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Background Cervical lymphadenopathy is commonly seen in general practice, and its etiology is diverse. Establishing the diagnostic strategy for lymphadenopathy would be desirable to avoid overlooking neoplasms or other critical conditions. This study aims to identify the useful laboratory parameters for cervical lymphadenopathy that require clinical observation or intervention. Methods The participants were outpatients presenting cervical swelling or cervical lymph node (LN) pain who consulted the General Internal Medicine department from 2010 to 2016. We evaluated the characteristics, physical findings, and laboratory parameters with final diagnoses by multivariate logistic regression analysis. We categorized the final diagnoses as “Clinical Intervention Required Group (CIRG)” including necrotizing lymphadenitis, hematologic neoplasms, metastatic lymphadenopathy, tuberculous lymphadenitis, bacterial infectious diseases, infectious mononucleosis, autoimmune diseases, and other abnormal conditions or “No‐CIRG” not requiring further clinical observation or intervention. Results We evaluated 409 participants, with 130 (31.8%) diagnosed as belonging to the CIRG. There was an association between CIRG and various parameters: age ≥60 years old (adjusted odds ratio [AOR], 2.70; 95% confidence interval [CI], 1.48‐4.90), having a referral (AOR, 1.83; 95% CI, 1.12‐3.00), diameter of LN ≥ 2 cm (AOR, 1.91; 95% CI, 1.05‐3.48), fixed LNs (AOR, 2.74; 95% CI, 1.02‐7.37), and lactate dehydrogenase (LD) ≥400 U/L (AOR, 3.78; 95% CI, 1.46‐9.77). Eighty‐two percent of LD ≥ 400 cases in the CIRG were infectious mononucleosis or necrotizing lymphadenitis. Conclusions Besides the clinical indicators reported previously, we may apply an elevated LD level as a useful indicator of cervical lymphadenopathy that requires further clinical observation or intervention., We evaluated 409 participants presenting cervical swelling or cervical lymph node pain to identify useful physical findings or laboratory parameters for cervical lymphadenopathy that require clinical observation or intervention. The risk factors associated with that by multivariate analysis were age ≥60 years, having a referral, diameter of cervical LN ≥2 cm, fixed cervical LNs, and LD ≥400 U/L.

Background: Strategies to prevent the development and progression of chronic kidney disease (CKD) are important in clinical practice due to increased life expectancy. The present study investigated the prevalence of CKD as well as lipid profiles affecting CKD, especially triglyceride (TG) levels.Methods: In total, 5,169 subjects were eligible for a cross-sectional analysis of baseline data from the Jichi Medical School Cohort Study. We examined CKD subjects with an estimated glomerular filtration rate (eGFR) of 59 mL/min/1.73m2 or lower and independent factors associated with reductions in eGFR.Results: The prevalence of CKD was 17.7%. Age, systolic blood pressure, and hyperlipidemia were defined as related factors for CKD. The lowest, second, third, and highest quartile ranges of total cholesterol (TC) and TG were 0-166, 167-188, 189-212, and 213 mg/dL or higher and 0-71, 72-100, 101-148, and 149 mg/dL or higher, respectively. The odds ratio (OR) of Q2 to Q4 of TC relative to that of Q1 for CKD increased linearly (OR [95%CI]: Q2, 1.3 [1.0-1.7]; Q3, 1.38 [1.1-1.8]; Q4, 1.5 [1.4-2.4]). The ORs of Q2 and Q3 of TG for CKD did not increase, whereas that of Q4 did (OR [95% CI]: Q2, 0.95 [0.7-1.2]; Q3, 0.98 [0.8-1.2]; Q4, 1.21 [1.0-1.5]). Conclusion: Increases in TC and TG levels were both independently associated with CKD. The relationship with CKD became stronger as TC increased, and the TG had threshold was 149 mg/dL.

Contrast-enhanced computed tomography angiography reveals "railroad track-like" calcifications bilaterally from the femoral to the popliteal arteries.

Summary: The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain. : Fujiyama et al. find that forebrain-specific Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sexually dimorphic behaviors, reproductive organs, and severely altered expression of sex-biased genes, including Kiss1, in the hypothalamus in both sexes, which suggests that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain. Keywords: sexual differentiation, sexual behavior, hypothalamus, Ptf1a, kisspeptin, central nervous system

Antineutrophil cytoplasmic antibody‐associated vasculitis (AAV) presents a variety of manifestations. Two patients with a history of intractable otitis media were diagnosed as having AAV. One was an 87‐year‐old woman who presented with cough, anorexia, and fever with a one‐year and four‐month history of otitis media, and the other was a 65‐year‐old woman with arthritis that appeared after the diagnosis of otitis media. The history of otitis media was a diagnostic clue to AAV in both patients. Diagnosis at the early localized stage is crucial to prevent irreversible status of AAV. Primary care physicians should be aware of the otological manifestation of AAV.

