Motoshi Ouchi

Relationship between daily and day-to-day glycemic variability and increased oxidative stress in type 2 diabetes

AIMS To determine the association of daily and day-to-day glucose variability with oxidative stress. METHODS This was a cross-sectional analysis of 68 patients with type 2 diabetes mellitus (T2DM) over 72h of continuous glucose monitoring. Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were measured before breakfast on day 1. Glucose variability, mean glucose level (MGL), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD) in glucose levels and area under the postprandial plasma glucose curve (AUCPP) were measured on days 2 and 3. Plasma oxidant capacity against N,N-diethylparaphenylenediamine was measured with the diacron-reactive oxygen metabolites (d-ROMs) test on day 1. RESULTS Overall, 66.2% males with the mean age of 63.2±12.6years, diabetes duration of 12.9±10.4years, and HbA1c level of 8.1±1.6% (65±17mmol/mol) were included. MGL (r=0.330), HbA1c (r=0.326), MAGE (r=0.565), MODD (r=0.488), and AUCPP (r=0.254) exhibited significant correlations with d-ROMs and not FPG; these correlations remained significant after adjustment for clinical factors (sex, age, duration of diabetes, smoking habit, insulin use, statin use, angiotensin II receptor blocker use, BMI, LDL-C, HDL-C, TG, eGFR, and systolic blood pressure) (R2=0.268, R2=0.268, R2=0.417, R2=0.314, and R2=0.347, respectively). MAGE was significantly correlated with MODD (r=0.708) and MAGE and MODD were independently correlated with d-ROMs by multivariate analysis. CONCLUSIONS Therefore, oxidative stress is associated with daily and day-to-day glucose variability in patients with T2DM.

Postprandial Glycemic Control Conditions in Relation to Urinary N-Acetyl-β-d-Glucosaminidase in Patients with Type 2 Diabetes Mellitus Without Low Glomerular Filtration Rate

BACKGROUND This study assessed the relationship between the serum level of 1,5-anhydroglucitol (1,5-AG), a marker of postprandial hyperglycemia, and the ratio of the urinary activity of N-acetyl-β-D-glucosaminidase (NAG) to creatinine (NAG index) in patients with type 2 diabetes mellitus. SUBJECTS AND METHODS This was a cross-sectional study with 153 patients who had an estimated glomerular filtration rate of ≥60 mL/min/1.73 m(2) and no proteinuria and who had never been treated with oral hypoglycemic agents or insulin. On the basis of 1,5-AG levels, the patients were divided into a High 1,5-AG group (>14.0 μg/mL) and a Low 1,5-AG group (≤14.0 μg/mL). RESULTS The logarithmically transformed NAG index was significantly higher in the Low 1,5-AG group than in the High 1,5-AG group when all glycated hemoglobin (HbA1c) levels were included. The logarithmically transformed NAG index was lowest in the High 1,5-AG group with an HbA1c level of ≤6.4% and was highest in the Low 1,5-AG group with an HbA1c level of ≥7.5%. Multivariate regression analysis showed that the NAG index had a higher independent association with 1,5-AG than with HbA1c or the fasting plasma glucose level. In all models, multivariate regression analyses showed that the NAG index was correlated with age. CONCLUSIONS These results suggest that postprandial hyperglycemia correlates with early renal tubule injury in type 2 diabetes mellitus.

Roles of organic anion transporters (OATs) in renal proximal tubules and their localization

Organic anions (OAs) are secreted in renal proximal tubules in two steps. In the first step, OAs are transported from the blood through basolateral membranes into proximal tubular cells. The prototypical substrate for renal organic anion transport systems, para-aminohippurate (PAH), is transported across basolateral membranes of proximal tubular cells via OAT1 (SLC22A6) and OAT3 (SLC22A8) against an electrochemical gradient in exchange for intracellular dicarboxylates. In the second step, OAs exit into urine through apical membranes of proximal tubules. This step is thought to be performed by multidrug efflux transporters and a voltage-driven organic anion transporter. However, the molecular nature and precise functional properties of these efflux systems are largely unknown. Recently, we characterized an orphan transporter known as human type I sodium-phosphate transporter 4, hNPT4 (SLC17A3), using the Xenopus oocyte expression system. hNPT4 acts as a voltage-driven efflux transporter (“human OATv1”) for several OAs such as PAH, estrone sulfate, diuretic drugs, and urate. Here, we describe a model for an OA secretory pathway in renal tubular cells in which OAs exit cells and enter the tubular lumen via hOATv1 (hNPT4). Additionally, hOATv1 functions as a common renal secretory pathway for both urate and drugs, indicating that hOATv1 may be a leak pathway for excess urate that is reabsorbed via apical URAT1 to control the intracellular urate levels. Therefore, we propose a molecular mechanism for the induction of hyperuricemia by diuretics: the diuretics enter proximal tubular cells via basolateral OAT1 and/or OAT3 and may then interfere with the NPT4-mediated apical urate efflux in the renal proximal tubule.

