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This study aims to investigate the association among metformin use, vit B12 deficiency, and DPN occurrence in diabetes. This retrospective, propensity-matched cohort study was performed using National Health Insurance Service database - National Sample Cohort in South Korea. Study 1 analyzed DPN incidence according to vit B12 deficiency and study 2 analyzed vit B12 deficiency incidence according to the presence/absence of DPN. Moreover, we compared the results with respect to metformin use. In study 1, DPN incidence per 10000 person-year (PY) was 179.7 and 76.6 in the vit B12 and non-vit B12 deficiency groups, respectively. The adjusted HR was 1.32 (95% CI; 1.21–1.44, P < 0.05) and metformin use elicited a more significant effect of DPN occurrence in patient with vit B12 deficiency (HR: 5.76 (95% CI; 5.28–6.29). In study 2, vit B12 deficiency incidence per 10000 PY was 250.6 and 129.4 in the DPN and non-DPN groups, respectively. The adjusted HR was 2.44 (95% CI; 2.24–2.66, P < 0.05), however, metformin prescription was associated with the reduced incidence of vit B12 deficiency in DPN patients (HR 0.68 (95% CI; 0.62–0.74, P < 0.05). DPN occurrence increased in diabetes with vit B12 deficiency and the incidence of vit B12 deficiency was also high in DPN patients. However, metformin showed opposite effects in both cohorts. Further studies clarifying the causal relationship among DPN occurrence, vit B12 deficiency, and metformin use are warranted. • We investigated the association among metformin use, vitamin B12 (vit B12) deficiency, and DPN occurrence in diabetes because vit B12 deficiency according to the presence or absence of diabetic peripheral neuropathy (DPN) in diabetes is needed to be clarified besides vit B12 deficiency induced DPN occurrence. • DPN incidence was higher in the patient with vit B12 deficiency compared with non-vit B12 deficiency group and metformin use elicited a more significant effect of DPN occurrence in patient with vit B12 deficiency. Vit B12 deficiency incidence was higher in the DPN group compared with non-DPN group, however, metformin treatment rather blunted the vit B12 deficiency in patient with DPN. • The implications of our findings is to clarify the causal relationship among DPN occurrence, vit B12 deficiency, and metformin use is needed in the patient with diabetes [ABSTRACT FROM AUTHOR]

Aims: We investigated the specificity of the 75g oral glucose tolerance test (OGTT) and the clinical usefulness of the 2h post loading glucose (2h PLG) value in the clinical care of diabetes patients.Methods: The 75g OGTT data of 1755 subjects were analyzed. The relationships and degrees of consistency among 2h PLG, fasting plasma glucose (FPG), and HbA1c values were assessed. We also investigated the degree of contribution of 2h PLG in the prescription of glucose-lowering agents and in the pitfall group for use of 75g OGTT.Results: Among 595 subjects with normal FPG, only 329 (55.3%) showed normal 2h PLG level, and 66 (11.1%) patients could be considered as having diabetes. Among 454 diabetes patients (based on FPG and HbA1c), 409(90.1%) showed 2h PLG values in the range of diabetes, 45 (9.9%) subjects did not exhibit diabetes. Pitfall group who used 75g OGTT for diagnosis diabetes (lower 2h PLG value compared to fasting and upper 2h PLG value compared to fasting) showed differences in body weight and height.Conclusions: Based on OGTT results, around 10% patients cannot be diagnosed with diabetes based solely on the 2h PLG value. Further studies on differences in glucose loading according to body weight, individual life pattern, and calorie requirement are needed for improvement of the specificity of the OGTT in the clinical management of diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Early detection and diagnosis is most important in small fiber diabetic peripheral neuropathy (DPN) management. Traditionally used diagnostic methods could not detect different nerve fiber function and had low sensitivity and specificity and huge inter- and intra-individual variation and coefficient of variance. So we need more objective and sensitive and specific diagnostic tools. In this review, we will discuss about recently developed diagnostic methods of small fiber DPN. [Copyright &y& Elsevier]