We investigated the effectiveness of epinephrine auto‐injector (EpiPen®) skill training for Yogo teachers in the community medicine. The auto‐injector skill training might be effective for establishing a caring system for anaphylaxis at schools in the context of community medicine.

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.

β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11β-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11β-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11β-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11β-HSD1 mRNA by IGF-I was attenuated in the presence of 1 μM linsitinib (17.2% vs. 53.3% of basal level, P

The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide (KGA-2727), which has a pyrazole-O-glucoside structure, as the first selective SGLT1 inhibitor. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. In a small intestine closed loop absorption test with normal rats, KGA-2727 inhibited the absorption of glucose but not that of fructose. After oral intake of starch along with KGA-2727 in normal rats, the residual content of glucose in the gastrointestinal tract increased. In the oral glucose tolerance test with streptozotocin-induced diabetic rats, KGA-2727 attenuated the elevation of plasma glucose after glucose loading, indicating that KGA-2727 improved postprandial hyperglycemia. In Zucker diabetic fatty (ZDF) rats, chronic treatments with KGA-2727 reduced the levels of plasma glucose and glycated hemoglobin. Furthermore, KGA-2727 preserved glucose-stimulated insulin secretion and reduced urinary glucose excretion with improved morphological changes of pancreatic islets and renal distal tubules in ZDF rats. In addition, the chronic treatment with KGA-2727 increased the level of glucagon-like peptide-1 in the portal vein. Taken together, our data indicate that the selective SGLT1 inhibitor KGA-2727 had antidiabetic efficacy and allow us to propose KGA-2727 as a candidate for a novel and useful antidiabetic agent.

Background Ambulatory blood pressure (BP) (ABP) is a better predictor of adverse cardiovascular events than office BP (OBP). Owing to the extensive literature on the 'white coat effect', it is widely believed that ABP tends to be lower than OBP, with statements to this effect in Joint National Committee VII. However, recent evidence suggests that the difference varies systematically with age. Methods We searched PubMed to identify population studies, published before April 2009, which assessed OBP and either ABP or home BP (HBP). On account of significant heterogeneity in the outcomes, random effect models were used for the meta-analyses. Results OBP increased with age more steeply than awake ABP. OBP became higher than awake systolic/diastolic ABP at the age of 51.3/42.7 years in men (13 studies, N=3562) and 51.9/42.3 years in women (11 studies, N=2585). In the data in which OBP and HBP were measured (eight studies, N=4916), OBP was higher than HBP at all ages. In the data in which OBP, awake ABP, and HBP were all measured (two studies, N=895), awake ABP was higher than HBP at younger ages, becoming similar at the older age. Conclusion OBP tends to be higher than awake ABP only after the age of 50 years for systolic and after the age of 45 years for diastolic BP, but is lower than ABP at younger ages; in contrast OBP tends to exceed HBP at all ages.

It has been reported that subjects with prehypertension (pre-HT) (systolic blood pressure [SBP] 120-139 mmHg and/or diastolic blood pressure [DBP] 80-89 mmHg) have an increased risk of cardiovascular disease (CVD). We evaluated the prevalence and determinants of pre-HT in a Japanese general population. We enrolled 4,706 males and 7,342 females aged 18 to 90 years whose BPs were measured at baseline. The subjects' BPs were classified as follows: normotension (NT: SPB/DBP120/80 mmHg), pre-HT (120/80-139/89 mmHg), and hypertension (HT:or = 140/90 mmHg or treated hypertension). The prevalence of pre-HT was 34.8% (males), and 31.8% (females). Body mass index (BMI) of more than 23.0 kg/m2 was the strongest determinant of pre-HT (Males--BMI: 23.0-24.9 kg/m2, odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.21-1.79; BMI: 25.0-26.9 kg/m2, OR = 2.20, 95% CI =1.68-2.87; BMI: 27.0-29.9 kg/m2, OR = 2.75, 95% CI = 1.80-4.19; BMI:or = 30.0 kg/m2, OR = 3.39, 95% CI = 1.21-9.46. Females--BMI: 23.0-24.9 kg/m2, OR = 1.67, 95% CI = 1.42-1.95; BMI: 25.0-26.9 kg/m2, OR = 1.79, 95% CI = 1.46-2.19; BMI: 27.0-29.9 kg/m2, OR = 3.65, 95% CI = 2.73-4.89; BMI:or = 30.0 kg/m2, OR = 4.23, 95% CI = 2.33-7.70). The other determinants of pre-HT were hyperlipidemia (Males: OR = 1.25; Females: OR = 1.43), and aging (by 10 years; Males: OR = 1.12; Females: OR = 1.48). Determinants of pre-HT in females were impaired glucose tolerance (OR = 1.41, 95% CI = 1.03-1.94), diabetes (OR = 2.01, 95% CI = 1.16-3.47) and a family history of HT in both parents (OR = 1.90, 95% CI = 1.38-2.62), whereas in males the only other predictor was alcohol drinking (OR = 1.45, 95% CI = 1.23-1.70). In conclusion, even subjects with a mild increase of BMI (23.0-24.9 kg/m2) had an increased risk of pre-HT in a Japanese population, and the level of BMI associated with pre-HT was lower than that in Western countries. Additionally, there were gender differences in the determinants of pre-HT.

