A new era for research publication: Will Open Access become the norm?

The progress of JDI travels in optimistic paces with optimistic persons. A remarkable rise in Impact Factor was observed after the introduction of Open Access. It seems that there is a positive relationship between online usage and Impact Factor.

A new perspective on the biguanide, metformin therapy in type 2 diabetes and lactic acidosis.

Recent topics about metformin mainly focus on clinical studies, briefly mentioning some new aspects on the mechanisms of metformin action.

A long-term effect of epalrestat on motor conduction velocity of diabetic patients: ARI-Diabetes Complications Trial (ADCT).

In order to study a long-term effect along with adverse action of epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.

Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.

OBJECTIVE: We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c)

Pathogenesis and neuroimaging of cerebral large and small vessel disease in type 2 diabetes: A possible link between cerebral and retinal microvascular abnormalities.

Diabetes patients have more than double the risk of ischemic stroke compared with non-diabetic individuals, and its neuroimaging characteristics have important clinical implications. To understand the pathophysiology of ischemic stroke in diabetes, it is important to focus not only on the stroke subtype, but also on the size and location of the occlusive vessels. Specifically, ischemic stroke in diabetes patients might be attributed to both large and small vessels, and intracranial internal carotid artery disease and small infarcts of the posterior circulation often occur. An additional feature is that asymptomatic lacunar infarctions are often seen in the basal ganglia and brain stem on brain magnetic resonance imaging. In particular, cerebral small vessel disease (SVD), including lacunar infarctions, white matter lesions and cerebral microbleeds, has been shown to be associated not only with stroke incidence, but also with the development and progression of dementia and diabetic microangiopathy. However, the pathogenesis of cerebral SVD is not fully understood. In addition, data on the association between neuroimaging findings of the cerebral SVD and diabetes are limited. Recently, the clinical importance of the link between cerebral SVD and retinal microvascular abnormalities has been a topic of considerable interest. Several clinical studies have shown that retinal microvascular abnormalities are closely related to cerebral SVD, suggesting that retinal microvascular abnormalities might be pathophysiologically linked to ischemic cerebral SVD. We review the literature relating to the pathophysiology and neuroimaging of cerebrovascular disease in diabetes, and discuss the problems based on the concept of cerebral large and small vessel disease.

Long-term treatment study of global standard dose metformin in Japanese patients with type 2 diabetes mellitus.

In 169 Japanese patients with type 2 diabetes mellitus with blood glucose levels that were inadequately controlled with diet and exercise therapy alone, or with diet and exercise therapy plus a sulfonylurea (SU) drug, we evaluated the safety and efficacy of global standard dose metformin given up to a maximum daily dose of 2250 mg for 54 weeks. The changes in HbA1c from baseline to the final evaluation visit were -1.32 ± 0.76% for metformin monotherapy and -1.29 ± 0.81% for metformin plus SU, both significantly lower than baseline. The incidences of adverse events and adverse drug reactions were 91.1% (154/169 patients) and 67.5% (114/169 patients), respectively. The most common adverse events were gastrointestinal symptoms, and most of the gastrointestinal symptoms were considered by investigators to be related to metformin treatment. An increased blood lactic acid level was observed in three subjects (1.8%); however, no clinical symptoms were reported, and there was no increase in mean lactic acid concentration throughout the evaluation period. Symptoms of hypoglycemia were reported in 16 patients, all receiving metformin plus SU, but none received metformin monotherapy. There was a decrease in mean body weight. Global standard dose metformin may be useful for maintaining good blood glucose control over the long term in the treatment of type 2 diabetes mellitus in Japanese patients.

Effect of re-coaching on self-injection of insulin in older diabetic patients - Impact of cognitive impairment.

AIMS: We investigated the effect of re-coaching on self-injection of insulin and impact of cognitive function in 100 older diabetic patients. METHODS: We examined patients on a variety of skills and knowledge regarding self-injection of insulin and evaluated the effect of re-coaching the patients after 3months and 4years. We also investigated the influence of cognitive impairment (CI) on coaching. RESULTS: Skills scores for self-injection of insulin and HbA1c improved significantly 3months after re-coaching. In 51 patients followed-up for 4years, skills scores were maintained during the 4years, while knowledge scores improved after 3months but then returned to the baseline level. In the group of patients with CI as determined by the Mini-Mental Status Examination, skills scores were similar to those in the group without CI, while knowledge scores were significantly lower as compared with those in the group without CI at any time point. Skills scores were maintained during the 4years regardless of CI. CONCLUSION: The present study showed that re-coaching in skills for self-injection of insulin was effective in improving and maintaining insulin treatment in older diabetic patients, even if patients had CI.

