusions While primary central nervous system lymphoma is rare, it is important to note that hypopituitarism can result and that the endocrinological abnormalities can be partially restored by its remission.

Abstract Aims/Introduction Pancreatic islets are heterogenous. To clarify the relationship between islet heterogeneity and incretin action in the islets, we studied gene expression and metabolic profiles of non‐large and enlarged islets of the Zucker fatty diabetes mellitus rat, an obese diabetes model, as well as incretin‐induced insulin secretion (IIIS) in these islets. Materials and Methods Pancreatic islets of control (fa/+) and fatty (fa/fa) rats at 8 and 12 weeks‐of‐age were isolated. The islets of fa/fa rats at 12 weeks‐of‐age were separated into non‐large islets (≤200 μm in diameter) and enlarged islets (>300 μm in diameter). Morphological analyses, insulin secretion experiments, transcriptome analysis, metabolome analysis and oxygen consumption analysis were carried out on these islets. Results The number of enlarged islets was increased with age in fatty rats, and IIIS was significantly reduced in the enlarged islets. Markers for β‐cell differentiation were markedly decreased in the enlarged islets, but those for cell proliferation were increased. Glycolysis was enhanced in the enlarged islets, whereas the tricarboxylic acid cycle was suppressed. The oxygen consumption rate under glucose stimulation was reduced in the enlarged islets. Production of glutamate, a key signal for IIIS, was decreased in the enlarged islets. Conclusions The enlarged islets of Zucker fatty diabetes mellitus rats, which are defective for IIIS, show tumor cell‐like metabolic features, including a dedifferentiated state, accelerated aerobic glycolysis and impaired mitochondrial function. The age‐dependent increase in such islets could contribute to the pathophysiology of obese diabetes.

Abstract Aims/Introduction Glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are used for treatment of type 2 diabetes mellitus worldwide. However, some patients do not respond well to the therapy, and caution must be taken for certain patients, including those with reduced insulin secretory capacity. Thus, it is clinically important to predict the efficacy of GLP‐1RA therapy. GLP‐1R‐targeted imaging has recently emerged to visualize and quantify β‐cells. We investigated whether GLP‐1R‐targeted imaging can predict the efficacy of GLP‐1RA treatment. Materials and Methods We developed 111Indium‐labeled exendin‐4 derivative (111In‐Ex4) as a GLP‐1R‐targeting probe. Diabetic mice were selected from NONcNZO10/LtJ male mice that were fed for different durations with 11% fat chow. After 3‐week administration of dulaglutide as GLP‐1RA therapy, mice with non‐fasting blood glucose levels 300 mg/dL were defined as responders and non‐responders, respectively. In addition, ex vivo 111In‐Ex4 pancreatic accumulations (111In‐Ex4 pancreatic values) were examined. Results The non‐fasting blood glucose levels after treatment were 172.5 ± 42.4 mg/dL in responders (n = 4) and 330.8 ± 20.7 mg/dL in non‐responders (n = 5), respectively. Ex vivo 111In‐Ex4 pancreatic values showed significant correlations with post‐treatment glycohemoglobin and glucose area under curve during an oral glucose tolerance test (R2 = 0.76 and 0.80; P

Abstract Aims/Introduction Although moderate alcohol consumption lowers the risk of type 2 diabetes in European populations, the same cannot be assumed for Japanese patients with diabetes related to low insulin secretion rather than resistance. We aimed to evaluate the effects of daily alcohol consumption on glucose tolerance and diabetes development risk in Japanese populations. Materials and methods This retrospective study randomly enrolled 452 men and 659 women aged 40–78 years in 2005 (Gifu, Japan). The participants completed a 75‐g oral glucose tolerance test and medical questionnaire. The homeostasis model assessment of insulin resistance, homeostasis model assessment of β‐cell function and insulinogenic index were used to estimate insulin sensitivity and secretion. The relationships between alcohol consumption and these parameters were analyzed using logistic regression after adjusting for potential confounders. The 5‐year changes in hemoglobin A1c levels were also evaluated. Results The adjusted odds ratios for elevated homeostasis model assessment of β‐cell function values (

