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The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodiumglucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) into four subgroups (≥90, 60 to 1c), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to 2. Bodyweight and HbA1c decreased in all subgroups, the latter by − 0.91% to − 0.40% (P 2 subgroup (+ 1.42 ± 8.77 mL/min/1.73 m2; P = 0.006). It decreased in the ≥90 and 60 to 2 subgroups (− 8.27 ± 13.73 and − 1.22 ± 10.34 mL/min/1.73 m2; P 2. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA1c and bodyweight were observed regardless of the presence of renal impairment.

Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy., Katagi et al. show that abnormal bone marrow-derived cells originated from hematopoietic stem cells (CD106-positive short-term HSCs) aberrantly fuse with neurons to develop diabetic neuropathy. This study suggests that the pathological abnormality is memorized in the bone marrow and that it cannot be erased by conventional therapy.

Introduction STELLA-LONG TERM is a post-marketing surveillance study evaluating the safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus. Methods Patients were classified by age at ipragliflozin initiation (

Aims/introduction:Treatment intensification is commonly delayed in people with type 2 diabetes, resulting in poor glycemic control for an unacceptable length of time and increased risk of complications., Materials and methods:This retrospective study investigated clinical inertia in 33,320 Japanese adults with type 2 diabetes treated with oral antidiabetic drugs (OADs) between 2009 and 2018, using data from the Computerized Diabetes Care (CoDiC® ) database., Results:The median time from first reported glycated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) to treatment intensification was considerably longer and HbA1c levels were higher the more OADs the patient was exposed to. For patients receiving three OADs, the median times from HbA1c ≥7.0% (53 mmol/mol) to intensification with OAD, glucagon-like peptide-1 receptor agonist or insulin were 8.1, 9.1 and 6.7 months, with a mean HbA1c level at the time of intensification of 8.4%, 8.9% and 9.3%, respectively. The cumulative incidence for time since the first reported HbA1c ≥7.0% (≥53 mmol/mol) to intensification confirmed the existence of clinical inertia, identifying patients whose treatment was not intensified despite poor glycemic control. HbA1c levels ≥7.0% (≥53 mmol/mol) after ≥6 months on one, two or three OADs were observed in 42%, 51% and 58% of patients, respectively, showing that approximately 50% of patients are above HbA1c target regardless of how many OADs they take., Conclusions:Real-world data here show clinical inertia in Japanese adults with type 2 diabetes from early diabetes stages when they are receiving OADs, and illustrate a need for earlier, more effective OADs or injectable treatment intensification and better communication around the existence of clinical inertia.

Background:The size of the remnant stomach with respect to weight loss failure after laparoscopic sleeve gastrectomy (LSG) remains controversial. This study aimed to evaluate the impact of the actual size and volume of the remnant stomach, as measured by three-dimensional computed tomography (3D-CT) volumetry, on weight loss after LSG., Methods:The clinical outcomes of 52 patients who underwent LSG between October 2008 and February 2019 were assessed. Weight metrics were recorded at 1, 3, and 6 months and 1 year postoperatively. 3D-CT volumetry was performed 1 year postoperatively, and the total remnant stomach volume (TSV), proximal stomach volume (PSV), antral stomach volume (ASV), and the distance between the pylorus and the distal edge of staple line (DPS) were measured. The relationship between the weight metrics and aforementioned factors was analyzed., Results:Of the 52 patients who underwent LSG, 40 patients participated in this study. The average body mass index preoperatively was 38.3 ± 5.1 kg/m2, and the average percentage of total weight loss (%TWL) 1 year after LSG was 26.6 ± 9.3%. The average TSV, PSV, ASV, and DPS were 123.2 ± 60.3 ml, 73.4 ± 37.2 ml, 49.8 ± 30.3 ml, and 59.9 ± 18.5 mm, respectively. The DPS (r = - 0.394, p = 0.012) and ASV (r = - 0.356, p = 0.024) were correlated with %TWL 1 year postoperatively., Conclusions:The actual DPS and ASV measured by 3D-CT affected weight loss after LSG. 3D-CT may be useful for the immediate identification of factors affecting insufficient weight loss in patients; this may, in turn, aid in the implementation of early intervention treatments.

Recent major clinical trials of the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three‐point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as “cardiomyopathy”. Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca2+ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies., Heart failure is a major determinant of life prognosis in diabetes patients. Two potential mechanisms for the progression of heart failure in diabetes are reviewed – the development of heart failure with preserved ejection fraction and heart failure with low ejection fraction. Sodium–glucose cotransporter 2 inhibitors can protect progression of heart failure with preserved ejection fraction in diabetes patients by improving multiple metabolic and hemodynamic derangements, as well as by improving endothelial dysfunction, oxidative stress, pro‐inflammatory cytokine signaling, Ca++ overloading and metabolic crisis in cardiomyocytes in diabetes.

Introduction:The effectiveness of basal insulin (BI) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in providing glycemic control in patients with type 2 diabetes (T2D) in Japanese routine practice is not well known. This real-world observational study evaluated the probability of achieving glycemic control in Japanese patients with T2D uncontrolled by oral antidiabetic drugs (OADs) who initiated BI or GLP-1 RA therapy., Methods:Patients with T2D aged ≥ 18 years initiating BI or GLP-1 RA therapy following treatment with OADs were selected from real-world data (RWD) retrieved from a large electronic medical record database in Japan, using data from 01 January 2010 to 30 June 2019. Patients were required to have glycated hemoglobin (HbA1c) ≥ 7% within 90 days prior to the first prescription of BI or GLP-1 RA. The probability of reaching first HbA1c < 7% was assessed over a 24-month period in cohorts of patients who initiated BI (n = 3477) or GLP-1 RA (n = 780) and in subcohorts by number of OADs at baseline (1, 2, or ≥ 3), HbA1c at baseline (≥ 7 to < 8%, ≥ 8 to < 9%, or ≥ 9%), and age (< 65 or ≥ 65 years)., Results:Mean (standard deviation) baseline HbA1c was 9.4% (1.8%) and 8.8% (1.4%) in patients initiating BI or GLP-1 RA therapy, respectively. The cumulative probability of achieving glycemic control was 50.1% with BI and 60.3% with GLP-1 RA therapy, respectively, at 12 months, and 60.8% and 66.6%, respectively, at 24 months. Quarterly (3-month intervals) conditional probabilities of achieving glycemic control decreased over time and were < 10% after 12 months. Patients with more OADs or higher HbA1c at baseline had a lower probability of achieving glycemic control., Conclusion:Among Japanese patients with T2D who initiated BI or GLP-1 RA therapy after treatment with OADs, the probability of reaching first glycemic control diminished over time. Further therapy intensification is warranted in patients who do not achieve glycemic control within 6-12 months with BI or GLP-1 RA, particularly those with high HbA1c or taking multiple OADs.