Association Between Pulse Wave Velocity and a Marker of Renal Tubular Damage (N-Acetyl-β-D-Glucosaminidase) in Patients Without Diabetes

The authors assessed the association between the ratio of urinary activity of N‐acetyl‐β‐D‐glucosaminidase (NAG) to creatinine and the brachial‐ankle pulse wave velocity (baPWV) in patients without overt diabetes mellitus (DM). This was a cross‐sectional study of 233 patients who had an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and no history of kidney disease. Patients were divided into two groups: high NAG group (>5.8 U/g creatinine) and low NAG group (≤5.8 U/g creatinine). Mean baPWVs of the high NAG group were significantly higher than those of the low NAG group in both the eGFR ≥30 and <60 tertiles and the eGFR ≥60 and <90 tertiles. The baPWV was positively correlated with NAG in all patients (r=0.341, P<.001). Stepwise multivariate regression analysis showed that the baPWV was significantly related with NAG, age, and systolic blood pressure. Elevated NAG is related to elevated arterial stiffness in patients without DM.

Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity

Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker.

Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin

An integrated analysis was performed with data from 4 phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium‐glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10‐transformed urinary N‐acetyl‐β‐D‐glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 and 24 weeks in multivariate analysis (respectively, P < .0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c > 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decreased in patients with moderate HbA1c levels.

LAT1 acts as a crucial transporter of amino acids in human thymic carcinoma cells

L-type amino acid transporter 1 (LAT1, SLC7A5) incorporates essential amino acids into cells. Recent studies have shown that LAT1 is a predominant transporter in various human cancers. However, the function of LAT1 in thymic carcinoma remains unknown. Here we demonstrate that LAT1 is a critical transporter for human thymic carcinoma cells. LAT1 was strongly expressed in human thymic carcinoma tissues. LAT1-specific inhibitor significantly suppressed leucine uptake and growth of Ty82 human thymic carcinoma cell lines, suggesting that thymic carcinoma takes advantage of LAT1 as a quality transporter and that LAT1-specific inhibitor might be clinically beneficial in therapy for thymic carcinoma.

HOXB9 acts as a negative regulator of activated human T cells in response to amino acid deficiency.

T‐cell activation is an energy expenditure process and should be properly controlled in accordance with the availability of nutrients such as amino acids to eliminate wasteful energy consumption. However, the details of response to amino acids insufficiency in activated T cells remain largely unknown. Here we show that homeobox B9 (HOXB9), a member of the homeobox gene family that is known as a morphogenesis regulator, acts as a suppressor of activated human T cells to address amino acid starvation. The expression of HOXB9 was triggered by amino acid deprivation as well as functional inhibition of L‐type amino acid transporter 1 (also known as SLC7A5) via activating transcription factor 4 in activated T cells. HOXB9 interfered the activities of NF‐κB, nuclear factor of activated T‐cells (NFAT) and AP‐1 but not retinoic acid receptor‐related orphan receptor, resulting in attenuation of the production of selective cytokines in activated T cells. Thus, the morphogenetic gene plays an unexpected role in the regulation of cellular metabolism with changes in the nutrition status in human T cells.

