Characterization of mutations in hepatitis B virus DNA isolated from Japanese HBsAg-positive blood donors in 2021 and 2022.

Missense mutations in certain small envelope proteins diminish the efficacy of antibodies. Consequently, tracking the incidence and types of vaccine-escape mutations (VEMs) was crucial both before and after the introduction of universal hepatitis B vaccination in Japan in 2016. In this study, we isolated hepatitis B virus (HBV) DNA from 58 of 169 hepatitis B surface antigen (HBsAg)-positive blood samples from Japanese blood donors and determined the nucleotide sequence encoding the small envelope protein. DNA from six (10%) of the samples had VEMs, but no missense mutations, such as G145R, were detected. Complete HBV genome sequences were obtained from 29 of the 58 samples; the viral genotype was A1 in one (3%), A2 in three (10%), B1 in nine (31%), B2 in five (17%), B4 in one (3%), and C2 in 10 (34%) samples. Tenofovir-resistance mutations were detected in two (7%) samples. In addition, several core promoter mutations, such as 1762A>T and 1764G>A, and a precore nonsense mutation, 1986G>A, which are risk factors for HBV-related chronic liver disease, were detected. These findings provide a baseline for future research and highlight the importance of ongoing monitoring of VEMs and drug resistance mutations in HBV DNA from HBsAg-positive blood donors without HBV antibodies.

Mycobacterium bovis BCG-mediated suppression of Th17 response in mouse experimental autoimmune encephalomyelitis.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease mediated by a pro-inflammatory immune response. Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with a myelin oligodendrocyte glycoprotein (MOG) peptide emulsified in killed Mycobacterium tuberculosis-containing complete Freund's adjuvant (CFA-EAE) is used as a model of MS. Mycobacterium bovis BCG has been reported to ameliorate clinical symptoms of CFA-EAE, although the precise mechanism has not yet been documented. Since CFA-EAE uses adjuvant with mycobacterial antigens, mycobacterial antigen-specific T cells induced by CFA may cross-react with BCG and modulate EAE. METHODS: To exclude the influence of cross-reactivity, a modified murine EAE model (cell wall skeleton (CWS)-EAE) that does not induce mycobacterial antigen-specific T cells was established and used to reevaluate the therapeutic effects of BCG on EAE. RESULTS: Inoculation with BCG 6 d after CWS-EAE induction successfully ameliorated EAE symptoms, suggesting that the therapeutic effects of BCG are independent of the mycobacterial antigen-specific T cells induced by the CFA-EAE protocol. BCG inoculation into the CWS-EAE mice resulted in reduced levels of MOG-specific Th17 in the central nervous system (CNS) with reduced demyelinated lesions of the spinal cord. In the draining lymph nodes of the MOG-immunized sites, BCG inoculation resulted in an increase in MOG-specific Th17 and Th1 cells at an early stage of immune response. CONCLUSION: The results suggest that BCG inoculation suppresses the Th17 response in the CNS of EAE mice via a mechanism that may involve the suppression of egress of encephalitogenic T cells from lymphoid organs.

Short duration of diabetes and disuse of sulfonylurea have any association with insulin cessation of the patients with type 2 diabetes in a clinical setting in Japan (JDDM 30).

Insulin therapy is often required to achieve good glycemic control for the patients with type 2 diabetes mellitus (T2DM), while protraction of glycemic control without insulin therapy may be preferable for patients. To determine the characteristics of and therapeutic regimen in outpatients with T2DM who were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan by a case-control study. The present study was performed on 928 patients with T2DM who started insulin therapy in 2007. Data regarding age, sex, body mass index, duration of diabetes, HbA1c, postprandial plasma glucose, plasma fasting C-peptide immunoreactivity and treatment modality were compared between patients who were able to stop insulin therapy and those who continued with insulin. Of the 928 patients, 37 had stopped insulin therapy within 1 year. In the patients who stopped insulin therapy, the duration of diabetes was significantly shorter and the daily insulin dosage at initiation and the prevalence of sulfonylurea pretreatment significantly lower compared with patients who continued on insulin. In conclusion, almost 4% of T2DM patients were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan. Shorter duration of diabetes and disuse of sulfonylureas prior to insulin may associate with stopping insulin therapy as a near-normoglycemic remission in outpatients with T2DM in Japan.

