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Akihiro Uchida,1,* Taro Yasuma,1,2,* Atsuro Takeshita,1,2,* Masaaki Toda,2 Yuko Okano,1,2 Kota Nishihama,1 Corina N D’Alessandro-Gabazza,2 Valeria Fridman D’Alessandro,2 Chisa Inoue,1 Takehiro Takagi,3 Hiroyuki Mukaiyama,4 Norio Takagi,4 Katsumi Shimizu,4 Yutaka Yano,1 Esteban C Gabazza2 1Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan; 2Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan; 3Iwasaki Hospital, Tsu, Mie, Japan; 4Tanisake Corporation, Gifu, Japan*These authors contributed equally to this workCorrespondence: Esteban C GabazzaDepartment of Immunology, Mie University School of Medicine, Edobashi 2-174, Tsu-City, Mie, 514-8507, JapanTel +81 59 231 5037Fax +81 59 231 5225Email gabazza@doc.medic.mie-u.ac.jpIntroduction: Diabetes mellitus is a serious threat to public health worldwide. It causes a substantial economic burden, mental and physical disabilities, poor quality of life, and high mortality. Limonite is formed when iron-rich materials from the underground emerge and oxidized on the ground surface. It is currently used to purify contaminated water, absorption of irritant gases, and improve livestock breeding. Limonite can change the composition of environmental microbial communities. In the present study, we evaluated whether limonite can ameliorate glucose metabolism abnormalities by remodeling the gut microbiome.Methods: The investigation was performed using mouse models of streptozotocin-induced diabetes mellitus and high-calorie diet-induced metabolic syndrome.Results: Oral limonite supplement was associated with significant body weight recovery, reduced glycemia with improved insulin secretion, increased number of regulatory T cells, and abundant beneficial gut microbial populations in mice with diabetes mellitus compared to control. Similarly, mice with obesity fed with limonite supplements had significantly reduced body weight, insulin resistance, steatohepatitis, and systemic inflammatory response with significant gut microbiome remodeling.Conclusion: This study demonstrates that limonite supplement ameliorates abnormal glucose metabolism in diabetes mellitus and obesity. Gut microbiome remodeling, inhibition of inflammatory cytokines, and the host immune response regulation may explain the limonite’s beneficial activity under pathological conditions in vivo.Keywords: insulin resistance, limonite, diabetes, streptozotocin, metabolic syndrome, gut microbiome

BACKGROUND Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of islet β cells. It is a very rare disease generally associated with ketoacidosis and the absence of circulating pancreatic islet-related autoantibodies. Diabetic ketoacidosis with normal blood glucose levels has been reported during sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy. CASE SUMMARY The patient was a 43-year-old woman that consulted a medical practitioner for malaise, thirst, and vomiting. Blood analysis showed high blood glucose levels (428 mg/dL), a mild increase of hemoglobin A1c (6.6%), and increased ketone bodies in urine. The patient was diagnosed with type 2 diabetes mellitus. The patient was initially treated with insulin, which was subsequently changed to an oral SGLT2 inhibitor. Antibodies to glutamic acid decarboxylase were negative. Four days after receiving oral SGLT2 inhibitor, she consulted at Mie University Hospital, complaining of fatigue and vomiting. Laboratory analysis revealed diabetic ketoacidosis with almost normal blood glucose levels. The endogenous insulin secretion was markedly low, and the serum levels of islet-related autoantibodies were undetectable. We made the diagnosis of FT1DM with concurrent SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis. The patient's general condition improved after therapy with intravenous insulin and withdrawal of oral medication. She was discharged on day 14 with an indication of multiple daily insulin therapy. CONCLUSION This patient is a rare case of FT1DM that developed SGLT2 inhibitor-associated diabetic ketoacidosis with almost normal blood glucose levels. This case report underscores the importance of considering the diagnosis of FT1DM in patients with negative circulating autoantibodies and a history of hyperglycemia that subsequently develop euglycemic diabetic ketoacidosis following treatment with a SGLT2 inhibitor.

Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-β1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-β1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-β1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis., Idiopathic pulmonary fibrosis is associated with increased abundance of Staphylococcus and Streptococcus in the lungs. Here, the authors identify a Staphylococcus nepalensis-derived peptide, named corisin, to induce apoptosis of lung epithelial cells and exacerbation of pulmonary fibrosis in mice.