Yukiko Ishikawa,1 Taro Takeshima,1,2 Junichi Mise,1 Shizukiyo Ishikawa,1 Masami Matsumura1 1Division of General Medicine, 2Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan Purpose: General practitioners have an important role in diagnosing a variety of patients, including psychiatric patients with complicated symptoms. We evaluated the relationship between physical symptoms and psychiatric disorders in general internal medicine (GIM) outpatients in a Japanese university hospital. Materials and methods: We coded the symptoms and diagnoses of outpatients from medical documents using the International Classification of Primary Care, second edition (ICPC-2). The participants were new outpatients who consulted the GIM outpatient division at Jichi Medical University Hospital in Tochigi, Japan from January–June, 2012. We reviewed all medical documents and noted symptoms and diagnoses. These were coded using ICPC-2. Results: A total of 1,194 participants were evaluated, 148 (12.4%) of whom were diagnosed as having psychiatric disorders. The prevalence of depression, anxiety disorder, and somatization was 19.6% (number [n] =29), 14.9% (n=22), and 14.2% (n=21), respectively, among the participants with psychiatric disorders. The presence of several particular symptoms was associated with having a psychiatric disorder as compared with the absence of these symptoms after adjusting for sex, age, and the presence of multiple symptoms (odds ratio [OR] =4.98 [95% confidence interval {CI}: 1.66–14.89] for palpitation; OR =4.36 [95% CI: 2.05–9.39] for dyspnea; OR =3.46 [95% CI: 1.43–8.36] for tiredness; and OR =2.99 [95% CI: 1.75–5.13] for headache). Conclusion: Not only the psychiatric symptoms, but also some physical symptoms, were associated with psychiatric disorders in GIM outpatients at our university hospital. These results may be of help to general practitioners in appropriately approaching and managing patients with psychiatric disorders. Keywords: physical symptoms, psychiatric disorders, university hospital, International Classification of Primary Care 2nd edition

In some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62+/-1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 microU/dl in 79% of the patients. Hypoglycemic attack was the onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4+/-0.6 kg/m2) and serum total protein levels (6.6+/-0.1g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients.