Changes in prescription patterns and doses of oral antidiabetic drugs in Japanese patients with type 2 diabetes (JDDM70).

We assessed the prescription patterns of oral antidiabetic drugs in Japanese patients with type 2 diabetes between 2002 and 2020 using data from the Computerized Diabetes Care database. Among 172,960 patients treated with oral antidiabetic drugs, both the sulfonylurea prescription rate and dose decreased from 2002 to 2020. Prescriptions of biguanides, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors increased; their dose and dose frequency remained relatively stable. Trends in oral antidiabetic drug prescriptions changed over time, reflecting guideline recommendations and existing evidence.

Self-reported rate of eating is significantly associated with body mass index in Japanese patients with type 2 diabetes. Japan Diabetes Clinical Data Management Study Group (JDDM26).

We examined whether the rate of eating was associated with the body mass index and glycemic control status in Japanese patients with type 2 diabetes (50% women, mean±SD age 59.4±7.5 years). Rapid eating was significantly associated with body mass index (p=0.047). The body mass index of those who reported eating quickly was 0.8 kg/m² higher than in individuals who reported eating at medium speed even after adjustment for known confounders. No significant association was observed between the rate of eating and HbA(1c). Our findings suggest an association between self-reported rapid eating and an elevated body mass index in patients with type 2 diabetes.

Current status of oral antidiabetic drug prescribing patterns based on the body mass index for Japanese type 2 diabetes mellitus patients and yearly changes in diabetologists' prescribing patterns from 2002 to 2019 (JDDM61).

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 <30 kg/m2 , they were the third most prescribed 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.

Cross sectional study on proportion of sulfonylureas among various oral antidiabetic drugs using for Japanese patients with type 2 diabetes, analyzed from NSAID Study-2.

AIM: We aimed to investigate the certainty of using sulfonylureas in Japanese patients with type 2 diabetes mellitus (T2DM) by analyzing data from the 2018 Nationwide Survey on Actual Intervention for T2DM by Japanese Practitioners (NSAID Study). METHODS: Of the 6525 and 1545 participants in the NSAID Study under the care of general practitioners (GP) and diabetes specialists (SP), respectively, we included 5423 (83.1%) and 1058 (68.5%) patients who were treated with only oral antidiabetic drugs (OADs) by GPs and SPs, respectively, in the analysis. RESULTS: Among the seven OAD classes in monotherapy, sulfonylureas were the third and fifth most prescribed OADs by GPs (7.1%) and SPs (6.4%), respectively. Sulfonylurea usage increased with combination therapy. Glimepiride was the most commonly prescribed sulfonylurea. Patients who used sulfonylureas had higher hemoglobin A1c (HbA1c) levels and lower body mass indices (BMIs) than patients who did not use sulfonylureas. CONCLUSION: The results of this study clearly demonstrated that, among the OADs, sulfonylureas were not frequently used in monotherapy, although the opportunity of using sulfonylurea increased with the number of OADs prescribed in combination therapies by both GPs and SPs in Japan. Moreover, low-dose glimepiride was the most-prescribed sulfonylurea for Japanese T2DM patients, especially for those who were lean and had higher HbA1c levels.

Differences in Dental Care Referral for Diabetic Patients Between General Practitioners and Diabetes Specialists in Japan, Analyzed from NSAID-Study 3.

INTRODUCTION: Periodontal disease is a common inflammation worldwide and is not only the foremost cause of tooth loss but also a cause of deterioration of glycemic control in patients with diabetes mellitus. In addition, effective glycemic management improves the control of periodontitis infection. The aim of this study was to clarify whether awareness of the need to refer their patients with diabetes to dentists differs between general practitioners and diabetes specialists. This was achieved by secondary analysis of data from the 2018 Nationwide Survey on Actual Intervention for Type 2 Diabetes Mellitus (T2DM) by Japanese Practitioners (NSAID Study). METHODS: Data from 380 general practitioners and 79 diabetes specialists who participated in the NSAID study and responded to the question of whether they referred T2DM patients to the dentist were analyzed in this study. RESULTS: The proportion of general practitioners who referred T2DM patients to dentists was significantly lower than that of diabetes specialists (35.4% vs. 64.1%, respectively). CONCLUSION: This result suggests that the general practitioners who participated in this study were less cognizant of oral hygiene in patients with diabetes than those who specialized in diabetes. It is also necessary to increase the opportunities for education of physicians who provide diabetic care to promote appropriate dental referrals.