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

Background A higher risk of cardiovascular events has been reported in patients with hypertension due to primary aldosteronism (PA) than essential hypertension. This study sought to determine the independent predictors for the risk of cardiovascular events in hypertensive patients with PA. Methods The Japan Primary Aldosteronism Study (JPAS) has retrospectively recruited 3,654 patients with PA between January 2006 and January 2019 as a nationwide registry and we evaluated the differences between patients with and without AF from these data. The patients underwent general laboratory test, electrocardiography, echocardiography, diagnostic confirmatory tests including saline-loading, captopril-challenge, and upright furosemide-loading tests and adrenal venous sampling (AVS). We evaluated the cardiovascular events including myocardial infarction, stroke, heart failure and renal failure, with a mean follow-up duration of approximately 4 years. Results The prevalence of AF was 2.4% (88/ 3,654). PA patients with AF were older (60.3 vs 52.8 years old), more male (77.3% vs 46.6%) and had longer duration of hypertension (14.3 vs 8.3 years) than those without AF. Each prevalence of cerebral infarction (12.5% vs 3.5%), chronic kidney disease (12.5% vs 4.8%), coronary artery disease (CAD) (10.2% vs 1.7%), heart failure (5.7% vs 0.7%) and left ventricular hypertrophy evaluated by echocardiography (46.4% vs 31.9%) was higher in PA patients with AF. Patients with AF had more kinds of antihypertensive drugs (1.3 vs 1.1). There was no significant difference of basal plasma aldosterone concentration (PAC), plasma renin activity, each confirmatory tests, lateralized ratio in AVS after stimulation with adrenocorticotropic hormone (ACTH) and laterality between the 2 groups. Logistic regression analysis showed that age, cardiothoracic ratio (CTR), past history of CAD and heart failure were independent determinants for AF. PA patients with AF had higher rates of cardiovascular events compared to those without AF (Figure, P Conclusions This study provides evidence that comorbid AF is associated with older age, male sex, X-ray CTR and prevalence of CAD and heart failure. Furthermore, AF is an independent predictor of cardiovascular events in patients with PA, in addition to the adrenal venous concentration of aldosterone, hypokalemia, older age and duration of hypertension. Earlier recognition and intervention of AF can prevent cardiovascular events in PA. Funding Acknowledgement Type of funding sources: None. Figure 1

Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorβ1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorβ1 is associated with insulin resistance and the rapid progression of transforming growth factorβ1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorβ1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorβ1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorβ1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorβ1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

Introduction: A higher risk of cardiovascular events has been reported in patients with hypertension due to primary aldosteronism (PA) than essential hypertension. Hypothesis: This study sought to determine the independent predictors for the risk of cardiovascular events in hypertensive patients with PA. Methods: The nation-wide PA registration study (JPAS/JRAS) included patients aged 20 years and older. Data were collected between January 2006 and January 2019, with a mean follow-up duration of approximately 4 years. Characteristics of patients with or without atrial fibrillation (AF) on the diagnosis of PA were compared. Patients were treated by surgery or MR antagonists and incident cardiovascular events were followed up. Results: A total of 3,647 patients with PA were included at the time of analysis. Prevalence of AF was 2.4% (87/ 3,647). PA patients with AF were older, more male and had longer duration of hypertension than those without AF. Each prevalence of cerebral infarction, chronic kidney disease, coronary artery disease, heart failure and left ventricular hypertrophy evaluated by echocardiography was higher in PA patients with AF than those without AF. Patients with AF had more kinds of antihypertensive drugs. There was no significant difference of basal plasma aldosterone concentration, plasma renin activity, unilateral subtype and rate of surgery between the 2 groups. PA patients with AF had higher rates of cardiovascular events compared to those without AF (14.9% vs 6.7%, P=0.002). Multivariate cox regression analyses demonstrated AF in addition to older age, male gender, duration of hypertension and surgery performance as an independent prognostic factor for cardiovascular events (HR, 1.950 [95%CI, 1.021-3.726], P Conclusions: Among patients with PA, male gender, older age, and longer duration of hypertension are the predisposing factors of AF in PA patients. In addition, AF was an independent risk factor for cardiovascular events in PA patients. It is warranted to prevent and to treat appropriately AF in patients with PA.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Background and study aims Magnifying endoscopy with narrow-band imaging (M-NBI) is reported to be useful in diagnosing invasion depth of superficial esophageal squamous cell carcinoma (SCC), but accurate diagnosis of deep submucosal invasion (SM2) has remained difficult. However, we discovered that irregularly branched microvessels observed with M-NBI are detected in SM2 cancers with high prevalence. Thus, this retrospective study aimed to investigate the diagnostic performance of irregularly branched microvessels as visualized by M-NBI for predicting SM2 cancers. Patients and methods Patients with superficial esophageal SCC lesions that were endoscopically or surgically resected at our hospital between September 2005 and December 2014 were included. Endoscopic findings by M-NBI of these lesions were presented to an experienced endoscopist who was unaware of the histopathological diagnosis and who then judged whether irregularly branched microvessels were present. Using the invasion depth according to postoperative histopathological diagnosis as the gold standard, we determined the diagnostic performance of the presence of irregularly branched microvessels as an indicator for SM2 cancers. Results A total of 302 superficial esophageal SCC lesions (228 patients) were included in the analysis. When irregularly branched microvessels were used as an indicator of SM2 cancers, the diagnostic accuracy was 94.0 % (95 % confidence interval [CI]: 91.1–96.1 %), sensitivity was 79.4 % (95 % CI: 66.6–88.4 %), specificity was 95.9 % (95 % CI: 94.3–97.0 %), positive predictive value was 71.1 % (95 % CI: 59.6–79.1 %), and negative predictive value was 97.3 % (95% CI: 95.7–98.5 %). Conclusions Irregularly branched microvessels may be a reliable M-NBI indicator for the diagnosis of cancers with deep submucosal invasion.