Toxic compounds in processed meat are considered major human health hazards. However, the effects of natural products on the reduction of potential carcinogenic substances are still unclear. In this paper, we present an overview of previously published studies on the effects of natural products on the reduction of potential carcinogenic substances in meat products and provide information on how to reduce these carcinogenic substances. We surveyed more than 200 related studies published in the past 20 years and found that numerous natural products containing antioxidants were able to prevent the production of potential carcinogenic substances. This reduction can be attributed to three possible mechanisms: antioxidative activities, antimicrobial activities, and regulation of the Maillard reaction in meat products. Numerous natural products have been shown to reduce oxidative stress, prevent meat oxidation, and exhibit iron scavenging activities, and these antioxidative activities can reduce potential carcinogenic substances, such as heterocyclic aromatic amines (HCAs). The antimicrobial activities of natural products can inhibit the formation of biogenic amines produced by microbial growth. Another possible mechanism for the reduction of potential carcinogenic substances in meat products is related to regulation of the Maillard reaction during heat exposure, as HCAs are produced during the Maillard reaction. Therefore, we assume that effective use of natural products could inhibit the production of carcinogens, such as HCAs, polycyclic aromatic hydrocarbons, and biogenic amines, in meat products. Image 1 • Formation of meat carcinogens affected from oxidation, microorganisms and Maillard reaction. • Natural products shown to have antioxidant and antimicrobial activities. • Antioxidant activities prevented the oxidation of heme iron in meat products. • Antimicrobial activities inhibited microbial growth and the formation of biogenic amines. • Use of natural products could inhibit the harmful substances in meat products. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To determine the prevalence and risk factors for painful diabetic peripheral neuropathy (PDPN) and evaluate sleep impairment and quality of life in patients with PDPN. Methods: Data from the Korean Diabetes Association Neuropathy Study Group were used to evaluate 3999 patients with type 2 diabetes. PDPN was diagnosed using visual analogue scales (VAS) and medical history. The patients were asked to answer the Brief Pain Inventory-Short Form (BPI-SF), Medical Outcomes Study Sleep (MOS-Sleep) Scale, EuroQol (EQ-5D), and VAS. Results: Among the patients with diabetic peripheral neuropathy (n =1338), 577 (43.1%) were diagnosed with PDPN (14.4% of all patients with type 2 diabetes). PDPN was independently associated with age, female gender, fasting plasma glucose, hypertension, and previous cerebrovascular events. All pain severity and interference measures were higher in patients with PDPN than in non-PDPN patients, and patients with PDPN reported more impaired sleep and lower EQ-5D and VAS scores. Conclusions: The prevalence of PDPN in Koreans was comparable to that in Western populations. PDPN may impair sleep and quality of life compared with non-PDPN, and physicians should carefully consider pain symptoms in patients with diabetic peripheral neuropathy. [Copyright &y& Elsevier]

Abstract: MICROMEGAS detectors have been developed for the detection and tracking of charged and neutral particles. The control parameters of MICROMEGAS include materials, the type of gases, the mixing ratio of gases and the geometry. Simulations of MICROMEGAS are conducted to optimize the characteristics and performance with respect to the nature of the gas mixture, applied voltages of drift and amplification regions. Quantities such as the equi-potential lines, electron drift lines, and avalanche process of electrons and ions are calculated. Two MICROMEGAS detectors are built and characterized by using standard X-ray sources. The voltage gains are measured against the applied voltage range for different gas pressures and are compared with our simulation results. [Copyright &y& Elsevier]