Periodontal disease is a common inflammation worldwide and not only causes tooth loss but also the deterioration of glycemic control in patients with diabetes. In addition, effective glycemic management improves the control of periodontitis infection. Physicians who care for diabetes patients need to be aware of the increased risk and need for improved oral hygiene and to refer their patients to dentists. This study aims to clarify whether awareness of the need to refer their patients with diabetes to dentists differs between general practitioners and diabetes specialists. Responses from 380 general practitioners and 79 diabetes specialists are analyzed in this study. The proportion of general practitioners who refer type 2 diabetes patients to dentists is shown to be significantly lower than that of diabetes specialists. It is necessary to increase the opportunities for education of physicians who provide diabetic care to promote appropriate dental referrals.

Present status of sulfonylurea treatment for type 2 diabetes in Japan: second report of a cross-sectional survey of 15,652 patients.

Sulfonylureas are commonly used for the treatment of patients with type 2 diabetes mellitus (T2DM). However, some clinical concerns regarding their use have grown over the past decade. Thus, results of a previous Japan-wide cross-sectional survey of patients with type 2 diabetes mellitus (T2DM) were analyzed to determine the present status and problems associated with the use of sulfonylureas in the treatment of T2DM by general practitioners (GPs) and diabetes specialists. Of 15,652 patients across 721 clinics and hospitals from the previous survey, 15,350 were diagnosed as T2DM (14,312 by GPs and 1,038 by specialists). For each patient, data were collected for HbA1c levels, age, height, body weight, and treatment modality. Of T2DM patients being treated by GPs, 35.4% and 60.0% received sulfonylureas in entire oral drugs or as monotherapy, respectively, compared with 29.2% and 61.2% of patients, respectively, treated by specialists. Of the patients treated with sulfonylurea monotherapy, 1335 patients (35.2%) achieved HbA1c <6.5%, whereas HbA1c was >or=8.0% in 531 patients (14.0%). Patients with HbA1c levels >or=8.0% had a higher body mass index, used glibenclamide more frequently, and used higher doses of sulfonylureas than patients in whom HbA1c levels were <6.5%. In conclusion, the present study shows that sulfonylureas are central in the treatment of T2DM in Japan. However, careful consideration of suitable patients, agents, and doses is necessary to achieve appropriate glycemic control.

Nationwide Survey on Actual Interventions for Type 2 Diabetes by Japanese Practitioners (NSAID Study-1): Glycemic, Weight, and Blood Pressure Management.

INTRODUCTION: Considering the increase in the number of patients with diabetes, the quality of diabetes care provided by general practitioners (GP) is critical for preventing complications. We performed a nationwide survey to determine whether the diabetic management provided to patients with type 2 diabetes mellitus (T2DM) by Japanese practitioners is appropriate. METHODS: We randomly selected 463 clinics throughout Japan; 8070 patients with T2DM (6525 and 1545 under the care of GP and specialists [SP], respectively) were enrolled. We obtained information on hemoglobin A1c (HbA1c) levels, age, height, body weight, diabetes type and treatment modality, blood pressure (BP), and hypertension or dyslipidemia from each patient. Additionally, we surveyed the collaborations among physicians. RESULTS: The median HbA1c level of patients treated by GP was lower than that of patients treated by SP (6.8 [6.2-7.3], median [interquartile range] vs. 6.9 [6.5-7.5], p < 0.0001). The percentage of patients receiving insulin therapy was also higher (23.8%) among patients treated by SP than among those treated by GP (8.6%). Patients not receiving insulin therapy showed lower median HbA1c levels than those receiving insulin therapy, irrespective of the care provider. The mean body mass index of patients with HbA1c levels < 6.9% or > 9.0% cared for by SP was lower than that of those cared for by GP. The rate of target BP (< 140/90 mmHg) achievement was 73.2% and 73.3% among patients with T2DM and hypertension cared for by GP and SP, respectively. Furthermore, 88.2% of GP reported that consulting with SP was easy. CONCLUSION: The present study clearly demonstrated that many patients with T2DM are appropriately cared for by general practitioners instead of diabetes specialists in Japan, although the number of diabetes specialists is insufficient to cover all patients with diabetes.