Abstract Genetic rearrangements of anaplastic lymphoma kinase contribute to the pathogenesis of non‐small‐cell lung cancer; the anaplastic lymphoma kinase inhibitor, ceritinib, is widely used, as it is effective even in patients with non‐small‐cell lung cancer resistant to other anaplastic lymphoma kinase inhibitors. Although a case of possible ceritinib‐induced hyperglycemia was reported, the association of ceritinib with hyperglycemia remains to be investigated. Disproportionality analysis was carried out using the Japanese Adverse Drug Event Report database, which contains all pharmacovigilance data based on spontaneous reports of adverse events between April 2004 and November 2018 to the Pharmaceuticals and Medical Devices Agency. The reporting odds ratio of ceritinib for hyperglycemia was 2.25 (95% confidence interval [CI] 1.24–4.08], whereas those of crizotinib and alectinib were 0.07 (95% CI 0.01–0.40) and 0.94 (95% CI 0.30–2.94), respectively. Among reported events without antidiabetes agent use, the reporting odds ratio of ceritinib was still 2.54 (95% CI 1.27–5.12). Thus, the possibility of hyperglycemia should be carefully monitored in patients receiving ceritinib.

Abstract A 70‐year‐old woman with type 2 diabetes was admitted to Gifu University Hospital, Gifu, Japan, because of ketosis. She was diagnosed with type 2 diabetes at age 49 years and started insulin therapy at age 57 years, which restored glycemic control. Insulin therapy was discontinued and oral antidiabetes drugs, including sodium–glucose cotransporter 2 inhibitor dapagliflozin, were initiated at age 69 years. Thereafter, her bodyweight declined from 40.0 kg to 29.8 kg in 12 months; glycated hemoglobin remained >8.0%. On admission to our hospital, her laboratory tests and computed tomography scan showed ketosis, insulinopenia, and the presence of dehydration and bacterial pneumonia. She also lost substantial bodyweight and developed sarcopenia. The current case shows the importance of patient assessment before sodium–glucose cotransporter 2 inhibitor initiation in the elderly.

Unimolecular peptide‐based dual agonists against glucagon‐like peptide‐1 receptor (GLP‐1R) and glucose‐dependent insulinotropic polypeptide receptor (GIPR) have been gaining much attention recently as novel antidiabetic agents that can potentially control glycemia and bodyweight. Although GLP‐1 and GIP both enhance insulin secretion and subsequently ameliorate postprandial glucose excursion, most research has focused on GLP‐1R as a therapeutic target for type 2 diabetes. This is partly because the effects of GIPR activation on glycemia and bodyweight have been controversial. GIPR‐deficient mice showed impaired glucose tolerance with reduced β‐cell function and resistance to high‐fat diet‐induced obesity, whereas GIPR agonists improved glycemia and prevented high‐fat diet‐induced obesity in mice. Conflicting results in mice might be explained by pharmacological levels of GIP signal in the central nervous systems decreasing food intake and overcoming the obesogenic effects of GIP at physiological levels in adipose tissues. Thus, GIPR activation at pharmacological levels might result in bodyweight reduction. Indeed, bodyweight reduction by GIPR/GLP‐1R dual agonists was greater than GLP‐1R single agonists in individuals with type 2 diabetes. Thus, GLP‐1R/GIPR dual agonists can add additional therapeutic efficacy to tailored diabetes care, especially among obese individuals with type 2 diabetes. However, caution should be exercised as to whether or not these drugs are appropriate for the management of Asian type 2 diabetes patients, which are primarily characterized by non‐obesity and impaired β‐cell function, as well as in that of elderly adults with type 2 diabetes, who tend to develop sarcopenia and frailty as a result of poor energy intake.

Abstract Aims/Introduction We investigated the safety and tolerability of empagliflozin (EMPA) in East Asian patients with type 2 diabetes. Materials and Methods Data were pooled from participants with type 2 diabetes evenly randomized to a placebo, EMPA 10 mg or EMPA 25 mg in 15 phase I–III trials. Adverse events (AEs) were analyzed in the subgroup of trial participants from East Asian countries/regions. Results In total, 709, 724 and 708 East Asian trial participants with type 2 diabetes received a placebo, EMPA 10 mg and EMPA 25 mg, respectively; total exposure was 953, 1,072, and 1,033 patient‐years in these groups, respectively. The EMPA and placebo groups had similar incidences of severe AEs, serious AEs and AEs leading to discontinuation. Incidences of hypoglycemia differed according to anti‐diabetes medication used at baseline. Higher rates of events consistent with genital infection were observed with EMPA (EMPA 1.5–1.7/100, placebo 0.2/100 patient‐years). Rates of AEs consistent with volume depletion were comparable among treatment groups (0.8–1.4/100 patient‐years), but in trial participants aged ≥65 years, the rate was greater with EMPA 25 mg (EMPA 25 mg 3.5/100, placebo 2.0/100 patient‐years). Incidences of events consistent with urinary tract infection, thromboembolic events, renal events, hepatic AEs, diabetic ketoacidosis, fractures and lower limb amputation were similar between EMPA and the placebo. Conclusions In the present pooled analysis, EMPA was well tolerated in East Asian type 2 diabetes patients based on >2,100 patient‐years’ exposure, consistent with results from the overall analysis population.