Abstract: We investigated whether sulodexide has additional protective effects against peripheral nerve damage caused by microvascular dysfunction in a rat model of diabetes. Female Sprague–Dawley (SD) rats were divided into the following 4 groups (n=7–9/group): Normal, Normal+Sulodexide (sulodexide 10mg/kg), diabetic group, and diabetic+Sulodexide (sulodexide 10mg/kg). We assessed current perception threshold, skin blood flow, superoxide dismutase, and proteinuria in experimental rats after oral administration of sulodexide for 20weeks. We also performed morphometric analysis of sciatic nerves and intraepidermal nerve fibers of the foot. Superoxide dismutase activity in the blood and sciatic nerve were increased significantly after sulodexide treatment in the diabetic group. Current perception threshold was reduced at 2000Hz (633.3±24.15 vs 741.2±23.5μA, P <0.05) and skin blood flow was improved (10.90±0.67 vs 8.85±0.49TPU, P <0.05) in the diabetic+Sulodexide group compared with the diabetic group. The mean myelinated axon area was significantly larger (56.6±2.2 vs 49.8±2.7μm2, P <0.05) and the intraepidermal nerve fiber density was significantly less reduced (6.27±0.24 vs 5.40±0.25/mm, P <0.05) in the diabetic+Sulodexide group compared to the diabetic group. Our results demonstrate that sulodexide exhibits protective effects against peripheral nerve damage in a rat experimental model of diabetes. Therefore, these findings suggest that sulodexide is a potential new therapeutic agent for diabetic peripheral neuropathy. [Copyright &y& Elsevier]

Abstract: The aim of this study is to investigate the effect of rimonabant, which has antiatherosclerotic and antiinflammatory properties, on peripheral neuropathy in a diabetic rat. Diabetic rat models were induced by treatment with streptozotocin and then either normal or diabetic rats were treated with an oral dose of 10mg/kg/day rimonabant or placebo for 24weeks. We quantified the densities of intraepidermal (PGP9.5+) nerve fiber and total skin (RECA-1+) capillary length. We also measured the current perception threshold, as defined by the intensity of sine-wave stimulus, skin blood flow after treadmill running and TNF-alpha level in spinal cord tissue or plasma. After 24weeks, rimonabant reduced the body weight and food intake in both diabetic and normal rats, but it had no effect on blood sugar levels. In addition, rimonabant treatment significantly improved the decreased intraepidermal nerve fiber density (5.53±0.12 vs. 4.36±0.27/mm, P <0.05) and alleviated the increased current perception threshold in rimonabant-treated versus control diabetic rats. These responses were closely associated with the attenuation of skin capillary loss (1.98±0.07 vs. 1.67±0.10mm/mm2, P <0.05), increase in skin blood flow (14.93±1.08 vs. 12.07±0.87 TPU, P <0.05) and reduction in TNF-alpha level in tissue (70.10±4.99 vs. 91.18±3.34pg/mg, P <0.05) in rimonabant-treated diabetic rats compared with placebo. These findings suggest that rimonabant can be beneficial for treatment of diabetic peripheral neuropathy, possibly due to its potential role in micro- and macrovessel protection and its anti-inflammatory properties. [Copyright &y& Elsevier]

Background and Aims: The aim of this study was to investigate the GLP-1 pathway effect on peripheral nerves using a DPP-IV inhibitor in streptozotocin (STZ)-induced diabetic rats. Methods: Adult male Sprague Dawley rats were divided into four groups and two groups (n =6 in each) were given a DPP-IV inhibitor of 0.3mg/kg/day or 10mg/kg/day dissolved in water. Intraepidermal innervation was quantified as nerve fiber abundance per unit length of epidermis (IENF/mm) following an immunohistochemical procedure using the polyclonal antibody of anti-protein gene product 9.5 (PGP 9.5). Results: Daily administration of DPP-IV inhibitor to the experimental diabetes model at doses of 10mg/kg for 32 weeks protected nerve fiber loss compared with untreated rats as follows (IENF/mm): normal (9.89±0.34), diabetes mellitus (DM) (8.42±0.28), DM with 0.3mg/kg DPP-IV inhibitor (9.88±0.38), and DM with 10mg/kg DPP-IV inhibitor (10.36±0.32) (p <0.05). There was a significant reduction (% change) in the decrease of intraepidermal nerve fiber density (IENFD) in the DPP-IV inhibitor-treated groups during the experimental period: normal (10.1%), DM (25.8%), DM with 0.3mg/kg DPP-IV inhibitor (13.3%), and DM with 10mg/kg DPP-IV inhibitor (7.9%) (p <0.05). Conclusions: Our study suggests that a DPP-IV inhibitor may prevent peripheral nerve degeneration in a diabetes-induced animal model and support the idea that GLP-1 may be useful in peripheral neuropathy. [Copyright &y& Elsevier]