Effect of canagliflozin on the overall clinical state including insulin resistance in Japanese patients with type 2 diabetes mellitus.

AIMS: Information on the clinical efficacy of SGLT2 inhibitors in the Japanese population is limited. The aim of this single-arm, single-center, open-label study was to confirm the body weight- and fat mass-lowering effects of canagliflozin (CANA) and the accompanying improvement in insulin resistance in Japanese patients with Type 2 diabetes mellitus (T2DM). METHODS: Thirty-eight patients were enrolled and administered 100 mg CANA once daily for 24 weeks. Blood and anthropometric parameters were examined before and after treatment. In a subset of patients, insulin sensitivity was assessed based on the glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp test. RESULTS: CANA treatment significantly decreased hemoglobin A1c, fasting plasma glucose, and plasma liver enzyme levels, and increased plasma adiponectin levels. In addition, a significant reduction in body weight, visceral and subcutaneous fat area, fat and lean mass, and liver steatosis was also observed. The change in plasma adiponectin levels significantly correlated with the changes in both body fat mass and visceral fat area. GIR increased from 3.25 ±â€¯1.53 to 4.11 ±â€¯1.30 mg/kg/min (P < 0.05). CONCLUSIONS: CANA improved insulin resistance and decreased visceral fat mass in Japanese patients with T2DM.

Association between body mass index and core components of metabolic syndrome in 1486 patients with type 1 diabetes mellitus in Japan (JDDM 13).

There is no recent study on the prevalence of overweight and obesity in patients with type 1 diabetes mellitus (T1DM) in Japan. Being overweight has a significant effect on the metabolic condition and glycemic control of such patients. In the present cross-sectional study, we investigated the effects of body mass index (BMI) on lipid profile, blood pressure, and glycemic control in patients with T1DM. In total, 1486 patients with T1DM (including 401 patients with early onset T1DM who were <20 years of age at diagnosis) were included. Patients were divided into four groups according to their BMI, and glycosylated hemoglobin (HbA1c), daily insulin dose per kg body weight, lipid profile, and blood pressure were compared between groups. We found that 15.7% of all patients were overweight (BMI >or= 25.0 kg/m(2)) and 2.0% were obese (BMI >or= 30.0 kg/m(2)), compared with 17.5% and 2.0%, respectively, in the early onset T1DM subgroup. Significant changes in lipid profiles and blood pressure were found with increasing BMI in both the entire population and the early onset T1DM subgroup. In the entire study population HbA1c and the body weight-adjusted daily insulin dose were significantly higher in patients with a BMI >or= 23 kg/m(2) compared with those with a BMI<23 kg/m(2); however, this was not the case in the early onset T1DM subgroup. This difference may be due to the relatively small number of patients in that subgroup. In conclusion, the prevalence of overweight and obesity in patients with T1DM was less than that in the normal Japanese population. For patients with T1DM, being overweight was associated with higher blood pressure and dyslipidemia. Furthermore, we cannot exclude an association between being overweight and the need for higher daily doses of insulin.

[Two cases of C1INH deficiency with paroxysmal abdominal pain].

We encountered two cases of C1 inhibitor deficiency (26-year-old man and 29-year-old woman). They had been suffering from paroxysmal abdominal pain for many years. Imaging studies showed wall thickening of the intestine and ascites and diagnosis was difficult. Decreased serum levels of C4 and C1INH activity indicated a diagnosis of C1INH deficiency. Although C1INH deficiency is rare, it should be considered as a differential diagnosis in young patients with paroxysmal abdominal pain.

Relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetic patients (JDDM38).

AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.

Surgical excision of neovascularization in retinal angiomatous proliferation.