A 43-year-old male patient on maintenance hemodialysis had an enhanced computed tomography scan examination with iohexol for the first time 10 min before regular hemodialysis therapy. At the start of hemodialysis, no symptoms were observed, and the platelet count was 148,000/μl. Approximately 1 h after starting hemodialysis, dyspnea and chest discomfort appeared. Since oxygen saturation of the peripheral artery decreased to 87%, oxygen administration was immediately started while continuing hemodialysis therapy. Furthermore, gingival hemorrhage was observed, and the platelet count decreased to 5000/μl. We were carefully monitoring his conditions while continuing hemodialysis and oxygen administration, but no further deterioration was observed. Thereafter, these symptoms and severe thrombocytopenia gradually improved without additional treatment. At the end of hemodialysis, these symptoms completely disappeared. As well, the platelet count recovered to 35,000/μl at the end of hemodialysis and increased to 92,000/μl the next morning. From the clinical course, we diagnosed with contrast medium-induced thrombocytopenia. Acute thrombocytopenia is a rare complication induced by the contrast medium. Until now, 16 cases on contrast medium-induced thrombocytopenia have been reported. Our case spontaneously recovered from severe thrombocytopenia relatively earlier than previous reports. Our patient started hemodialysis therapy 10 min after an enhanced computed tomography examination. Early removal of contrast medium by hemodialysis might be associated with early improvement. We should acknowledge that contrast media have potential to induce severe thrombocytopenia, even in patients on maintenance hemodialysis.

To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5-/-) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5-/- mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5-/- mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5-/- mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy.

AIMS The roles of urinary albumin, eGFRcystatin (eGFRcys), and eGFRcreatinine (eGFRcre) in the progression of coronary artery calcification (CAC) remain unclear. Therefore, the present study investigated the relationship between kidney function and CAC progression. METHODS A total of 760 Japanese men aged 40-79 years were enrolled in this population-based study. Kidney function was measured using eGFRcre, eGFRcys, and the urine albumin-to-creatinine ratio. CAC scores were calculated using the Agatston method. CAC progression was defined as an annual increase of ＞10 Agatston units (AU) among men with 0＜CAC＜100 AU at baseline, that of ＞10% among those with CAC ≥ 100 AU, and any progression for those with CAC=0 at baseline. The relative risk (RR) of CAC progression based on kidney function was assessed using a robust Poisson regression model. RESULTS The mean follow-up period was 4.9 years. CAC progression was detected in 45.8% of participants. Positive associations between CAC progression and albuminuria (＞30mg/g) (RR: 1.29; 1.09 to 1.53; p=0.004) and low eGFRcys (＜60ml/min/1.73m2) (RR: 1.27; 1.05 to 1.53; p=0.012) remained significant after adjustments for age, the follow-up time, and computerized tomography type. Following further adjustments for hypertension, diabetes mellitus, dyslipidemia, C-reactive protein, and lifestyle factors, CAC progression was associated with albuminuria (RR: 1.20; 1.01 to 1.43; p=0.04) and low eGFRcys (RR: 1.19; 0.99 to 1.43; p=0.066), but not with eGFRcre. CONCLUSION CAC progression was associated with albuminuria; however, its relationship with eGFRcys was weakened by adjustments for risk factors.

OBJECTIVE Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes. RESEARCH DESIGN AND METHODS A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR ( RESULTS During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher. CONCLUSIONS Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.

Diabetic nephropathy is a leading cause of proteinuria, kidney fibrosis, and subsequent end-stage renal disease. The renal prognosis of diabetic patients with refractory proteinuria is extremely poor. Therefore, identification of novel therapeutic targets to combat this serious condition and improve renal prognosis is urgently necessary. In diabetic patients, in addition to blood glucose levels, serum levels of free fatty acids (FFAs) are chronically elevated, even during postprandial periods. Of the various types of FFAs, saturated FFAs are highly cytotoxic and their levels are elevated in the serum of patients with diabetes. Thus, an increase in saturated FFAs is currently thought to contribute to proximal tubular cell damage and podocyte injury in diabetic nephropathy. Therefore, protecting both types of kidney cells from saturated FFA-related lipotoxicity may become a novel therapeutic approach for diabetic patients with refractory proteinuria. Interestingly, accumulating evidence suggests that controlling intracellular nutrient signals and autophagy can ameliorate the FFA-related kidney damage. Here, we review the evidence indicating possible mechanisms underlying cell injury caused by saturated FFAs and cell protective roles of intracellular nutrient signals and autophagy in diabetic nephropathy.

Aims/Introduction Preprandial metformin administration significantly reduces postprandial plasma triglyceride levels in animal studies by reducing intestinal absorption through delayed gastric emptying. However, this effect has not been shown in a clinical study. Therefore, we planned to investigate the efficacy of preprandial metformin administration on postprandial hypertriglyceridemia and the related gastrointestinal effects in patients with type 2 diabetes mellitus. Materials and Methods A total of 11 patients taking single‐dose metformin at 500–1,000 mg, with non‐fasting plasma triglyceride levels of 150–1,000 mg/dL, were recruited at a single university hospital. The difference between preprandial and postprandial metformin administration on postprandial hypertriglyceridemia was examined by a meal test. The gastrointestinal effects of metformin, including stomach heaviness, heartburn and satiety, were also assessed using a visual analog scale. Results The mean bodyweight of patients was 80.6 kg (body mass index 27.9 kg/m2), and the mean non‐fasting plasma triglyceride level was 275.9 ± 57.0 mg/dL. The area under the curve of triglyceride during the meal test was significantly lower in the preprandial protocol than in the postprandial protocol (P