We report here a persistent form of Coxiella burnetii infection. There have been no prospective surveys of chronic C. burnetii infection reported in Japan. Until recently, it was not possible to distinguish between previous and current infection with serological tests for antibody to C. burnetii. The nested PCR method, however, allows us to appreciate the current infection by detecting C. burnetii DNA with high sensitivity. Inoculation method using an A/J mouse was performed to confirm the viability of C. burnetii. To obtain an approximation of the prevalence of C. burnetii infection in the general population, we evaluated a random sample of patients with symptoms of continuous low-grade fever for one month or more. Analysis of 54 subjects with protracted debility and fatigue symptoms identified 13 subjects as carriers of C. burnetii (24.1%). There were no significant differences in age, C-reactive protein levels (0.69 +/- 1.19 mg/dl), white blood cell counts (6,089 +/- 2,189/microliter), eosinophil (3.4 +/- 3.6%) between the patients with C. burnetii infection and infection-free subjects. All thirteen patients had experienced protracted low-grade fever (up to 37.5 degrees C) for four months to seven years (30.5 +/- 27.7 months). Transthoracic echocardiography showed no evidence of endocarditis, or echosonography revealed no abnormal findings in the liver or kidneys. Although domestic animals constitute an important reservoir of C. burnetii, only two of the positive subjects had direct contact with them and none of the positive subjects were occupationally exposed to farm animals or common sources of infection. None had a history of hospitalizations for pneumonia or hepatic disease. Interestingly, five of the thirteen patients had a history of consulting a psychiatrist, and furthermore, one had a history of several admissions in a psychiatric hospital due to chronic fatigue symptoms. Ten of the patients had a high IgE titer (> 295 IU/ml), which shows a higher prevalence than in patients without C. burnetii (76.9%: 22.0%, P = 0.001). Four of them had markedly elevated IgE levels, in excess of 2,000 IU/ml. The mean value of IgE was higher in the patients with C. burnetii infection than in infection-free subjects (1,388 +/- 1,706: 533 +/- 913 IU/ml, p < 0.045). Two subjects were rheumatoid factor positive and another three had autoimmune thyroiditis. Twelve of the 13 subjects provided written informed consent for treatment with minocycline (200 mg/day). One month later, all subject became asymptomatic and apyretic (37.1 +/- 0.43 degrees C to 36.7 +/- 0.56 degrees C; p < 0.025), and nested PCR did not identify C. burnetii DNA in serum samples. It should be noted that persistent symptoms including low-grade fever were observed for two weeks after the start of medication. Furthermore, three patients had persistent symptoms, and DNA detection by the nested PCR method became positive in all three patients within a few months.

In serum, insulin-like growth factors (IGFs) are primarily present as a approximately 150 kDa ternary protein complex, which consists of IGFs, IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS). Like IGF-I and IGFBP-3, serum levels of ALS depend on growth hormone (GH). To date, the diagnostic relevance of ALS in adult GH deficiency (GHD) has remained uncertain. To clarify the clinical utility of ALS measurement in adults, we measured serum ALS levels in patients with adult GHD or acromegaly. We also measured the levels of serum IGF-I and IGFBP-3 in these patients to compare the utility of ALS with IGF-I and IGFBP-3 as a marker of GH secretion. Serum ALS was measured by radioimmunoassay (RIA) kit, and serum IGF-I and IGFBP-3 were measured by immunoradiometric assay (IRMA) kits in 56 patients with adult GHD (adult-onset (AO)/child-onset (CO), 13/43) and 43 patients with acromegaly. Serum ALS levels were less than 5th percentile in 40 of 56 (71%) patients with adult GHD (32/43 (74%) for CO and 8/13 (62%) for AO), and more than 95th percentile in 38 of 43 (88%) patients with acromegaly, respectively. Serum IGF-I levels were less than -1.96 SD in 43 of 56 (77%) patients with adult GHD (35/43 (81%) for CO and 8/13 (62%) for AO) and more than +1.96 SD in 42 of 43 (98%) patients with acromegaly, respectively. Serum IGFBP-3 levels were less than -1.96 SD in 51 of 56 (91%) patients with adult GHD (42/43 (98%) for CO and 9/13 (69%) for AO) and more than +1.96 SD in 31 of 43 (72%) patients with acromegaly, respectively. These data suggested that measurement of ALS offers no advantage over measurements of serum IGF-I and IGFBP-3. Furthermore, our results indicate that serum IGFBP-3 is the most suitable marker of GH secretion for adult GHD, especially CO, while IGF-I may be the most useful in acromegaly.

The lack of the neuropeptide orexin, also known as hypocretin, results in narcolepsy, a chronic sleep disorder characterized by frequent sleep/cataplexy attacks and rapid eye movement sleep abnormalities. However, the downstream pathways of orexin signaling are not clearly understood. Here, we show that orexin activates the mTOR pathway, a central regulator of cell growth and metabolism, in the mouse brain and multiple recombinant cell lines that express the G protein-coupled receptors (GPCRs), orexin 1 receptor (OX1R) or orexin 2 receptor (OX2R). This orexin/GPCR-stimulated mTOR activation is sensitive to rapamycin, an inhibitor of mTOR complex 1 (mTORC1) but is independent of two well known mTORC1 activators, Erk and Akt. Rather, our studies indicate that orexin activates mTORC1 via extracellular calcium influx and the lysosome pathway involving v-ATPase and Rag GTPases. Moreover, a cytoplasmic calcium transient is sufficient to mimic orexin/GPCR signaling to mTORC1 activation in a v-ATPase-dependent manner. Together, our studies suggest that the mTORC1 pathway functions downstream of orexin/GPCR signaling, which plays a crucial role in many physiological and metabolic processes.

