Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study).

A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m2 . Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000-1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12.06% vs. -3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Association of morning fasting blood glucose variability with insulin antibodies and clinical factors in type 1 diabetes.

The fasting blood glucose concentration in type 1 diabetes may vary without being much affected by diet and exercise. This study aimed to identify association of morning fasting blood glucose concentration variability with insulin antibodies and clinical factors. The subjects in this study were 54 patients with type 1 diabetes who had high variation of fasting blood glucose. The insulin antibody level was measured, and correlations of glycemic variability with antibody levels, binding rates, and other clinical factors were investigated. The standard deviation (SD) of the 30-day morning self-monitored fasting blood glucose concentration (FBG SD) was evaluated as an index of glycemic variability. The mean glucose level was 159.8±42.1 mg/dL and the FBG SD was 47.5±22.0 mg/dL. Glycemic variability (FBG SD) was positively correlated with insulin antibody level, but not with insulin antibody binding rate, and had a negative correlation with C-peptide immunoreactivity/plasma glucose (CPR/PG) and positive correlations with diabetes duration, basal insulin dose and bolus insulin dose. Glycemic variability was not correlated with BMI, HbA1c or age. In multiple regression analysis of glycemic variability, CPR/PG was the only significant related factor. The results showed that glycemic variability was mainly influenced by endogenous insulin secretion capacity and was high in patients with high insulin antibody levels. In some patients with a high insulin antibody titer, the antibody may have an effect on the variability of the fasting glucose concentration in type 1 diabetes.

An autopsy case of macroglobulinemia complicated with syndrome of inappropriate secretion of ADH (SIADH) like hyponatremia, hypopituitarism and AL amyloidosis.

An 88-year-old male patient with macroglobulinemia was admitted to our hospital because of severe hyponatremia and unconsciousness. Laboratory findings showed decreased inhibition of antidiuretic hormone (ADH) and he was diagnosed with syndrome of inappropriate secretion of ADH (SIADH). Hyponatremia improved with only limitation of water intake and the patient was followed up on a continuing outpatient basis. However, soon after discharge from hospital, his legs started swelling with edema and hyponatremia worsened. He was re-admitted due to a fall at home. Hyponatremia was observed at re-admission. A CRH challenge test showed partial dysfunction of ACTH secretion. Corticosteroid therapy was performed, but the patient subsequently died from pneumonia. Pathological findings at autopsy revealed invasion of plasma cells and amyloid depositions in multiple organs, including the pituitary, adrenal cortex, heart, liver, kidney, lymph nodes and bone marrow. Consistent with these results, fibrosis was observed in the anterior lobe of the pituitary, suggesting that the autopsy findings were related to the clinical observations and diagnosis. This is the first reported case of macroglobulinemia complicated with multiple hormone dysfunction.

Risk factors for chronic kidney disease progression over 20 years for primary prevention in Japanese individuals at a preventive medicine research center: Focus on the influence of plasma glucose levels.

AIMS/INTRODUCTION: Chronic kidney disease (CKD) is a very important issue globally because of the risk of its progressing to end-stage renal disease. We aimed to identify factors contributing to long-term estimated glomerular filtration rate (eGFR) decline to determine an early diagnosis and prevent CKD progression. MATERIALS AND METHODS: From January 2003 to December 2006, 5,507 individuals underwent health checkups at our hospital's Preventive Medicine Research Center. We ultimately enrolled 2,175 individuals. The eGFR was ≥60 mL/min/1.73 m2 at the start of observation period, which was 20 years. The event onset time was the day that the eGFR became <30 mL/min during the 20-year period. Baseline risk factors - in particular, the effect of plasma glucose levels on the eGFR - were extracted and evaluated by using Fine and Gray analysis. RESULTS: During the 20-year observation, the hazard ratio (HR) of CKD progression was examined. A fasting plasma glucose (FPG) level ≥105 mg/dL was significantly associated with the risk of CKD progressing to an eGFR <30 mL/min. This trend was similar in the slope of eGFR. An FPG ≥105 mg/dL or an glycated hemoglobin level ≥6.5% was useful for intervening in CKD progression. Multivariate analysis showed that independent risk factors were an FPG level ≥105 mg/dL (HR 1.9; P < 0.001), age ≥60 years (HR 3.86; P < 0.001), obesity (HR 1.61; P < 0.01) and urinary protein (HR 1.55; P < 0.01). CONCLUSIONS: For early intervention against a reduction in the eGFR, detecting mild increases in FPG ≥105 mg/dL in patients with CKD with or without diabetes is useful.