Aims To investigate the effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors vs. dipeptidyl peptidase‐4 (DPP‐4) inhibitors on renal function preservation (RFP) using real‐world data of patients with type 2 diabetes in Japan, and to identify which subgroups of patients obtained greater RFP benefits with SGLT2 inhibitors vs. DPP‐4 inhibitors. Methods We retrospectively analysed claims data recorded in the Medical Data Vision database in Japan of patients with type 2 diabetes (aged ≥18 years) prescribed any SGLT2 inhibitor or any DPP‐4 inhibitor between May 2014 and September 2016 (identification period), in whom estimated glomerular filtration rate (eGFR) was measured at least twice (baseline, up to 6 months before the index date; follow‐up, 9 to 15 months after the index date) with continuous treatment until the follow‐up eGFR. The endpoint was the percentage of patients with RFP, defined as no change or an increase in eGFR from baseline to follow‐up. A proprietary supervised learning algorithm (Q‐Finder; Quinten, Paris, France) was used to identify the profiles of patients with an additional RFP benefit of SGLT2 inhibitors vs. DPP‐4 inhibitors. Results Data were available for 990 patients prescribed SGLT2 inhibitors and 4257 prescribed DPP‐4 inhibitors. The proportion of patients with RFP was significantly greater in the SGLT2 inhibitor group (odds ratio 1.27; P = 0.01). The Q‐Finder algorithm identified four clinically relevant subgroups showing superior RFP with SGLT2 inhibitors (P

Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (

Homing peptides to the spinal cord were identified and isolated using phage display technology. In vivo biopanning was performed by intravenous systemic injection of a phage library to screen specific peptides targeting the spinal cord of mice. Analyses of the sequences of targeted phages yielded two candidate peptides targeting the spinal cord: SP1 (C-LHQSPHI-C) and SP2 (C-PTNNPRS-C). These peptides were synthesized and intravenously injected into mice to evaluate their tissue specificity and potential as gene delivery carriers. The complexes between SP1 or SP2 peptides and the plasmid vector expressing the reporter gene could induce gene transduction in the spinal cord through systemic injection without gene expression in the brain, liver, and kidney. In addition, intravenous injection of the complex between SP1 and the vectors induced interleukin-4 expression in the spinal cord, resulting in effective suppression of lipopolysaccharide-induced hyperalgesia. Therefore, intravenously administered spinal cord homing peptides complexed with a plasmid vector provided tissue-specific treatment featuring gene delivery to the CNS through systemic circulation. This novel method of gene delivery is feasible and has great potential for clinical application., Graphical Abstract

Introduction The combined effects of energy intake (EI) and physical activity (PA) on obesity have been poorly investigated. We have investigated the combined effects of EI and PA quantitatively in Japanese men and women with type 2 diabetes. Methods Data on 1395 patients with type 2 diabetes who attended 25 diabetes clinics located throughout Japan, obtained by questionnaire, were analyzed. A logistic regression model was used to calculate the odds ratio for obesity. Results Multi-adjusted odds ratios for the top versus the bottom tertile of EI and the bottom versus the top tertile of PA were 1.39 (95% confidence interval [CI] 1.02–1.89) and 1.64 (95% CI 1.22–2.22), respectively. The combination of EI (kcal/day) ≥ 1967 and PA (metabolic equivalents [METs] h/week) ≤ 9.9 for men and of EI ≥ 1815 and PA ≤ 8.3 for women were significantly associated with obesity. Conclusions The existence of “allowable maximum EI” and “required minimum PA” that is significantly associated with “not being obese” is implied, suggesting the need for lifestyle education for Japanese patients with type 2 diabetes. Electronic Supplementary Material The online version of this article (10.1007/s13300-019-0610-x) contains supplementary material, which is available to authorized users.

The aim of this study was to evaluate the efficacy and safety of pemafibrate in people with type 2 diabetes and hypertriglyceridaemia over a 52-week period. Participants were randomly assigned to receive treatment with placebo or pemafibrate at a dose of 0.2 or 0.4 mg/d for 24 weeks (treatment period 1). The main results from treatment period 1 have been reported previously. The assigned treatment was continued up to week 52, except that the placebo was changed to pemafibrate 0.2 mg/d after week 24 (treatment period 2). The percentage changes in fasting serum triglyceride (TG) levels at week 52 (last observation carried forward) were -48.2%, -42.3%, and -46.4% in the placebo/pemafibrate 0.2 mg/d (n = 57), pemafibrate 0.2 mg/d (n = 54), and pemafibrate 0.4 mg/d (n = 55) groups, respectively. Levels of TG, non-HDL cholesterol and total cholesterol stably decreased, whereas levels of HDL cholesterol increased with pemafibrate treatments over 52 weeks. Pemafibrate was well tolerated throughout the study period. The present study is the first to show that pemafibrate treatment substantially ameliorated lipid abnormalities and was well tolerated for 52 weeks in people with type 2 diabetes and hypertriglyceridaemia.

AIMS: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy. METHODS: A retrospective study was conducted using CoDiC database. Adult T2DM patients treated with sitagliptin monotherapy for ≥ 6 months and adding one OAD were extracted. Association between patient characteristics at the time of add-on OAD and following HbA1c reduction was assessed. RESULTS: Of 444 included patients, mean age was 62 years and 33% were female. All add-on OAD classes demonstrated further HbA1c reduction (p

Aims/Introduction:Type 2 diabetes mellitus is caused by a relative imbalance between insulin secretion and sensitivity related to the body mass index (BMI). Seven categories of oral antidiabetic drugs (OADs) are available in Japan. It is important to assess the OAD utilization patterns based on patients’ BMI levels., Materials and methods:OAD prescribing patterns from 2002 to 2019 were analyzed using the data collected in the computerized diabetes care database provided by the Japan Diabetes Clinical Data Management Study Group; OAD utilization patterns in 25,751 OAD-treated type 2 diabetes mellitus patients registered in 2019 were analyzed after classifying them into five categories of BMI., Results:Comparing OAD usage between 2002 and 2019, sulfonylureas decreased from 44.5 to 23.2%, and biguanides (BGs) increased from 19.3 to 50.3%. Dipeptidyl peptidase-4 inhibitors (DPP4is) increased to 56.9% in 2019. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) increased to 23.6% in 2019. About 90% of type 2 diabetes mellitus patients had BMI < 30 kg/m2 . DPP4is were the most used OADs in 2019. When BMI exceeded 30 kg/m2 , use of BGs and sodium-glucose cotransporter 2 inhibitors increased, and use of sulfonylureas and DPP4is decreased. Although DPP4is were the most used OADs for patients with BMI 35 kg/m2 after BGs and sodium-glucose cotransporter 2 inhibitors ., Conclusions:DPP4i usage was as high as that of BG in the analysis of Japanese type 2 diabetes mellitus patients with relatively low BMI. This was considered to be a treatment option appropriate for the pathophysiology in Japanese patients.