BACKGROUND: We report the postoperative outcomes of surgical neovascularization excision in patients with retinal angiomatous proliferation (RAP). METHODS: Nine eyes of eight patients with RAP who underwent surgical excision of neovascularization were studied. Surgical indications were as follows: RAP diagnosed by fluorescein and indocyanine green angiography, foveal or perifoveal neovascularization, preoperative visual acuity of 0.1 or less, Yannuzzi's stage II with detachment of retinal pigment epithelium (RPE) or stage III, and leakage on late-phase fluorescein angiography. After cataract surgery, vitreous surgery and neovascularization excision were conducted, followed by fluid-air or fluid-gas exchange. RESULTS: Visual acuity was 0.02-0.1 before surgery and 0.03-0.2 after surgery. Macular hole formation was seen in one eye but did not lead to retinal detachment. In two eyes, subretinal bleeding occurred during excision leading to vitreous bleeding after surgery. Although defects of the RPE and choriocapillaries were observed after surgery, the exudation and bleeding were absorbed. CONCLUSIONS: In stage II RAP cases with RPE detachment, surgical excision maintains constant postoperative visual acuity but results in defects of RPE and choriocapillaris; therefore, other treatment options should be examined. Surgical excision of stage III RAP seems to be promising, as postoperative visual acuity remains stable after neovascularization removal in those advanced pathologic situations.

Both corticotropin-releasing factor receptor type 1 and type 2 are involved in stress-induced inhibition of food intake in rats.

RATIONALE: Stress-induced inhibition of food intake is reportedly blocked by a selective corticotropin-releasing factor (CRF) type 1 receptor (CRF1) antagonist, suggesting the involvement of CRF1 in the inhibitory mechanism. CRF1 and CRF2 are considered to function in the inhibition of food intake by CRF-related peptides with different time courses. OBJECTIVES: This study was designed to clarify whether CRF2 is also involved in stress-induced inhibition of food intake and to examine the relation of CRF1to CRF2 in the inhibitory mechanism. METHODS: Antisauvagine-30 (AS-30), a selective CRF2 antagonist, and/or CRA1000, a selective CRF1 antagonist, were pre-administered intracerebroventricularly and intraperitoneally, respectively, to male Wistar rats deprived of food for 24 h before the animals were exposed to a 1-h period of stressors and food intake in 1 h after stress exposure was examined. The effect of both antagonists on locomotor activity was also examined. RESULTS: Pre-administration of 5-30 microg of AS-30 attenuated inhibition of food intake induced by restraint, electric footshock or emotional stress using a communication box. CRA1000 also attenuated the restraint-induced inhibition of food intake at doses of 5 and 10 mg/kg body weight. The reversal of restraint-induced inhibition of food intake by co-administration of AS-30 and CRA1000 was not larger than that by AS-30 or CRA1000 alone. Both antagonists did not affect locomotor activity. CONCLUSIONS: These results suggest that not only CRF1, but also CRF2, are involved in stress-induced inhibition of food intake, and that both subtypes of CRF receptor function probably in series in 1 h after stress exposure.

Effects of food restriction on peroxisome proliferator-activated receptor-gamma and glucocorticoid receptor signaling in adipose tissues of normal rats.

In adipocytes, peroxisome proliferator-activated receptor (PPAR)-gamma activates adipocyte differentiation and glucocorticoid (GC) stimulates the expression of PPAR-gamma mRNA. The local tissue concentrations of GC, in turn, are modulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). To clarify the change of energy metabolism in condition of reduced energy intake, we investigated whether food restriction alters the adipocyte size and levels of PPAR-gamma, GC receptor (GR), and 11beta-HSD1 mRNA expression in the white adipose tissues of normal rats. Male Wistar rats weighing 340 g were housed under free feeding or 20% reduction of food intake for 2 or 14 days. We found that 2-day food restriction did not cause any change in the mean size or number of adipocytes in the omentum, while 14-day food restriction decreased the size and increased the number of adipocytes. In addition, the levels of PPAR-gamma2, GR, and 11beta-HSD1 mRNA expression in the omentum were lower in the food-restricted rats after 2 days, while they did not differ after 14 days. Also, after both 2 and 14 days, plasma concentrations of free fatty acid (FFA) were higher in the food-restricted rats than in control rats. Finally, plasma concentrations of adrenocorticotropin (ACTH) and corticosterone were the same in the both groups after 2 days, although they were higher in the food-restricted rats after 14 days. These results suggest that adipocyte differentiation in the omentum of food-restricted rats is attenuated after 2 days but recovers after 14 days, resulting in an increase in the number of small adipocytes. It is also likely that lipolysis induced during the 14-day period of food restriction decreased the size of adipocytes. Further, food restriction may affect the efficiency of local GC effects by altering GR and 11beta-HSD1 mRNA expression. Also, higher levels of plasma GC and recovery of GR and 11beta-HSD1 mRNA expression may contribute to the recovery of the levels of PPAR-gamma2 mRNA expression in the omentum and result in the recovery of adipocyte differentiation.