Sex differences in predictive factors for onset of type 2 diabetes in Japanese individuals: A 15-year follow-up study.

AIMS/INTRODUCTION: The increase in the number of patients with type 2 diabetes mellitus is an important concern worldwide. The goal of this study was to investigate factors involved in the onset of type 2 diabetes mellitus, and sex differences in long-term follow up of people with normal glucose tolerance. MATERIALS AND METHODS: Of 1,309 individuals who underwent screening at our facility in 2004, 748 individuals without diabetes were enrolled. Correlations of metabolic markers including serum adiponectin (APN) with onset of type 2 diabetes mellitus were examined over 15 years in these individuals. RESULTS: The Kaplan-Meier curve for onset of type 2 diabetes mellitus for 15 years in the decreased APN group was examined. Hazard ratios for the APN concentration for onset of diabetes were 1.78 (95% confidence interval [CI] 1.20-2.63, P = 0.004) in all participants, 1.48 (95% CI 0.96-2.29, P = 0.078) for men and 3.01 (95% CI 1.37-6.59, P = 0.006) for women. During the follow-up period of 15 years, body mass index, estimated glomerular filtration rate, fatty liver, C-reactive protein and alanine aminotransferase in men were significant in univariate analysis, but only estimated glomerular filtration rate and fatty liver were significantly related to onset of type 2 diabetes mellitus in multivariate analysis. In women, body mass index, systolic blood pressure, triglyceride, fatty liver and APN were significant in univariate analysis, and APN was the only significant risk factor in multivariate analysis (P < 0.05). CONCLUSIONS: There are differences between men and women with regard to targets for intervention to prevent the onset of type 2 diabetes mellitus. Individuals requiring intensive intervention should be selected with this finding to maximize the use of limited social and economic resources.

A case of TSH-producing adenoma treated with octreotide in combination with thiamazole for the control of TSH and thyroid hormones after trans-sphenoidal neurosurgery.

While TSH-producing adenoma (TSHoma) is rare, the diagnosis is often delayed because the clinical features are heterogeneous. The patient was a 69-year-old woman who had been referred to the Yachiyo Medical Center in August 2008, because of dyspnea, loss of appetite, weight loss of 10 kg, and diarrhea that lasted 4 years. We diagnosed this patient with pituitary TSH-producing macroadenoma. Thyroid hormone concentration was increasing although the serum TSH level was within a normal range after trans-sphenoidal surgery. We considered that because of enlargement of the thyroid gland due to long-term stimulation by TSH, a low concentration of TSH could stimulate the thyroid gland to produce excess T3 or T4. The somatostatin analogue, octreotide was used to control the TSHoma and serum TSH concentration but not thyroid hormone. The octreotide in combination with thiamazole treatment for 14 months controlled thyroid hormone concentration and decreased the thyroid mass, and ultimately, the thiamazole could be stopped. To date, the use of combination therapy of octreotide with thiamazole in patients with remaining TSH-producing adenoma without Basedow's disease is rare, and we suggest that this treatment is one of the therapeutic means to treat recurrence of TSH-producing adenoma after surgery with progressive complications or large thyroid gland.

Hyperferritinemia Is a Predictor of Onset of Diabetes in Japanese Males Independently of Decreased Renal Function and Fatty Liver: A Fifteen-Year Follow-Up Study.