The STELLA-LONG TERM prospective post-marketing surveillance study assessed ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis of patients with liver impairment used the final 3-year results. Data on patients, adverse drug reactions (ADRs), and changes in glycemic parameters and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [γ-GTP] and alkaline phosphatase [ALP]) were collected, and the fatty liver index (FLI) was calculated. In the effectiveness analysis (n = 8,763), baseline liver function was normal in 2,605 patients (ALT

Aims/Introduction Knowing the collective clinical factors that determine patient response to glucose‐lowering medication would be beneficial in the treatment of type 2 diabetes. We carried out a retrospective cohort study to explore the combination of clinical factors involved in its therapeutic efficacy. Materials and Methods The results of cohort studies retrieved using the CoDiC® database across Japan from January 2005 to July 2018 were analyzed based on criterion that using insulin therapy indicates severe type 2 diabetes. Results A logistic regression analysis showed that age at diagnosis, disease duration, hemoglobin A1c (HbA1c) and serum C‐peptide reactivity (CPR) at medication commencement were associated with the probability of insulin treatment. Receiver operating characteristic curve showed that these clinical factors predicted insulin treatment positivity with an area under the curve of >0.600. The area under the curve increased to 0.674 and 0.720 for the disease duration‐to‐age at diagnosis ratio and HbA1c‐to‐CPR ratio, respectively. Furthermore, area under the curve increased to 0.727 and 0.750 in the indices (duration‐to‐age ratio at diagnosis × 43 + HbA1c) and (duration‐to‐age ration at diagnosis × 21 + HbA1c‐to‐CPR ratio), respectively. After stratification to three groups according to the indices, monthly HbA1c levels during 6 months of treatment were higher in the upper one‐third than in the lower one‐third of patients, and many patients did not achieve the target HbA1c level (53 mmol/mol) in the upper one‐third, although greater than fourfold more patients were administered insulin in the upper one‐third. Conclusions The combination of disease duration‐to‐age at diagnosis and HbA1c‐to‐CPR ratios is a collective risk factor that predicts response to the medications., Knowing the collective clinical factors that determine patient response to glucose‐lowering medication would be beneficial in the treatment of type 2 diabetes. The combination of disease duration‐to‐age at diagnosis and hemoglobin A1c‐to‐serum C‐peptide reactivity ratios is a collective risk factor that predicts the response to medications.

Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for eight weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart, and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.

BACKGROUND: STELLA-LONG TERM was a 3-year post-marketing surveillance study that evaluated the long-term safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis examined the safety and effectiveness of ipragliflozin in treatment-naïve and non-naïve patients. MATERIALS AND METHODS: Patients were stratified into two subgroups: treatment-naïve (patients who had not received any antidiabetic drugs before starting ipragliflozin monotherapy) and non-naïve (all other patients). Patients who had added or switched antidiabetic drugs during follow-up were excluded from the analysis from that point. The incidence of adverse drug reactions (ADRs) and changes from baseline in glycosylated hemoglobin (HbA1c), body weight, fasting plasma glucose (FPG) and laboratory parameters were assessed. RESULTS: Of the 11,051 patients in the safety analysis set, 1980 patients (17.92%) were treatment-naïve and 9071 (82.08%) were non-naïve. In the safety analysis set, treatment-naïve patients reported significantly lower incidences of ADRs (10.81% vs 20.87%; p

The aim of this study was to investigate the association between habitual dietary intake for patients with diabetes and the content of family support for medical nutritional therapy (MNT). Analyzed were 289 Japanese with type 2 diabetes (men, 58.5%, mean age, 62.0 years, mean HbA1c, 53.4 mmol/mol) who completed the Food Frequency Questionnaire and Diabetes Family Behavior Checklist (DFBC). Relationships of mean values for food group intake to DFBC responses regarding MNT were examined using multivariate analysis of covariance. Positive response to &ldquo, Praise for following diet&rdquo, was associated with lower sweets intake (none: 60.1 g/day, &ge, once monthly: 50.9 g/day, p = 0.038) and higher seasoning intake (none: 21.6 g/day, &ge, once monthly: 24.1 g/day, p = 0.046). Energy intake was higher with positive responses to &ldquo, Eat at the same time that you do&rdquo, (none: 1636 kcal/day, &ge, once monthly: 1818 kcal/day, p = 0.038). &ldquo, Nags about not following diet&rdquo, was associated with higher fish (none: 68.7 g/day, &ge, once monthly: 78.7 g/day, p = 0.042) and salt intake (none: 8.3 g/day, &ge, once monthly: 9.0 g/day, p = 0.014). Eating foods not part of the diabetic diet (none: 218.4 g/day, &ge, once monthly: 246.9 g/day, p = 0.014) resulted in a higher vegetable intake. In females, significant differences in relationships in the overall analysis were reversed. Our results clarified relationships between types of family support of patients with type 2 diabetes and their dietary intake and the importance of sex differences for more effective MNT.

The clinical implications of alcohol consumption have been extensively examined; however, its effects on brain structures in apparently healthy community-dwellers remain unclear. Therefore, we investigated the relationship between alcohol consumption and brain gray matter volume (GMV) in community-dwelling Japanese men using voxel-based morphometry (VBM). We recruited cognitively intact Japanese men, aged 40-79 years, from a population-based cohort in Shiga, Japan. Brain magnetic resonance imaging was performed, on average, 2 years after demographic and medical information was obtained in 2010-2014. A multivariable linear regression analysis of 639 men was conducted to elucidate the relationship between the amount of alcohol consumed and GMV. VBM statistics were analyzed by threshold-free cluster enhancement with a family-wise error rate of, Research members：Minoru Horie, Yoshihisa Nakagawa, Takashi Yamamoto, Yasutaka Nakano, Emiko Ogawa, Hiroshi Maegawa, Katsutaro Morino, Itsuko Miyazawa, Yoshiyuki Watanabe, Kazuhiko Nozaki, Ikuo Tooyama, Akihiko Shiino, Akira Andoh, Teruhiko Tsuru, Hisakazu Ogita, Naomi Miyamatsu, Yasuyuki Nakamura, Aya Kadota, Keiko Kondo, Sayuki Torii, Takashi Kadowaki, Sayaka Kadowaki, Sentaro Suzuki, Takahiro Ito, Ayako Kunimura, Hiroyoshi Segawa, Akira Fujiyoshi, Aya Higashiyama, Tomonori Okamura, Koichiro Azuma, Tatsuya Sawamura, Michiya Igase, Yasuharu Tabara, Akira Sekikawa, Emma J M Barinas-Mitchell, Daniel Edmundowicz, Takayoshi Ohkubo, Atsushi Hozawa, Yoshitaka Murakam, Nagako Okuda, Hisatomi Arima, Atsushi Satoh, Yoshikuni Kita, Takashi Hisamatsu, Masahiko Yanagita, Robert D Abbott, Seiko Ohno, Naoyuki Takashima, Naoko Miyagawa, Maryam Zaid, Yoshino Saito