Effect of chronic administration of a CRF(1) receptor antagonist, CRA1000, on locomotor activity and endocrine responses to stress.

Corticotropin-releasing factor (CRF) is involved in the regulation of stress responses. The actions of CRF in the brain are mediated through two distinct CRF receptor subtypes, CRF(1) and CRF(2) receptors. In the present study, we examined the effects in rat of chronic administration of a nonpeptidic CRF(1) receptor-selective antagonist, CRA1000, 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine), on locomotor activity, feeding behavior and the hypothalamic-pituitary-adrenal axis. Chronic CRA1000 treatment significantly decreased locomotor activity in the dark phase of the diurnal cycle. However, chronic CRA1000 treatment showed no effect on food and water intake, or on body weight. After a 10-day period of CRA1000 treatment, plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in basal conditions and under immobilization stress were no different from those in rats treated with vehicle. However, CRA1000 administered 2 h before immobilization stress significantly reduced ACTH and corticosterone responses to stress with no effect on basal ACTH and corticosterone concentrations. These results suggest that CRF(1) receptors are involved in the regulation of locomotor activity during the dark period, but are not involved in the regulation of feeding behavior under non-stressful conditions. Furthermore, the results suggest that a 10-day treatment with CRA1000 does not affect hypothalamic-pituitary-adrenal axis activity either under basal conditions or after acute stress.

[Genetic disorders caused by gain or loss of function of the mineralocorticoid receptor].

Aldosterone has crucial role for sodium conservation in the kidney, salivary glands, sweat glands and colon. It exerts its effects via the mineralocorticoid receptor (MR) which belongs to the member of the nuclear receptor superfamily. Recently, genetic disorders have been reported to be caused by gain or loss of function of the MR. The amino acid substitution of the ligand-binding domain(S810L) of the MR resulted in the early-onset hypertension exacerbated by pregnancy. This mutation results in constitutive MR activity and alters receptor specificity for progesterone. Pseudohypoaldosteronism type 1 (PHA1) is characterized by congenital aldosterone resistance of the kidney and/or other mineralocorticoid target tissues, resulting in excessive salt wasting. The heterozygous nonsense or missense mutations were identified in the patients with autosomal dominant PHA1 and a sporadic PHA1. This suggests that the full expression of the MR is necessary for salt conservation.

Both glimepiride and high-dose metformin are important for sustained glucose lowering in Japanese type 2 diabetes patients on glimepiride-sitagliptin-metformin therapy: subanalysis of a single-center, open-label, randomized study.

BACKGROUND: In a previous single-center, open-label randomized 3-month study of triple oral antidiabetes drug (OAD) therapy, we investigated factors affecting the glycemic control afforded by sitagliptin, high-dose metformin, and low-dose glimepiride. Patients were prospectively assigned to either Group 1 (50% reduction in metformin) or Group 2 (discontinuation of glimepiride) and compared. The results showed that the glycated hemoglobin (HbA1c) levels of patients in Group 2 deteriorated more than those in Group 1, whereas HbA1c levels were maintained in some patients in both groups. MATERIALS AND METHODS: To determine the factors associated with maintenance of HbA1c under this triple OAD regimen, data from the prospective study were further analyzed. RESULTS: In both Groups 1 and 2, the baseline HbA1c level was higher in patients with HbA1c ≥7.0% after 3 months of treatment than those with an HbA1c level of <7.0%. A generalized linear model revealed that high-dose metformin was associated with a deterioration of HbA1c levels in Group 2. CONCLUSIONS: Together, the findings indicate that glimepiride and high-dose metformin are important for sustained glycemic control in triple OAD therapy with sitagliptin, metformin, and sulfonylurea.