Soluble adhesion molecules and C-reactive protein in the progression of silent cerebral infarction in patients with type 2 diabetes mellitus.

The purpose of this study was to investigate the association between the progression of silent cerebral infarction (SCI) and levels of soluble adhesion molecules and high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetic patients. One hundred twenty middle-aged and elderly diabetic patients without histories of vascular events were followed up for a period of 3 years. We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, E-selectin, and hs-CRP and assessed brain ischemic lesions by magnetic resonance imaging at baseline and 3 years later. Silent cerebral infarction was observed in 13% of the patients at baseline, and these patients were significantly older and had significantly higher blood pressure than those without SCI. Thirty-two patients had newly diagnosed SCI after 3 years. There were no significant differences in factors such as age, blood pressure, and diabetic control between patients without SCI and those in whom it was newly diagnosed. However, only sICAM-1 levels, but not the other soluble adhesion molecules or hs-CRP, were associated with the progression of SCI, and this relationship remains after adjustment for risk factors. On the other hand, higher levels of sICAM-1 and hs-CRP at baseline were observed in 7 patients who were excluded from the present study because of the onset of symptomatic cerebral infarction during follow-up. Our present study suggests that sICAM-1 levels may be a potential marker for SCI, which may lead to future stroke and vascular dementia, and that this marker could be useful in monitoring disease progression and as a surrogate marker in treatment studies.

Clinical study of repaglinide efficacy and safety in type 2 diabetes mellitus patients with blood glucose levels inadequately controlled by sitagliptin.

AIMS/INTRODUCTION: The aim of the present study was to evaluate the long-term efficacy and safety of adding repaglinide in patients with type 2 diabetes mellitus whose blood glucose levels were not sufficiently controlled by treatment with a dipeptidyl peptidase-4 inhibitor, sitagliptin, in addition to diet and exercise therapies. MATERIALS AND METHODS: This was a multicenter, uncontrolled, dose-titration study with a treatment period of 52 weeks. The primary end-point was the change in glycated hemoglobin levels from baseline. RESULTS: The glycated hemoglobin level was 7.43 ± 0.57% (mean ± standard deviation) at baseline, and decreased to 6.93 ± 0.91% at the end of the study. The mean changes in glycated hemoglobin levels at 4 weeks and at the end of the study were -0.44 ± 0.28% and -0.50 ± 0.82%, respectively. The glycated hemoglobin-lowering effect was maintained for 52 weeks. The rate of adverse events was 86.0% (86/100), and there were 352 adverse events. The rate of adverse drug reactions was 21.0% (21/100). Hypoglycemia was reported in 5.0% (5/100) of patients, but there was no incidence of 'major hypoglycemia'. CONCLUSIONS: Combination therapy with repaglinide and sitagliptin was considered effective for a long term without clinical safety problems in patients with type 2 diabetes mellitus.

Efficacy and safety of 40 mg or 60 mg duloxetine in Japanese adults with diabetic neuropathic pain: Results from a randomized, 52-week, open-label study.

INTRODUCTION: To examine the long-term efficacy and safety of duloxetine in the treatment of Japanese patients with diabetic neuropathic pain, we carried out a 52-week, randomized, open-label extension of a 12-week, double-blind, placebo-controlled study. MATERIALS AND METHODS: Japanese adults with diabetic neuropathic pain who completed the double-blind study were eligible for this long-term study, carried out at 71 sites in Japan (March 2008 to March 2010). Participants (n = 258) were re-randomized (1:1) to 40 mg/day or 60 mg/day duloxetine. Pain (Brief Pain Inventory severity and interference), quality of life (Patient's Global Impression of Improvement), and safety (primary outcome; adverse events, vital signs, metabolic measures) were measured. RESULTS: Significant (P < 0.0001) and sustained improvements (change ± standard deviation; n = 257) were observed in Brief Pain Inventory severity (average pain score -2.1 ± 1.7). Improvements were also seen in Brief Pain Inventory interference (mean of subscores -0.96 ± 1.52) and Patient's Global Impression of Improvement (-0.9 ± 1.1) scores; these scores decreased significantly (P < 0.0001) during the long-term study. Frequently reported adverse events included somnolence (13.6%), constipation (13.2%) and nausea (10.5%). Increases were observed in plasma glucose, glycosylated hemoglobin and total cholesterol levels, and in bodyweight and heart rate; however, none of these were clinically meaningful. Overall, there were no clinically significant safety concerns. CONCLUSIONS: This is the first publication of a long-term study carried out in Asia with an entirely Japanese patient population to suggest that long-term duloxetine therapy for diabetic neuropathic pain is effective and has an acceptable safety profile.