BACKGROUND: Type 2 diabetes is an important health concern worldwide. The disease etiology may depend on multiple environmental and genetic factors that cause insulin resistance, including dysregulation of iron storage. The goal of this study was to examine the relationship of the serum ferritin concentration with onset of diabetes over a long period. METHODS: Correlations of serum ferritin and metabolic markers with onset of diabetes mellitus were examined over 15 years in 150 males participating in a health screening program. RESULTS: HOMA-ß showed a gradual significant decrease in the first 4 years in subjects with ferritin > 190 ng/mL (group H) compared to those with ferritin ≤ 190 ng/mL, but there was no difference in HOMA-R between these groups. A significant number of cases with onset of diabetes was observed over 15 years (hazard ratio (HR): 3.97), and obesity, fasting blood glucose level, hemoglobin A1c (HbA1c), HOMA-R, fasting immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR) were all significant in univariate comparison between non-diabetes and diabetes-onset groups. In multivariate analysis, ferritin in group H (HR: 3.25), fatty liver (HR: 3.38), estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73 m2 (HR: 3.48) and high-density lipoprotein (HDL) < 40 mg/dL (HR: 2.61) were significant predictive factors for onset of type 2 diabetes mellitus. CONCLUSIONS: These results suggest that the serum ferritin level is an important index for priority intervention in preventive medicine for reduction of onset of diabetes.

Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study).

AIMS/INTRODUCTION: Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear. MATERIALS AND METHODS: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m2 and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. RESULTS: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption. CONCLUSIONS: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin.

Neuropathic pain is associated with increased nodal persistent Na(+) currents in human diabetic neuropathy.

Peripheral nerve injury alters function and expression of voltage gated Na(+) channels on the axolemma, leading to ectopic firing and neuropathic pain/paresthesia. Hyperglycemia also affects nodal Na(+) currents, presumably due to activation of polyol pathway and impaired Na(+)-K(+) pump. We investigated changes in nodal Na(+) currents in peripheral sensory axons and their relation with pain in human diabetic neuropathy. Latent addition using computerized threshold tracking was used to estimate nodal persistent Na(+) currents in radial sensory axons of 81 diabetic patients. Of these, 36 (44%) had chronic neuropathic pain and severe paresthesia. Compared to patients without pain, those with pain had greater nodal Na(+) currents (p = 0.001), smaller amplitudes of sensory nerve action potentials (SNAP) (p = 0.0003), and lower hemoglobin A1c levels (p = 0.006). Higher axonal Na(+) conductance was associated with smaller SNAP amplitudes (p = 0.03) and lower hemoglobin A1c levels (p = 0.008). These results suggest that development of neuropathic pain depends on axonal hyperexcitability due to increased nodal Na(+) currents associated with structural changes, but the currents could also be affected by the state of glycemic control. Our findings support the view that altered Na(+) channels could be responsible for neuropathic pain/paresthesia in diabetic neuropathy.

Idiopathic bilateral adrenal haemorrhage related to acute adrenal insufficiency.

A 54-year-old woman presented with sudden epigastralgia and left back pain. She had no significant history. Laboratory data showed mild inflammation and no liver or renal dysfunction. Abdominal CT showed left adrenal enlargement and haemorrhage. Hydrocortisone therapy was started to prevent adrenal insufficiency before laboratory findings for ACTH (adrenocorticotropic hormone) and cortisol levels. On the second hospital day, abdominal CT showed additional right adrenal enlargement and haemorrhage. The serum cortisol level suggested adrenal insufficiency. No specific findings were detected by bilateral adrenal angiography. 6 to 12 months later, abdominal CT showed decreased bilateral adrenal haemorrhage. This case illustrates the importance of prompt diagnosis and treatment of acute adrenal insufficiency, and shows sequential changes in the size of bilateral adrenal haemorrhage. Rapid corticosteroid replacement is important if acute adrenal insufficiency is suspected. In a case with unilateral adrenal haemorrhage, the possibility of additional adrenal haemorrhage on the opposite side should also be considered.