Introduction There are limited real-world data on the prescribing of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for patients with type 2 diabetes mellitus (T2DM). Methods This was a retrospective analysis of the CoDiC® database of the Japan Diabetes Clinical Data Management Study Group (JDDM). Demographic and clinical characteristics, concomitant treatment patterns, and GLP-1 RA treatment persistence or modification in patients with T2DM initiating GLP-1 RA therapy were evaluated. Results The analysis included 932 eligible patients with T2DM who had their first GLP-1 RA prescription (index date) between September 2016 and July 2018. Mean age was 63.8 years and 56.0% were male. Most patients had an index GLP-1 RA of dulaglutide (65.7%) or liraglutide (29.1%). Common comorbidities were obesity (58.7%), hypertension (54.7%), dyslipidemia (52.0%), retinopathy (11.3%), and nephropathy (10.2%). Mean hemoglobin A1c (HbA1c) levels decreased from 8.3 to 7.8% over 6 months after GLP-1 RA initiation, and the proportion of patients achieving HbA1c, Plain Language Summary Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are drugs that patients with type 2 diabetes mellitus (T2DM) take to help control their blood sugar levels. In Japan, the GLP-1 RAs that doctors can prescribe are dulaglutide, exenatide, liraglutide, and lixisenatide as of May 2020. We conducted a study of how GLP-1 RAs are used to treat patients with T2DM in Japanese real-world clinical practice. We used a large database of anonymous information from hospitals and clinics in Japan. Over 900 adult patients started their first GLP-1 RA treatment for T2DM between September 2016 and July 2018. Before these patients started GLP-1 RA treatment, many were overweight, had high blood pressure, and had abnormal levels of lipids in their blood. Six months after starting GLP-1 RA treatment, on average these patients had lower hemoglobin A1c (a measure of average blood sugar levels), lower body weight, and better blood lipid levels than before they started GLP-1 RA treatment. Dulaglutide was the most common GLP-1 RA prescribed, then liraglutide. After 6 months, most patients (four-fifths) continued to use their GLP-1 RA treatment without stopping or changing to another treatment. After 18 months, half of the patients were still using their GLP-1 RA. Two-thirds of patients on dulaglutide and one-third of patients on liraglutide continued the treatment after 18 months. This study shows that GLP-1 RAs can benefit patients with T2DM in real-world clinical practice. It also shows that patients may be able to take long-term dulaglutide treatment. Supplementary Information The online version of this article (10.1007/s13300-020-00977-w) contains supplementary material, which is available to authorized users.

Background & aims:Although accurate assessment of energy intake (EI) is critical in diabetes care, underreporting of EI on dietary records (DR) is often an issue. However, few studies have examined EI with doubly labeled water (DLW) in patients with diabetes mellitus. We aimed to investigate the impact of sex and obesity on the dissociation of DR from total energy expenditure (TEE) evaluated with DLW in patients with type 2 diabetes., Methods:Fifty-two patients with type 2 diabetes aged 60–79 years were enrolled for the Clinical Evaluation of Energy Requirements in Patients with Diabetes Mellitus (CLEVER-DM) study at a single university hospital. TEE was measured over 14 days by the DLW method as standard. EI was calculated by assessment of 3-day DR by registered dietitians., Results:The mean difference between EI and TEE was 238 ± 412 kcal/day (~10% of TEE). Neither EI nor TEE was significantly different between obese (body mass index (BMI) ≥25 kg/m 2) and non-obese (BMI, Conclusions:EI calculated by 3-day DR may underestimate habitual intake, which is assumed to be equal to TEE measured by the DLW method except in non-obese women with diabetes., Clinical trial registration number:UMIN000023051.

Recent studies using genetically manipulated mouse models have shown the pivotal role of O‐linked N‐acetylglucosamine modification (O‐GlcNAcylation) in the metabolism of multiple organs. The molecular mechanism involves the sensing of glucose flux by the hexosamine biosynthesis pathway, which leads to the adjustment of cellular metabolism to protect against changes in the environment of each organ through O‐GlcNAcylation. More recently, not only glucose, but also fluxes of amino acids and fatty acids have been reported to induce O‐GlcNAcylation, affecting multiple cellular processes. In this review, we discuss how O‐GlcNAcylation maintains homeostasis in organs that are affected by diabetes mellitus: skeletal muscle, adipose tissue, liver and pancreatic β‐cells. Furthermore, we discuss the importance of O‐GlcNAcylation in the pathogenesis of diabetic complications. By elucidating the molecular mechanisms whereby cellular homeostasis is maintained, despite changes in metabolic flux, these studies might provide new targets for the treatment and prevention of diabetes and its complications., This article briefly reviews recent studies related with role of O‐linked N‐acetylglucosamine modification in specific organs in diabetes and its complications.

Aims/Introduction Specified Drug Use Results Survey of Ipragliflozin Treatment in Type 2 Diabetic Patients: Long‐term Use is an ongoing postmarketing study of ipragliflozin for long‐term use in Japanese patients with type 2 diabetes mellitus. A subgroup analysis of data from the study was carried out to investigate the impact of obesity on the efficacy and safety of ipragliflozin in this population. Materials and Methods Patients were divided into the following subgroups according to their body mass index (BMI)

Although both average BMI and foods vary greatly between Asian and Western countries, few studies have examined the relationship between dietary patterns and obesity in Asians. We investigated dietary patterns significantly associated with obesity in Japanese with diabetes. Cross-sectionally analyzed were 2070 Japanese with type 2 diabetes (mean age, 62 y; men, 62%) who completed the Food Frequency Questionnaire. Principal component analysis was performed on 20 food groups to elucidate dietary patterns significantly associated with obesity. We also divided participants into quintiles according to factor scores of each dietary pattern. The adjusted odds ratios (ORs) for obesity, defined as BMI ≥25 according to the Asian cutoff, were calculated with other covariates including energy intake. Six dietary patterns were determined from eigenvalues (≥1) and screen plots. For Factor 1, characterized by a well-balanced food group with high intake of light-colored vegetables, green and yellow vegetables, sugar, seaweed, beans, fish and seafood, fruit and potato, the OR for obesity in Quintile5 compared to Quintile1 was 0.34 (95% CI: 0.22-0.53). Conversely, that of Factor 2, characterized by high intake of seasoning and spices, sugar-sweetened beverages, rice and eggs, was 2.56 (1.69-3.89) (Table). In conclusion, a balanced diet with various food groups might help to avoid obesity in Japanese with type 2 diabetes. Disclosure M. Hatta: None. K. Fujihara: None. I. Ikeda: None. M. Takeuchi: None. R. Nedachi: None. S.Y. Morikawa: None. C. Horikawa: None. M. Kato: None. N. Kato: None. H. Maegawa: Speaker’s Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Takeda Pharmaceutical Company Limited. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.