Factors Associated with Changes in Brain Atrophy during a Three-Year Observation in Elderly Diabetic Patients: Effect of Renal Impairment on Hippocampal Atrophy.

BACKGROUND/AIMS: We conducted a 3-year longitudinal study concerning factors associated with changes in brain atrophy in elderly diabetic patients. METHODS: We evaluated hippocampal and global brain atrophy using automatic voxel-based morphometry of structural magnetic resonance images, 4 cognitive function tests, and cerebral small vessel disease (SVD) in 66 diabetic patients. RESULTS: During the 3-year follow-up, hippocampal and global brain atrophy advanced, and cognitive functions worsened. For changes in hippocampal atrophy, changes in estimated glomerular filtration rate (eGFR), albuminuria, and being an ApoE ε4 carrier were independent factors; change in the number of silent brain infarctions was an independent factor for changes in global brain atrophy. A significant association of changes in eGFR and albuminuria with hippocampal atrophy remained after adjusting for confounders including SVD. Both types of brain atrophy at baseline were significantly correlated with cognitive impairment at baseline and especially associated with changes in delayed word recall during the follow-up after adjusting for confounders. CONCLUSION: Changes in eGFR and albuminuria during follow-up were independent risk factors for hippocampal atrophy, which was associated with decline in delayed word recall, suggesting that management of chronic kidney disease may prevent the progression of hippocampal atrophy.

A copper chelating agent suppresses carbonyl stress in diabetic rat lenses.

To clarify whether transition metals are involved in carbonyl stress in diabetic tissues, we observed the effects of a metal chelating agent, trientine (TE) hydrochloride on the levels of methylglyoxal (MG), 3-deoxyglucosone (3-DG), advanced glycation end products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and polyol pathway metabolites along with semicarbazide-sensitive amine oxidase (SSAO) enzyme activity in lenses from streptozotocin-induced diabetic rats. Lens MG and 3-DG levels were significantly higher in diabetic rats than nondiabetic controls, and TE significantly restored the increase of these compounds. Lens argpyrimidine was also increased in diabetic rats as compared with controls and was significantly reduced by TE. Lens SSAO activity and 8-OHdG were also significantly elevated in diabetic rats, and TE suppressed both of them, whereas TE showed no effect on the polyol pathway metabolites. The results indicate that transition metals play a significant role in the formation of MG and 3-DG via oxidative stress and SSAO activity.

The role of polyol pathway in glucose-induced apoptosis of cultured retinal pericytes.

The pathogenesis of pericyte loss, an initial deficit in the early stage of diabetic retinopathy, remains unclear. Recent studies have suggested that polyol pathway hyperactivity and apoptosis may be involved in pericyte loss. The mechanisms of the glucose-induced apoptosis in retinal pericytes were investigated to evaluate the pathogenesis of diabetic retinopathy. Under the 20 mM glucose condition, intracellular calcium concentrations and caspase-3 activities were significantly increased, and reduced glutathione (GSH) contents were significantly decreased compared with those under the 5.5 mM glucose condition. These abnormalities were all significantly prevented by an aldose reductase inhibitor, SNK-860. Glucose-induced apoptosis was partially but significantly prevented by SNK-860, an inhibitor of calcium-dependent cysteine protease, calpain, or GSH supplementation, and completely normalized by a caspase-3 inhibitor. These observations suggest that glucose-induced apoptosis in retinal pericytes, as one of the pathogenic factors of diabetic retinopathy, would be mediated through an aldose reductase-sensitive pathway including calcium-calpain cascade and increased oxidative stress, and that caspase-3 would be located furthest downstream of these apoptotic signals.

Effects of a Novel Aldose Reductase Inhibitor, Fidarestat (SNK-860), on Vibration Perception Threshold and Subjective Symptoms in Patients with Diabetic Polyneuropathy : An Open-Label Pilot Study.