Background. We have observed changes in body reactions during cooking, which is one of the treatment modalities used in occupational therapy. The perception of food-related odors during cooking may have behavioral effects on human activities through the activation of appetitive motivation. Objectives. We investigated whether odor components contained in seasonings could facilitate the human motor system and the specificity of this effect. Methods. The subjects were 72 healthy adults, randomly assigned to a water exposure group, a phenylethyl alcohol (PEA, pleasant rose-like odor) exposure group, and a Japanese soy sauce (Koikuchi Shoyu) exposure group (n=24 each). The subjects’ olfactory sense was stimulated by their sniffing of three different test tubes containing 5 ml of water, PEA, or Japanese soy sauce for 20 sec while they were seated. The modified Functional Reach Test (mFRT), which mimics a functional activity that is required in daily living and assesses a reliable measure of sitting balance, was performed prior to and immediately after the sniffing. Results. Sniffing the soy sauce increased the subjects’ mFRT scores. This facilitation effect was odorant-specific and was absent when the subjects were presented with water or PEA. Conclusions. Cooking interventions are aimed at improving tool-handling skills such as using knives and chopsticks. The results indicate that treatment interventions using odors of seasonings would be effective for improving subjects’ physical functions.

Patient: Female, 65-year-old Final Diagnosis: Type 1 diabetes mellitus Symptoms: Unconsciousness Medication:— Clinical Procedure: Insulin pump Specialty: Endocrinology and Metabolic Objective: Unusual or unexpected effect of treatment Background: Hypoglycemia is a frequent complication observed in diabetic patients under treatment. This metabolic complication is associated with an increased mortality rate in diabetic patients. The use of sensor-augmented pump therapy with predictive low glucose management systems has improved blood glucose level control and reduced the incidence of hypoglycemic attacks. However, this therapy may be associated with adverse events. Case Report: A 65-year-old Japanese woman with type 1 diabetes mellitus underwent hemodialysis with end-stage renal failure due to diabetic nephropathy. The patient received sensor-augmented pump therapy with the predictive low glucose management system to prevent recurrent severe hypoglycemia. Hypoglycemia was infrequent when the sensor-augmented pump therapy with a predictive low-glucose management system was properly working. However, the patient suddenly died 3 months after starting the treatment. A record of continuous glucose monitoring showed that hypoglycemia occurred before the sudden death of the patient. Conclusions: The current case shows that sudden death associated with severe hypoglycemia may also occur during sensor-augmented pump therapy with a predictive low glucose management system. This case report underscores the need for close follow-up of diabetic patients receiving sensor-augmented pump therapy with the predictive low glucose management system and the critical importance of patient education on diabetes technology in high-risk patients.