Bile duct hamartomas (von Meyenburg complexes) associated with a bacterial infection: Case report of elderly diabetic patient

Bile duct hamartomas (BDH), also known as von Meyenburg complexes, are rare, benign neoplasms of the liver, which contain cystic dilated bile ducts embedded in a fibrous stroma. They occur at all ages but are seen more frequently in older people. An increasing number of cases have been reported along with the recent development of diagnostic imaging technology. However, BDH associated with an infection are uncommon and are therefore very difficult to differentiate from multiple bacterial liver abscesses. We experienced a 75-year-old man with BDH suspected of complicating a cystic infection. He was admitted to our hospital because of high fever and disturbance of consciousness in late October 2008. He was first seen in our department in December 2006 as an Alzheimer’s disease patient with type 2 diabetes mellitus and atrial fibrillation. In February 2008, abdominal ultrasonography (US) performed for screening purposes showed multiple hyperechoic and hypoechoic lesions less than 1 cm in diameter with both multiple comettail echoes in the liver and gallstones. Subsequent findings of magnetic resonance cholangiopancreatography (MRCP) were highly suggestive of BDH. On admission, his body temperature was 39.1°C, blood pressure 118/68 mmHg and pulse 108 b.p.m. (irregular). The chest radiograph identified no significant findings, and the electrocardiogram revealed tachycardic atrial fibrillation. Laboratory findings included C-reactive protein (CRP) of 32.07 mg/dL, white blood cell count of 10 900/mL, aspartate aminotransferase level of 42 IU/L, alanine aminotransferase of 41 IU/L, alkaline phosphatase of 344 IU/L and gglutamyltransferase of 184 IU/L. Blood culture, urine culture, sputum culture and stool culture were all performed on admission, but only the blood culture revealed growth of Escherichia coli. Abdominal US (Fig. 1a) showed multiple hyperechoic and hypoechoic lesions less than 1 cm in diameter with multiple, scattered comet-tail echoes and localized dilation of the bile ducts in the liver. There were multiple strong echoes with acoustic shadows in the gallbladder, suggesting gallstones, but no obvious abnormalities were found in the common bile duct or the main pancreatic duct. Plain abdominal computed tomography (CT) showed multiple small cystic lesions in the liver. Non-contrast abdominal magnetic resonance imaging (MRI) was performed and confirmed the presence of multiple hepatic nodules, hypointense on T1-weighted images and hyperintense on T2-weighted images. MRCP showed multiple irregularly delineated hyperintense nodules, not communicating with the biliary tree (Fig. 2). These results of the laboratory and imaging findings suggested that the patient was suffering from a biliary tract infection. Therefore, administration of a thirdgeneration cephem (ceftriaxone 2 g/day) was started. On hospital day 3, his fever subsided. He showed satisfactory progress thereafter, and CRP was normalized on hospital day 17. Abdominal US findings after improvement of the inflammatory process (Fig. 1b) showed that the intensity of echo levels in multiple hyperechoic lesions and comet-tail sign echoes had decreased in a similar way to findings obtained in February 2008. Furthermore, follow-up non-contrast abdominal MRI examination after 2 months revealed no remarkable changes of distribution, size and number of the cystic lesions when compared with the findings of MRI images at the time of admission. Multiple bacterial liver abscesses were not considered according to these imaging findings. Therefore, on the basis of the clinical course and imaging findings, we suspected the cystic Geriatr Gerontol Int 2011; 11: 534–536

Reproducible insulin secretion from isolated rat pancreas preparations using an organ bath

Diabetes mellitus is a lifestyle-related disease that is characterized by inappropriate or diminished insulin secretion. Ex vivo pharmacological studies of hypoglycemic agents are often conducted using perfused pancreatic preparations. Pancreas preparations for organ bath experiments do not require cannulation and are therefore less complex than isolated perfused pancreas preparations. However, previous research has generated almost no data on insulin secretion from pancreas preparations using organ bath preparations. The purpose of this study was to investigate the applicability of isolated rat pancreas preparations using the organ bath technique in the quantitative analysis of insulin secretion from β-cells. We found that insulin secretion significantly declined during incubation in the organ bath, whereas it was maintained in the presence of 1 µM GLP-1. Conversely, amylase secretion exhibited a modest increase during incubation and was not altered in the presence of GLP-1. These results demonstrate that the pancreatic organ bath preparation is a sensitive and reproducible method for the ex vivo assessment of the pharmacological properties of hypoglycemic agents.