OBJECTIVE: To evaluate the effects of fidarestat (SNK-860) on vibration perception threshold, as measured by C64 quantitative tuning fork (64Hz) analysis, as well as its effects on subjective symptoms in patients with diabetic polyneuro-pathy. DESIGN AND SETTING: Open-label, prospective study conducted at 12 hospitals in the central area of Honshu, Japan. INTERVENTIONS: Fidarestat was administered at a dosage of 1mg once daily after breakfast for 28 weeks. MAIN OUTCOME MEASURES: Vibration perception threshold of upper and lower extremities was determined using a C64 quantitative tuning fork, and measured at baseline and after 12 and 28 weeks of treatment. Subjective symptoms, including numbness, spontaneous pain and hypoaesthesia, were evaluated every 4 weeks. RESULTS: Subjective symptoms were evaluated in 22 patients, and vibration perception threshold data were available for 19 patients. Vibration perception threshold at baseline was negatively correlated with the severity of the following subjective symptoms: numbness in the upper limbs, and numbness, coldness and hot flushes, smarting pain causing difficulty walking and hypoaesthesia in the lower limbs. During treatment with fidarestat, vibration perception threshold increased significantly in the upper (p = 0.0017) and lower (p = 0.0001) limbs. The following symptoms were also significantly improved: severity of numbness in the lower limbs, heaviness in the foot, coldness and hot flushes in the lower limbs, smarting pain causing difficulty walking, sensation as if walking on sand, sensation as if walking on an uneven road, spontaneous pain in the lower limbs, and dizziness. Adverse events occurred in four patients. CONCLUSION: Administration of fidarestat after breakfast was effective in significantly alleviating some symptoms of diabetic polyneuropathy. The C64 quantitative tuning fork analysis is useful in the diagnosis of diabetic polyneuropathy, and as a measure of the severity of the neuropathological symptoms of this condition.

Effect of combination therapy with repaglinide and metformin hydrochloride on glycemic control in Japanese patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: We investigated the efficacy and safety of repaglinide as an add-on therapy for Japanese patients with type 2 diabetes mellitus receiving metformin monotherapy (at a dose of 1,500 mg/day, mainly) in addition to diet and exercise. MATERIALS AND METHODS: In the 16-week multicenter, placebo-controlled, randomized, double-blind, parallel-group trial (the phase III study), patients with type 2 diabetes mellitus with metformin monotherapy were randomly assigned to the repaglinide or placebo group. Thereafter, a 36-week, multicenter, uncontrolled, dose-titration method study was extended to a total duration of 52 weeks (the long-term study). The primary end-point of each study was a change in glycated hemoglobin (HbA1c) from baseline. RESULTS: After 16 weeks, mean reductions in HbA1c were significantly greater for the repaglinide group than for the placebo group (-0.98 ± 0.72% vs 0.13 ± 0.63%, P < 0.001). In the long-term study, the mean change in HbA1c was -0.76 ± 0.83%. The rate of adverse events was 60.6 and 50.0% in the repaglinide and placebo groups, respectively, in the phase III study, and 78.3% in the long-term study. Hypoglycemia was reported in 11.7, 0 and 13.3% of patients in the repaglinide group, placebo group and long-term study, respectively. CONCLUSIONS: Combination therapy with repaglinide and metformin resulted in an approximately 1% reduction in HbA1c at week 16 and in a significant long-term improvement in HbA1c at the end of the study. No safety problems were noted during the concomitant use of repaglinide and metformin. These studies were registered with JapicCTI (nos. JapicCTI-101202 and JapicCTI-101203).

Effect of renal impairment on cognitive function during a 3-year follow up in elderly patients with type 2 diabetes: Association with microinflammation.

AIMS/INTRODUCTION: We investigated the effect of renal impairment on cognitive function during a 3-year follow up in elderly type 2 diabetic patients, and an association with microinflammation. MATERIALS AND METHODS: Four cognitive function tests - Mini-Mental State Examination (MMSE), word recall, Digit Symbol Substitution (DSS) and Stroop Color Word - were carried out in 67 patients. Renal impairment was defined as the presence of albuminuria and a decline in estimated glomerular filtration (eGFR) <60 mL/min/1.73 m(2). Inflammatory markers, such as highly sensitive C-reactive protein (hs-CRP), tumor necrotizing factor-α (TNF-α), interleukin (IL)-1ß and IL-6, were measured at baseline. RESULTS: At baseline, cognitive decline was found in patients with renal impairment. The DSS test was independently associated with eGFR decline, whereas MMSE tended to be associated with albuminuria after adjusting for confounding factors. Regarding changes in cognitive function and renal impairment, changes in urinary albumin to creatinine ratios were strongly and independently associated with changes in word recall scores. In patients with persistent eGFR decline, there was a tendency toward a greater decrease in MMSE and DSS scores, whereas in those with newly detected albuminuria, there was a tendency toward a greater decrease in word recall scores. Increased baseline levels of hs-CRP, TNF-α and IL-6 were associated with renal impairment and cognitive function, especially DSS tests, respectively. However, the increased levels were not independent predictors for cognitive decline. CONCLUSIONS: The present study showed a reciprocal relationship between cognitive decline and renal impairment, especially progression of albuminuria. Thus, monitoring treatment using renal biomarkers will be important for preserving both renal and cognitive function.