Case A 64-year-old Japanese woman with diabetes mellitus was admitted for hypoglycemia. Her diabetes had been under good control with glimepiride, voglibose, exenatide, and metformin for a few years. Although overt proteinuria was observed, the serum creatinine values were within normal range during the routine outpatient follow-up. Hypoglycemic attack caused by glimepiride and loss of appetite by urinary tract infection were diagnosed. Then, metformin-associated lactic acidosis with acute renal failure caused by dehydration was detected. Outcome Her condition was improved by continuous veno-venous hemodiafiltration and hemodialysis, known to be useful to remove metformin. Conclusion We reported a case of metformin-associated lactic acidosis with hypoglycemia during routine treatment of diabetes that was successfully rescued by early renal replacement therapy.

Protein S is an anticoagulant factor that also regulates inflammation and cell apoptosis. The effect of protein S on diabetes and its complications is unknown. This study compared the development of diabetes between wild-type and transgenic mice overexpressing human protein S and the development of diabetic glomerulosclerosis between mice treated with and without human protein S and between wild-type and protein S transgenic mice. Mice overexpressing protein S showed significant improvements in blood glucose level, glucose tolerance, insulin sensitivity, and insulin secretion compared with wild-type counterparts. Exogenous protein S improved insulin sensitivity in adipocytes, skeletal muscle, and liver cell lines in db/db mice compared with controls. Significant inhibition of apoptosis with increased expression of BIRC3 and Bcl-2 and enhanced activation of Akt/PKB was induced by protein S in islet β-cells compared with controls. Diabetic wild-type mice treated with protein S and diabetic protein S transgenic mice developed significantly less severe diabetic glomerulosclerosis than controls. Patients with type 2 diabetes had significantly lower circulating free protein S than healthy control subjects. This study shows that protein S attenuates diabetes by inhibiting apoptosis of β-cells and the development of diabetic nephropathy.

The early stages of acromegaly are characterized by slow and progressive acral overgrowth without major systemic complications. Failure to diagnose acromegaly at an early stage may have devastating consequences on patient care. The case in the present report was a 44-year-old Japanese man, referred to Kuwana City Medical Center due to severe hyperglycemia detected in a general checkup. The patient had no acromegaly-related complaints. Laboratory data revealed high blood levels of hemoglobin A1c and glucose. Careful physical examination revealed enlargement of extremities and soft tissues. Laboratory investigation indicated a high blood concentration of growth hormone, and magnetic resonance imaging disclosed an enhanced pituitary tumor. The diagnosis was pituitary tumor-associated acromegaly with severe diabetic complications. The pituitary tumor became large and unresectable following 10 years of misdiagnosis. The patient was treated with somatostatin receptor ligands (lanreotide and pasireotide), as well as bromocriptine in Mie University Hospital. The tumor size was reduced following treatment, though it was still unresectable at the time of this report. The case highlights the importance of hyperglycemia and abnormal manifestations of the feet in patients with acromegaly. In addition, these findings highlight the need for a thorough examination of the feet in diabetic patients, and the critical importance of the early diagnosis of acromegaly for preventing the consequences of inappropriate patient care.

A 47-year-old woman with diabetes treated with high-dose insulin was admitted to Mie University Hospital, Tsu, Japan, for screening of secondary diabetes mellitus and obesity. Laboratory tests and imaging studies were consistent with Cushing's disease (CD). The patient underwent trans-sphenoidal pituitary surgery. The patient exhibited loss of body weight (85.9 to 80.0 kg), improved glycated hemoglobin (HbA1c) (11.2 to 7.8%) and required lower doses of insulin (112 to 46 U/day) 6 months after surgery. The patient's body weight and daily insulin dose remained stable during the following 5 months (6–11 months after surgery). At that point, the patient was administered with canagliflozin, a sodium-glucose cotransporter 2 inhibitor. The patient required lower daily insulin dose without decreasing the dose of postoperative hydrocortisone concurrent to the administration of canagliflozin (100 mg/day). The patient's body weight decreased to 69.5 kg and withdrawal of insulin therapy was possible 8 months after initiation of canagliflozin. Despite withdrawal of insulin therapy, the HbA1c levels remained at