Aim: The present study is the first to investigate association between Diabetic Kidney Disease (DKD) and Visit-to-Visit Variability (VVV) of HbA1c, blood pressure (BP), and body mass index (BMI) in patients with T2DM whose HbA1c, BP, and BMI were measured ≥12 times during a 2-year period. Material and Methods: This retrospective clinical trial initially analyzed data on 104,601 persons with T2DM in 38 clinical centers. We included 20- to 75-year-old patients whose HbA1c, systolic BP (SBP), and BMI were measured ≥12 times during a 2-year period. VVV was calculated using the coefficient of variation. VVVs of HbA1c, SBP, and BMI respectively, were divided into two groups by median value (high or low VVV). Risk of DKD were analyzed by multivariate logistic regression analysis. DKD was defined as urine albumin-to-creatinine ratio ≥30mg/g Cr or eGFR Results: A total of 12,575 patients who met the inclusion criteria were finally analyzed. Adjusted odds ratios (ORs) for high risk of DKD were 1.33 (95% CI 1.22-1.46, p < 0.001) for high VVV of HbA1c, 1.18 (1.08-1.28, p < 0.001) for high VVV of SBP, and 1.19 (1.10-1.30, p < 0.001) for high VVV of BMI. Male sex 1.29 (1.12-1.34, p < 0.001), advanced age, longer diabetes duration, presence of hypertension 1.19 (1.03-1.38, p = 0.02), anti-hypertensive agent use 1.40 (1.22-1.61, p < 0.001), presence of dyslipidemia 1.24 (1.11-1.39, p < 0.001), higher 2-year mean HbA1c, higher 2-year mean SBP, and higher 2-year mean BMI were also related to high risk of DKD. Additionally, the analysis of antidiabetic drug use revealed that particularly use of insulin 1.50 (1.34-1.68, p < 0.001) and sulfonylurea use 1.24 (1.13-1.37, p < 0.001) were associated with high risk of DKD. Conclusion: High VVV of HbA1c, SBP, and BMI were associated with DKD independently of mean HbA1c, SBP, and BMI values. Disclosure D. Matsutani: None. S. Minato: None. Y. Tsujimoto: None. H. Maegawa: Speaker’s Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Takeda Pharmaceutical Company Limited. M. Sakamoto: None.

Previous studies have shown that diabetes and obesity increase the severity of periodontal disease—a well-known risk factor for tooth loss. However, the effect of obesity on tooth loss has not yet been fully characterized. Thus, we investigated the association between obesity and residual teeth (number and sites) using a large database of the Japanese population. We used the MinaCare database, composed of data from Japanese health insurance claims and health check-ups in 2015 to select 233,517 subjects from 706,150 based on the availability of BMI, HbA1c, teeth, and smoking information. Obesity was defined as BMI ≥25.0. The number of residual teeth at every age group was correlated with 4 BMI subsets (30.0). The unadjusted and adjusted odds ratios (ORs) for fewer than 24 residual teeth were estimated using logistic regression models. The number of residual teeth decreased with age (p for trend Disclosure M. Hayashi: Employee; Self; Sunstar Group. K. Morino: None. K. Harada: Employee; Self; Sunstar Group. M. Ishikawa: None. I. Miyazawa: None. A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. H. Maegawa: Speaker’s Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Takeda Pharmaceutical Company Limited.

Introduction The present interim report of the STELLA-LONG TERM study aimed to examine the safety and effectiveness of ipragliflozin in real-word clinical practice in Japan using data up to 12 months. We also evaluated the effect of ipragliflozin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with normal vs. abnormal liver function. Methods This is an ongoing 3-year post-marketing surveillance study. We analyzed data from Japanese type 2 diabetes mellitus (T2DM) patients who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan, and whose data were locked by 16 January 2018. The incidence of adverse drug reactions (ADRs) was evaluated for safety. Changes in glycemic control and body weight were evaluated for effectiveness. The effect on liver function was evaluated by changes in the fatty liver index, and changes in AST and ALT were evaluated in patients with normal and abnormal liver function. Results The safety analysis set comprised 11,051 patients and the efficacy analysis set comprised 8788 patients. The incidence rates of ADRs and serious ADRs were 14.6% (1616/11,051) and 0.97% (107/11,051), respectively. Significant reductions (all P

OBJECTIVE Type 2 diabetes is frequently complicated with atherogenic dyslipidemia. This study aimed to evaluate the efficacy and safety of pemafibrate (K-877) in patients with type 2 diabetes comorbid with hypertriglyceridemia. RESEARCH DESIGN AND METHODS Patients were randomly assigned to three groups and received placebo (n = 57), 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks (treatment period 1). Subsequently, the patients received follow-up treatment for another 28 weeks (treatment period 2), in which the placebo was switched to 0.2 mg/day pemafibrate. This article presents the results of treatment period 1, which were the primary objectives. RESULTS The pemafibrate groups showed significantly reduced fasting serum triglyceride levels by ∼45% compared with the placebo group (P < 0.001). Additionally, the pemafibrate groups displayed significant decreases in non-HDL and remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, ApoB48, and ApoCIII levels and significant increases in HDL cholesterol and ApoA-I levels. LDL cholesterol levels were not considerably altered in the pemafibrate groups. Furthermore, the 0.2 mg/day pemafibrate group showed a significantly reduced HOMA–insulin resistance score compared with the placebo group; however, no significant changes compared with placebo were found in fasting plasma glucose, fasting insulin, glycoalbumin, or HbA1c levels. The pemafibrate groups also showed significantly increased fibroblast growth factor 21 levels compared with the placebo group. All groups displayed comparable rates of adverse events and drug reactions. CONCLUSIONS Pemafibrate significantly ameliorated lipid abnormalities and was well tolerated in patients with type 2 diabetes comorbid with hypertriglyceridemia.