Prehypertension is associated with an increased risk of the development of hypertension and subsequent cardiovascular disease. However, it is unclear whether the increased risk of cardiovascular disease associated with prehypertension varies by duration of follow-up (i.e., the first 5 years vs. second 5 years) or varies between nonelderly and elderly individuals.We enrolled 11,000 community dwelling persons (6739 women and 4261 men, aged 18-90 years) from the Japanese general population, followed them for an average of 10.7 +/- 2.4 years (117,517 person-years) and evaluated the incidence of cardiovascular events (including both stroke and myocardial infarction).In the full cohort, prehypertension was associated with a 45% higher risk of cardiovascular events than normal blood pressure after adjusting for traditional cardiovascular risk factors (hazard ratio = 1.45, P = 0.03). The risk of cardiovascular events with prehypertension during the second 5-year period was elevated in the nonelderly subgroup (65 years) (hazard ratio = 2.13, P = 0.01), but not in the elderly subgroup (or=65 years) (hazard ratio = 0.93, P = 0.82) (P = 0.054 for the difference in hazard ratio). The elevated risk with prehypertension during the first 5-year period was not significant in either the nonelderly (hazard ratio = 1.60, P = 0.36) or elderly (hazard ratio = 1.19, P = 0.63) group. However, the risks with prehypertension were not statistically different between the first and second 5-year period.Prehypertension is associated with an increased 10-year risk of cardiovascular disease; the provocative finding that this risk may be especially elevated during the second 5-year period in the nonelderly requires confirmation in a larger cohort.

One of the observations in malnutrition is that serum insulin-like growth factor (IGF)-I levels are decreased, and this decrease is associated with an altered profile of IGF binding proteins (IGFBPs). In human circulation, IGFs are mostly present as an approximately 150-kDa ternary protein complex consisting of IGFs, IGFBP-3, and acid-labile subunit (ALS). In the present study, to clarify the effect of nutrition on serum ALS levels, we investigated 33 patients with anorexia nervosa. Serum levels of ALS were measured by RIA. Furthermore, we measured serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 levels in the patients. From these data, we investigated which was the best predictor of body mass index (BMI) as a nutritional status marker. In the patients with anorexia nervosa, the serum ALS levels ranged from 0.7–16.9, with a mean of 10.6 ± 0.7 mg/L, and the levels were significantly lower than those of normal subjects (13.8 ± 0.8 mg/L, P < 0.05). Serum ALS levels positively correlated with BMI (r = 0.41, P < 0.05...

The low-affinity sodium glucose cotransporter (SGLT2) is responsible for most of the glucose reabsorption in the kidney and has been highlighted as a novel therapeutic target for the treatment of diabetes. We discovered sergliflozin etabonate, a novel selective SGLT2 inhibitor, and found that selective inhibition of SGLT2 increased urinary glucose excretion and consequently decreased plasma glucose levels. In this report, we examined the antihyperglycemic effects of sergliflozin etabonate in normal and diabetic rats in comparison with those of a sulfonylurea (gliclazide) and an alpha-glucosidase inhibitor (voglibose). Sergliflozin etabonate increased urinary glucose excretion in a dose-dependent manner, and inhibited the increase in plasma glucose after sucrose loading independently of insulin secretion in normal rats. Sergliflozin etabonate also improved postprandial hyperglycemia in neonatal streptozotocin-induced diabetic rats; whereas gliclazide did not improve it. In rats with mild or moderate streptozotocin-induced diabetes, the degree of the antihyperglycemic effects of sergliflozin etabonate correlated with the severity of the diabetic condition. Sergliflozin etabonate did not affect the plasma glucose level of normal rats as seen with gliclazide. Chronic treatment with sergliflozin etabonate reduced the levels of glycated hemoglobin and fasting plasma glucose, and improved the glycemic response after glucose loading in Zucker fatty rats. In addition, sergliflozin etabonate did not affect the body weight or food intake. These data indicate that sergliflozin etabonate could improve glycemic control without its use resulting in insulin secretion, hypoglycemia, and body weight gain, and may provide a unique approach to the treatment of diabetes.