Background In this study, survival and cause of death were investigated in patients with Crohn’s disease (CD) at a tertiary referral center. Methods A database was created based on the medical records of 1108 CD patients who had a history of visiting our hospital to investigate background characteristics, cumulative survival rates from diagnosis, causes of death, and the standardized mortality ratio (SMR) for each cause of death. A follow-up questionnaire survey of patients followed up inadequately was also conducted. The cumulative survival rate from diagnosis was determined using the life table method and compared with that of a sex- and age-matched population model from the year 2000. Results The study included 1108 patients whose mean age at diagnosis was 25.6 ± 10.8 years. The mean duration of follow-up was 14.6 ± 9.4 years, and there were 52 deaths. The cumulative survival rate was significantly lower 25 years after the diagnosis of CD (91.7%) than in the standard population model (95.7%). SMRs for both all causes [3.5; 95% confidence interval (CI): 2.7–4.6] and CD-specific causes (36.7; 95% CI 26.1–51.6) were high. Among the CD-specific causes, SMRs were especially high for small intestine and colorectal cancers, gastrointestinal diseases including intestinal failure (IF), perioperative complications, and amyloidosis. Conclusion The SMRs for both all causes and CD-specific causes were high in CD patients. CD-specific causes including intestinal cancer, IF, perioperative complications, and amyloidosis showed especially high SMRs.

It remains unknown which surrogate markers can predict diagnostic test results for primary hyperaldosteronism (PA). The Secondary Hypertension Registry Investigation in Mie Prefecture (SHRIMP) study has sequentially and prospectively recruited 128 patients with hypertension with an aldosterone-to-renin ratio (ARR) greater than 20, evaluated the differences among essential hypertension (EHT), idiopathic hyperaldosteronism (IHA), and aldosterone-producing adenoma (APA), and analyzed the predictors for the confirmatory tests. The patients underwent saline-loading, captopril-challenge, and upright furosemide-loading tests. Carotid, renovascular, and cardiac echography, brachial ankle pulse wave velocity (baPWV), endothelial function, nocturnal blood pressure decline, and the apnea hypopnea index were evaluated. Multivariate regression analyses showed that the plasma aldosterone concentration (PAC) at screening was a strong predictor of the saline and captopril test results. The plasma renin activity (PRA) at screening, urine β2-microglobulin, and left ventricular mass index (LVMI) were independent predictors for the captopril test. The estimated saline PAC and captopril 60 and 90 min ARRs predicted by the equations were highly correlated with the real values. The ROC curve analysis showed PAC at screening among each of predictors for the diagnostic tests and PAC after the saline-loading test had the highest diagnostic abilities of APA. Patients with IHA were older and had glucose intolerance and increased U-Alb/gCre and resistive indices. In patients with APA, the levels of U-Alb/gCre and urine β2-microglobulin were increased, and levels of insulin and the HOMA-IR were decreased. In conclusion, our proposed equations may be useful for estimating saline PAC and captopril ARR. Diagnostic predictors may differ for each confirmatory test.

In Japan, the incidence of type 2 diabetes mellitus (T2DM) is increasing for several reasons, including increased consumption of sugar-sweetened beverages (SSBs). However, whether SSBs cause T2DM by excess of energy production resulting in obesity remains unclear. Therefore, the present study was designed to evaluate the effects of SSB intake on the development of T2DM in subjects with impaired glucose tolerance (IGT). Ninety-three subjects (30 males and 63 females) with IGT aged 40-69 y and residing in the Mihama district (southern Mie Prefecture, Japan) were included in the study. The mean observational period was 3.6 y. All subjects underwent the 75-g oral glucose tolerance test (OGTT) and completed a lifestyle questionnaire survey related to SSB intake. OGTT results and SSB intake were evaluated before and after the observational period. In addition, the correlation between SSB intake and development of T2DM was investigated. Of the 93 subjects, 20 (21.5%) developed T2DM (T2DM group) and demonstrated a significantly high SSB intake compared with the group that did not develop the disease (non-T2DM group). The odds ratio for the incidence of T2DM based on SSB intake was 3.26 (95% confidence interval, 1.17-9.06). The body mass index (BMI; kg/m(2)) and the homeostasis model assessment for insulin resistance (HOMA-R) values was significantly higher in the T2DM group than in the non-T2DM group, while the insulinogenic indices were significantly lower in the former than in the latter group. The sum of insulin secretion levels during OGTT was not significantly different between groups. SSB intake correlated with the predisposition for developing T2DM, possibly by influencing body weight, insulin resistance, and the ability of the pancreatic beta cells to effectively compensate for the insulin resistance.