Segmental progeroid syndromes with lipodystrophy are extremely rare, heterogeneous, and complex multi-system disorders that are characterized by phenotypic features of premature aging affecting various tissues and organs. In this study, we present a "sporadic/isolated" Japanese woman who was ultimately diagnosed with mandibular hypoplasia, deafness, progeroid features, and progressive lipodystrophy (MDPL) syndrome (MIM #615381) using whole exome sequencing analysis. She had been suspected as having atypical Werner syndrome and/or progeroid syndrome based on observations spanning a 30-year period; however, repeated genetic testing by Sanger sequencing did not identify any causative mutation related to various subtypes of congenital partial lipodystrophy (CPLD) and/or mandibular dysplasia with lipodystrophy (MAD). Recently, MDPL syndrome has been described as a new entity showing progressive lipodystrophy. Furthermore, polymerase delta 1 (POLD1) gene mutations on chromosome 19 have been identified in patients with MDPL syndrome. To date, 21 cases with POLD1-related MDPL syndrome have been reported worldwide, albeit almost entirely of European origin. Here, we identified a de novo mutation in exon 15 (p.Ser605del) of the POLD1 gene in a Japanese case by whole exome sequencing. To the best of our knowledge, this is the first identified case of MDPL syndrome in Japan. Our results provide further evidence that mutations in POLD1 are responsible for MDPL syndrome and serve as a common genetic determinant across different ethnicities.

Data regarding the efficacy and safety of sodium-glucose cotransporter 2 inhibitors in the real-world setting in Japan are limited. The STELLA-LONG TERM study is an ongoing 3-year post-marketing surveillance study of ipragliflozin in type 2 diabetes (T2D) patients. Here, we report the interim results (including 3-, 12-, and 24-month data).All Japanese patients with T2D who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan were registered in STELLA-LONG TERM.At 3, 12, and 24 months, the safety analysis set comprised 11,053, 5475, and 138 patients, respectively; the efficacy analysis set comprised 8757 patients. Ipragliflozin treatment resulted in statistically significant improvements versus baseline in hemoglobin A1c, fasting plasma glucose concentration, body weight, blood pressure, heart rate, and serum concentrations of low-density lipoprotein cholesterol and triglycerides. The adverse drug reaction incidence rate was 10.71%, the most common reactions being renal and urinary disorders (5.06%), infections and infestations (1.24%), and skin and subcutaneous tissue disorders (1.14%).Ipragliflozin was well tolerated and effective in Japanese patients with T2D; no new safety issues were identified.

Aim/Introduction Diabetes and obesity are important health and economic concerns. We investigated the influence of obesity on diabetes control, the annual medical expenditures, and medications in Japanese patients with type 2 diabetes who were relatively lean in comparison to those in Western countries. Materials and Methods A total of 402 Japanese patients with type 2 diabetes were enrolled and their annual medical expenditures investigated. Obesity was defined as body mass index over 25 kg/m2, according to the obesity classifications from the Japan Society for the Study of Obesity. Results A total of 165 patients (41.0%) were classified as obese. The obese group was younger, had poor glycemic control, and higher frequency of hypertension than the non-obese group. The median total annual medical expenditures for all participants was 269,333 Japanese yen (interquartile: 169,664 to 437,437 Japanese yen), which was equivalent to approximately 2,450 US dollars. The annual medical expenditure was significantly higher in patients with obesity than in non-obese patients (P

Aims/Introduction To investigate the current status of achieved blood pressure levels in association with the number of antihypertensive drug classes as of 2013, and to explore the clinical correlates with achievement of target blood pressure in a large-scale cohort of Japanese individuals with type 2 diabetes. Materials and Methods A nationwide survey was carried out including 12,811 individuals with type 2 diabetes. Participants were divided by achieved blood pressure

The specific sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) inhibit glucose reabsorption in proximal renal tubular cells, and both fasting and postprandial glucose significantly decrease because of urinary glucose loss. As a result, pancreatic β‐cell function and peripheral insulin action significantly improve with relief from glucose toxicity. Furthermore, whole‐body energy metabolism changes to relative glucose deficiency and triggers increased lipolysis in fat cells, and fatty acid oxidation and then ketone body production in the liver during treatment with SGLT2 inhibitors. In addition, SGLT2 inhibitors have profound hemodynamic effects including diuresis, dehydration, weight loss and lowering blood pressure. The most recent findings on SGLT2 inhibitors come from results of the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial. SGLT2 inhibitors exert extremely unique and cardio‐renal protection through metabolic and hemodynamic effects, with long‐term durability on the reduction of blood glucose, bodyweight and blood pressure. Although a site of action of SGLT2 inhibitors is highly specific to inhibit renal glucose reabsorption, whole‐body energy metabolism, and hemodynamic and renal functions are profoundly modulated during the treatment of SGLT2 inhibitors. Previous studies suggest multifactorial clinical benefits and safety concerns of SGLT2 inhibitors. Although ambivalent clinical results of this drug are still under active discussion, the present review summarizes promising recent evidence on the cardio‐renal and metabolic benefits of SGLT2 inhibitors in the treatment of type 2 diabetes.

Objective:To evaluate the long-term safety and effectiveness of ipragliflozin in real-world clinical practice in Japanese patients with type 2 diabetes mellitus (T2DM)., Research design and methods:This post-marketing surveillance study (STELLA-LONG TERM) included Japanese patients newly initiated on ipragliflozin between 17 July 2014 and 16 October 2015 (data lock: 30 September 2019). Survey items included demographics, treatments, adverse drug reactions (ADRs), vital signs, and laboratory variables., Results:Of 11,424 registered patients, safety and efficacy analysis sets comprised of 11,051 and 8,763 patients, respectively. ADRs occurred in 2,129 patients (19.27%) and serious ADRs occurred in 210 patients (1.90%). Renal and urinary disorders (n = 739, 6.69%), particularly polyuria/pollakiuria (n = 612, 5.54%) and volume depletion-events, including dehydration (n = 243, 2.20%), comprised the most common ADRs. Mean (SD) change in hemoglobin A1c (─0.66 [1.25] %), fasting plasma glucose (─28.8 [50.1] mg/dL) and body weight (─3.33 [4.32] kg) from baseline to 36 months were statistically significant (P < 0.001)., Conclusions:The safety profile of long-term ipragliflozin treatment in routine clinical practice is consistent with previously reported interim data at 12 or 24 months and pre-approval clinical trials. Ipragliflozin treatment was also associated with sustained improvements in efficacy parameters for over 3 years.