Introduction Elderly people (≥65 years) with type 2 diabetes mellitus (T2DM) are becoming increasingly prevalent, notably in Japan. As cardiovascular (CV) risk increases with age and sodium–glucose cotransporter-2 (SGLT2) inhibitors reduce CV risk, elderly patients with T2DM are increasingly likely to be prescribed these glucose-lowering drugs. There is controversy surrounding the effects of SGLT2 inhibitors on muscle mass, particularly in elderly patients for whom loss of muscle is especially undesirable; however, robust evidence on this important issue is lacking. Consequently, we have designed a clinical trial of the SGLT2 inhibitor empagliflozin in elderly Japanese patients with T2DM (Empagliflozin in Elderly T2DM Patients (EMPA-ELDERLY)) to assess its effects on body composition as well as glycaemic control. EMPA-ELDERLY will be the first randomised clinical trial of an SGLT2 inhibitor in elderly patients with T2DM to evaluate effects on skeletal muscle mass, muscle strength and physical performance concurrently.Methods and analysis EMPA-ELDERLY is a randomised, double-blind, placebo-controlled, parallel-group clinical trial to be conducted in Japan. Patients with T2DM aged ≥65 years are eligible if they are Japanese with a body mass index of ≥22 kg/m2 and glycated haemoglobin (HbA1c) levels from ≥7.0% to ≤10.0% from either diet and exercise alone or treatment with oral glucose-lowering drugs. Approximately 128 participants will be randomised 1:1 to once per day, oral, double-blind treatment with empagliflozin 10 mg or matching placebo for 52 weeks. The primary endpoint is the change in HbA1c level from baseline at week 52. Secondary endpoints include changes from baseline to 52 weeks in body composition, including muscle mass and body fat, measured by bioelectrical impedance analysis, as well as skeletal muscle index, grip strength and time in the five-time chair stand test. Other endpoints include changes in patient-reported outcomes (including quality of life), cognitive function and safety.Ethics and dissemination We will submit the trial results to conferences and peer-reviewed journals.Trial registration number NCT04531462.

Abstract Aim To evaluate the effectiveness of empagliflozin in clinical practice in East Asia in the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) East Asia study. Materials and methods Data were obtained from the Medical Data Vision database (Japan), National Health Insurance Service database (South Korea) and National Health Insurance database (Taiwan). Patients aged ≥ 18 years with type 2 diabetes initiating empagliflozin or a dipeptidyl peptidase‐4 (DPP‐4) inhibitor were 1:1 propensity score (PS) matched into sequentially built cohorts of new users naïve to both drug classes. This design reduces confounding due to switching treatments, time lag and immortal time biases. Outcomes included hospitalization for heart failure (HHF), end‐stage renal disease (ESRD) and all‐cause mortality. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional models, controlling for > 130 baseline characteristics in each data source and pooled by random‐effects meta‐analysis. Results Overall, 28 712 pairs of PS‐matched patients were identified with mean follow‐up of 5.7‐6.8 months. Compared with DPP‐4 inhibitors, the risk of HHF was reduced by 18% and all‐cause mortality was reduced by 36% with empagliflozin (HR 0.82; 95% CI 0.71‐0.94, and HR 0.64; 95% CI 0.50‐0.81, respectively). Reductions were consistent across countries, and in patients with and without baseline cardiovascular disease. ESRD was also significantly reduced with empagliflozin versus DPP‐4 inhibitors (HR 0.37; 95% CI 0.24‐0.58). Conclusions Empagliflozin treatment was associated with reduced risk for HHF, all‐cause mortality and ESRD compared with DPP‐4 inhibitors in routine clinical practice in Japan, South Korea and Taiwan.

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.