The low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes. We have discovered remogliflozin etabonate, which is a novel category of selective SGLT2 inhibitors. Remogliflozin etabonate is a prodrug based on benzylpyrazole glucoside and is metabolized to its active form, remogliflozin, in the body. We identified remogliflozin to be a potent and highly selective SGLT2 inhibitor by examining COS-7 cells transiently expressing either high-affinity sodium glucose cotransporter (SGLT1) or SGLT2. Orally administered remogliflozin etabonate increased urinary glucose excretion in a dose-dependent manner in both mice and rats. By increasing urinary glucose excretion, remogliflozin etabonate inhibited the increase in plasma glucose after glucose loading without stimulating insulin secretion in normal rats. Remogliflozin etabonate also showed antihyperglycemic effects in both streptozotocin-induced diabetic rats in oral glucose tolerance and in db/db mice in the fed condition. Chronic treatment with remogliflozin etabonate reduced the levels of fasting plasma glucose and glycated hemoglobin, and it ameliorated glucosuria in db/db mice. In high-fat diet-fed Goto-Kakizaki rats, remogliflozin etabonate improved hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and insulin resistance. This study demonstrates that treatment with remogliflozin etabonate exhibits antidiabetic efficacy in several rodent models and suggests that remogliflozin etabonate may be a new and useful drug for the treatment of diabetes.

Atherosclerosis and insulin resistance are common complications of adult growth hormone deficiency (GHD) and acromegaly. Circulating adiponectin, an adipocyte-derived protein, has both anti-atherogenic and insulin-sensitising effects. In this study, we measured serum adiponectin levels in patients with either adult GHD or acromegaly to clarify the impact of GH secretory states on the regulation of serum adiponectin levels. Serum adiponectin level was measured by radioimmunoassay in 32 patients with adult GHD, 49 patients with acromegaly and 25 normal subjects. The relationships between adiponectin and insulin sensitivity index assessed as quantitative insulin sensitivity check index (QUICKI), BMI, and serum GH and IGF-I levels were then investigated. The values of QUICKI were significantly lower in patients with acromegaly or adult GHD compared to normal subjects (0.33 +/- 0.03, P0.01, 0.35 +/- 0.04, P0.05 and 0.36 +/- 0.01, respectively). While patients with adult GHD had significantly lower serum adiponectin levels than patients with acromegaly (6.5 +/- 3.9, 9.2 +/- 5.0, P0.01) these levels were not significantly different from those found in normal subjects (7.8 +/- 4.3 mug/ml). There was an inverse correlation between serum adiponectin levels and BMI in both patient groups (GHD r = -0.39, P0.05; Acromegaly r = -0.35, P0.05). However, serum adiponectin levels correlated positively with QUICKI (R(s) = 0.37, P0.05) only in patients with adult GHD. In patients with acromegaly, the levels of circulating adiponectin showed an inverse correlation with serum IGF-I levels (R(s) = -0.34, P0.05), but not with basal GH levels. These results demonstrate that adiponectin levels are significantly lower in patients with adult GHD than in patients with acromegaly. Adiponectin levels are similar in patients with GHD and healthy controls, whereas in patients with acromegaly, insulin resistance appears to be not closely related to adiponectin levels compared with BMI. The different relationship between adiponectin and QUICKI observed in the adult GHD and acromegaly groups presumably reflects differences in the mechanisms of insulin resistance under states of GH deficiency or excess.

Background Subjects with prehypertension (pre-HT; 120/80 to 139/89 mm Hg) have an increased risk of cardiovascular disease (CVD); however, whether the risk of pre-HT can be seen at the pre-HT status or only after progression to a hypertensive (HT; ≥140/90 mm Hg) state during the follow-up period is unknown. Methods The Jichi Medical Cohort study enrolled 12,490 subjects recruited from a Japanese general population. Of those, 2227 subjects whose BP data at baseline and at the middle of follow-up and tracking of CVD events were available (median follow-up period: 11.8 years). We evaluated the risk of HT in those with normal BP or pre-HT at baseline whose BP progressed to HT at the middle of follow-up compared with those whose BP remained at normal or pre-HT levels. Results Among the 707 normotensive patients at baseline, 34.1% and 6.6% of subjects progressed to pre-HT and HT, respectively, by the middle of follow-up. Among 702 subjects with pre-HT at baseline, 26.1% progressed to HT. During the follow-up period, there were 11 CVD events in normotensive patients and 16 CVD events in pre-HT patients at baseline. The subjects who progressed from pre-HT to HT had 2.95 times higher risk of CVD than those who remained at normal BP or pre-HT in a multivariable-adjusted Cox hazard model. Conclusion This relatively long-term prospective cohort study indicated that the CVD risk with pre-HT might increase after progression to HT; however, the number of CVD events was small. Therefore, the results need to be confirmed in a larger cohort.