The role of the hypoxia-inducible factor 1 binding site in the induction of aquaporin-1 mRNA expression by hypoxia.

Aquaporin-1 (AQP1), a water channel protein, has been shown to play an important role in tumor growth and angiogenesis in mouse endothelial cells. We recently reported that the expression of AQP1 mRNA was induced in cultured human retinal vascular endothelial cells (HRVECs) under hypoxia. In the present study, HRVECs were cultured under normoxia or hypoxia (1% O(2)) to elucidate the mechanism of hypoxic induction of AQP1. AQP1 mRNA expression was increased 1.7 ± 0.24-fold under hypoxia compared with that under normoxia (p < 0.01). This increase was almost completely blocked by the transcriptional inhibitor actinomycin D (p < 0.01). The degradation of AQP1 mRNA showed no difference under normoxia or hypoxia. These data suggest that the hypoxia-induced expression of AQP1 results from RNA transcription. The sequence located from -1338 to -1334 bp is identical to the consensus sequence of the hypoxia-inducible factor 1 (HIF-1) binding site. The promoter activities of the two constructs including this putative HIF-1 binding site showed 2.0 ± 0.67-fold increase and 2.9 ± 1.9-fold increase under hypoxia when compared with those under normoxia. However, both deletion and mutation of the HIF-1 binding site abrogated this effect. These data suggest that this sequence mediates the transcriptional activation of AQP1 by hypoxia. The chromatin immunoprecipitation assay showed that HIF-1α bound to the putative HIF-1 binding site. In conclusion, hypoxia-induced expression of AQP1 requires transcriptional activation, and the HIF-1 binding site of the 5'-promoter is necessary for transcriptional activation in HRVECs.

Effect of gamma-ray irradiation on degradation of di(2-ethylhexyl)phthalate in polyvinyl chloride sheet.

The risk assessment of di(2-ethylhexyl)phthalate (DEHP) migration from polyvinyl chloride (PVC) medical devices is an important issue for patients. The aim of this study was to determine DEHP degradation and migration from PVC sheets. To this end, the method for the simultaneous determination of DEHP and its breakdown products (mono(2-ethylhexyl)phthalate (MEHP) and phthalic acid (PA)) was improved. Their migration levels from 0 to 50 kGy gamma-ray irradiated PVC sheets were determined. DEHP migration level decreased in proportion to the dose of gamma-ray irradiation, while MEHP and PA migration levels increased. The hardness and the elastic modulus of PVC sheets were examined, but no clear relationship between DEHP migration and these parameters was observed.

Extracranial-intracranial bypass for reconstruction of internal carotid artery in the management of head and neck cancer.

Extracranial-intracranial bypass surgery was performed prior to carotid resection in eight patients with head and neck carcinoma that involved the carotid artery near the skull base. Four patients underwent the standard one-stage extracranial-intracranial bypass procedure. A two-stage procedure was performed in the remaining four patients. The procedure first involved an anastomosis between the M3 segment of the middle cerebral artery and the superficial temporal artery, followed by a bypass between the M2 segment of the middle cerebral artery and the internal carotid artery. One of the patients who underwent the standard one-stage extracranial-intracranial bypass procedure suffered an intraoperative infarction. Despite even longer occlusion times of the M2 segment, none of the patients who underwent the two-stage bypass suffered from any serious neurologic consequences. Three of seven patients who underwent the curative operations, survived more than 4 years, however, the remaining patients died within 1 year from recurrence. Our results show that carotid artery resection yields an opportunity for cure. In extracranial-intracranial bypass surgery, the temporary occlusion of the middle cerebral artery may also induce serious ischemia; however, the two-stage extracranial-intracranial bypass procedure appears to minimize the risk.