Background: Diabetes mellitus (DM) is a well-known risk factor for periodontal disease, independent of age and smoking. However, the relationship between glycaemic control and tooth loss has not been well characterized. We aimed to determine whether the haemoglobin A1c (HbA1c) level is associated with the number of teeth remaining. Methods: This was a cross-sectional study of 233,567 individuals aged 20–74 years in a database comprising health insurance claim and health check-up data that was collected between April 1, 2015 and March 31, 2016. The participants were allocated to five groups according to their HbA1c, and the number of teeth was compared between age-groups. DM was defined by an HbA1c ≥6·5%. Findings: Fifty-two-point-seven percent were women and the mean (SD) age was 47·7 (9·6) years. Higher HbA1c was associated with fewer teeth if >30 years of age ( P for trend 30 years of age ( P

Objective: STELLA-LONG TERM is an ongoing post-marketing surveillance study examining the safety and effectiveness of ipragliflozin in real-world clinical practice in Japan. This interim report of ...

Introduction: Evaluation of total energy expenditure (TEE) and physical activity level (PAL) is important for treatment of patients with type 2 diabetes mellitus (T2DM). However, the validity of accelerometers (ACC) and physical activity questionnaires (PAQ) for estimating TEE and PAL remains unknown in elderly populations with T2DM. We evaluated the accuracy of TEE and PAL results estimated by an ACC (TEEACC and PALACC) and a PAQ (TEEPAQ and PALPAQ) in elderly patients with T2DM. Methods: Fifty-one elderly patients with T2DM (aged 61–79 years) participated in this study. TEEACC was calculated with PALACC using a triaxial ACC (Active style Pro HJA-750c) over 2 weeks and predicted basal metabolic rate (BMR) by Ganpule’s equation. TEEPAQ was estimated using predicted BMR and the PALPAQ from the ­Japan Public Health Center Study-Long questionnaire. We compared the results to TEEDLW measured with the doubly labeled water (DLW) method and PALDLW calculated with BMR using indirect calorimetry. Results: TEEDLW was 2,165 ± 365 kcal/day, and TEEACC was 2,014 ± 339 kcal/day; TEEACC was strongly correlated with TEEDLW (r = 0.87, p < 0.01) but significantly underestimated (–150 ± 183 kcal/day, p < 0.05). There was no significant difference in TEEPAQ and TEEDLW (–49 ± 284 kcal/day), while the range of difference seemed to be larger than TEEACC. PALDLW, PALACC, and PALPAQ were calculated to be 1.71 ± 0.17, 1.69 ± 0.16, and 1.78 ± 0.24, respectively. ­PALACC was strongly correlated with PALDLW (r = 0.71, p < 0.01), and there was no significant difference between the 2 values. PALPAQ was moderately correlated with PALDLW (r = 0.43, p < 0.01) but significantly overestimated. Predicted BMR was significantly lower than the BMR ­measured by indirect calorimetry (1,193 ± 186 vs. 1,262 ± 155 kcal/day, p < 0.01). Conclusions: The present ACC and questionnaire showed acceptable correlation of TEE and PAL compared with DLW method in elderly patients with T2DM. Systematic errors in estimating TEE may be improved by the better equation for predicting BMR.

Laparoscopic sleeve gastrectomy has been proven effective in treating obesity-associated type 2 diabetes mellitus (T2DM). However, reports of the effect of laparoscopic sleeve gastrectomy on glucose metabolism in Japanese obese patients with T2DM are rare. The aim of this study was to evaluate the effects of laparoscopic sleeve gastrectomy on glucose tolerance in Japanese obese patients with T2DM, and to analyze factors influencing diabetes remission after surgery. This was a retrospective analysis of data for 24 consecutive patients with T2DM who underwent laparoscopic sleeve gastrectomy. We investigated weight loss and its impact on T2DM 1 year postoperatively. We also compared baseline characteristics and postoperative factors between patients who achieved diabetes remission and patients without remission. Mean body weight loss and percent total weight loss were 23.9 kg and 23.3%, respectively. Mean hemoglobin A1c levels dropped from 7.3 ± 0.3% to 6.1 ± 0.2%, and 18 patients (75%) achieved diabetes remission 1 year postoperatively. Patients achieving remission had significantly lower hemoglobin A1c levels (p = 0.026), higher fasting C-peptide values (p < 0.001), shorter diabetes duration (p < 0.001), lower insulin requirement (p = 0.002), and higher area under the insulin response curve (p < 0.001) and insulinogenic index (p < 0.001) during oral glucose tolerance testing. In conclusion, laparoscopic sleeve gastrectomy is an effective treatment for Japanese obese patients with T2DM. Preserving insulin secretion is the major determinant of diabetes remission.

Obesity is known to increase the risks of cardiovascular events and mortality in patients with diabetes. Low serum magnesium (Mg) levels are reportedly associated with obesity and incident diabetes mellitus among nondiabetic individuals. Since only a few studies have addressed the relationship between intake of Mg and obesity, we analyzed our nationwide registry of diabetic patients to determine if there was an association between intake of Mg and obesity in Japanese patients with T2DM. We analyzed data on 1891 Japanese patients with T2DM (mean age, 62 y; men, 62%) who completed a food frequency questionnaire. Obesity was defined as BMI ≥25. Associations between obesity and intake of Mg were determined by multivariate regression and quintile analyses. After adjusting for confounders including energy intake, the odds ratio (OR) for obesity was 0.93 (0.91,0.96) per 10 mg increase in Mg intake. Quintile analysis revealed a stepwise significant decrease in ORs for obesity from Q1 (lowest, ref.) to Q5 (highest) (Table). Food groups potently related to Mg intake in our patients were beans (correlation coefficients, 0.64), vegetables (0.62), and fish (0.57). These results imply that intake of Mg might be closely associated with obesity in patients with T2DM, which should have clinical relevance in nutrition therapy. Disclosure R. Nedachi: None. K. Fujihara: None. M. Hatta: None. Y. Matsubayashi: None. Y. Takeda: None. D. Ishii: None. C. Horikawa: None. M. Kato: None. H. Maegawa: Research Support; Self; Antares Pharma, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.