Background Chronic progression of diabetes is associated with decreased pancreatic islet mass due to apoptosis of β-cells. Patients with diabetes have increased circulating matrix metalloproteinase-2 (MMP2); however, the physiological significance has remained elusive. This study tested the hypothesis that MMP2 inhibits cell apoptosis, including islet β-cells. Methods Samples from diabetic patients and newly developed transgenic mice overexpressing human MMP2 (hMMP2) were harnessed, and diabetes was induced with streptozotocin. Results Circulating hMMP2 was significantly increased in diabetic patients compared to controls and significantly correlated with the serum C-peptide levels. The diabetic hMMP2 transgenic mice showed significant improvements in glycemia, glucose tolerance and insulin secretion compared to diabetic wild type mice. Importantly, the increased hMMP2 levels in mice correlated with significant reduction in islet β-cell apoptosis compared to wild-type counterparts, and an inhibitor of hMMP2 reversed this mitigating activity against diabetes. The increased activation of Akt and BAD induced by hMMP2 in β-cells compared to controls, links this signaling pathway to the anti-apoptotic activity of hMMP2, a property that was reversible by both an hMMP2 inhibitor and antibody against integrin-β3. Conclusion Overall, this study demonstrates that increased expression of hMMP2 may attenuate the severity of diabetes by protecting islet β-cells from apoptosis through an integrin-mediated activation of the Akt/BAD pathway.

Summary Background Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. Methods In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45–69 years with hypertension, dyslipidaemia, or both, and an HbA 1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA 1c 1c 1c , and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Findings Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3–9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA 1c , systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p vs 283 [22%] in the conventional therapy group, p vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Interpretation Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Funding Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.

Background and Aim The prevalence of ulcerative colitis (UC) is increasing steadily in Japan. In Western countries, a bimodal distribution, with UC onset peaks in youth and middle age, is observed, and smoking cessation is reported as a risk factor for UC. However, there are few reports on a bimodal distribution of onset age among Japanese patients. Therefore, the distribution of onset age and factors related to late onset (i.e. onset at 50 years old or later) were investigated in UC patients in Japan. Methods A questionnaire survey of UC patients was conducted to investigate the distribution of the age of onset and factors that may be related to UC onset in a Japanese university hospital. Results Among 465 UC patients, 343 patients responded. In the distribution of onset age, a large peak was seen in patients aged 10–20s, and small peaks were seen at age 40–44 years and then in 50–60s. In addition, the onset age was older in the UC patients diagnosed in 2001 or later than in those diagnosed in 2000 or earlier. Late onset was more common among the UC patients diagnosed in 2001 or later (vs 2000 or earlier: interaction odds ratio = 4.98, 95% CI: 2.21–11.25, P

Background and Aim The aim of the present study was to endoscopically evaluate ileal mucosal healing during maintenance therapy with infliximab in order to investigate the clinical significance of endoscopic examination of ileal lesions in Crohn's disease patients. Methods This study retrospectively analyzed 54 patients who mainly had active ulcers of the ileum on endoscopy at baseline who were responsive to infliximab induction and who received infliximab maintenance therapy. Mucosal healing was defined as no ulcer or only ulcer scar. At the time of follow-up endoscopy after starting infliximab, endoscopic score, mucosal healing, and clinical remission were evaluated. On long-term follow up, correlations between mucosal healing and long-term clinical remission, and between mucosal healing and the need for major abdominal surgery, were also evaluated. Results Ileal mucosal healing and complete mucosal healing were significantly correlated with clinical remission (P = 0.046, P = 0.0001, respectively). The rate of long-term clinical remission was significantly higher in patients with complete mucosal healing (P = 0.025). The rate of major abdominal surgery for strictures was significantly lower in patients with complete mucosal healing (P = 0.044). Conclusions Complete mucosal healing after 1–2 years was a predictive factor for long-term clinical remission up to 4 years after starting infliximab. A lack of complete mucosal healing was a predictive factor for major abdominal surgery for strictures. The present study suggests that endoscopic evaluation of ileal lesions is useful for long-term prognosis of Crohn's disease patients.