Abstract: Background: Vascular and inflammatory processes have been reported to be factors in the pathogenesis of diabetic neuropathy. Angiopoietin-1 (Ang1) plays essential roles in regulating vascular growth, development, maturation, permeability, and inflammation. Objective: The aim of this study was to investigate the effect of cartilage oligomeric matrix protein (COMP)-Ang1, which is a soluble, stable, potent Ang1 variant, on peripheral nerves in db/db diabetic mice. Methods: The db/db diabetic mice were randomized into 2 groups based on their weight and glucose level and treated with recombinant adenovirus (Ade), expressing either COMP-Ang1 or the β-galactosidase gene (LacZ) (control), for 8 weeks. Immunohistochemistry was performed using a polyclonal antibody of antiprotein gene product and a secondary antibody. Intraepidermal nerve fiber density (IENFD) was quantified as nerve fiber abundance per unit length of epidermis (IENF/mm). In addition, the total capillary length (TCL) per unit length of epidermis was summed (mm/mm2). All slides were coded and the capillary length and the number of nerve fibers were calculated by a blinded observer. Results: Ten diabetic db/db mice (mean [SD] weight, 38.7 [1.95] g) were randomized to receive Ade-COMP-Ang1 or Ade-LacZ. IENFD was significantly greater in the Ade-COMP-Ang1 group compared with the Ade-LacZ group (mean [SD] 8.95 [3.30] vs 3.57 [0.73]/mm; P < 0.05). TCL was also significantly greater in the Ade-COMP-Ang1 group (2.79 [0.99] vs 2.04 [0.58] mm/mm2; P < 0.05). Compared with baseline, fasting blood glucose concentration after 8 weeks of treatment decreased significantly more in the Ade-COMP-Ang1 group than in the Ade-LacZ group (489 [45] to 361 [81] vs 495 [48] to 521 [70] mg/dL; P < 0.05). Conclusions: These results suggest that Ade-COMP-Ang1 might have had proliferative effects on peripheral nerve and cutaneous capillaries in this small animal study. Further investigation of the metabolic effect, target site, and related mediator of COMP-Ang1 is needed. [Copyright &y& Elsevier]

Abstract: This study was done to see whether 27-base pair repeats polymorphism in intron 4 of ecNOS gene is associated with carotid atherosclerosis in type 2 diabetic patients. The polymorphism was identified by polymerase chain reaction (PCR). Ultrasound parameters of carotid atherosclerosis were analyzed in relation to the genotype in 210 patients with type 2 diabetes. The ecNOS4a allele was detected in 34 (16.2%) of this study group. With the exception of the plaque count (P =0.069), all other parameters obtained by ultrasound examination of carotid arteries were significantly correlated with presence of ecNOS4a allele (P <0.05). As all the measured carotid parameters correlated well each other, we selected the total mean carotid IMT (intima-media thickness) value to be used for this analysis. In the multivariate analysis including several variables such as age, sex, hypertension, LDL cholesterol, waist–hip ratio, and fasting insulin, all determined to be significant by univariate analysis, ecNOS4a allele had a significant correlation with total mean IMT (P <0.001). In conclusion, the ecNOS4a allele is associated with carotid atherosclerosis in type 2 diabetic patients in Korea. [Copyright &y& Elsevier]