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Abstract: Glucagon-like peptide 1 (GLP-1) is an insulinotropic protein. It was reported that the continuous infusion of GLP-1 normalized the blood glucose level in type 2 diabetes animal model. However, the short half-life of GLP-1 has limited its application in clinical settings and prompted us to develop a GLP-1 gene therapy system. Our previous results showed that the delivery of pβ-GLP-1 using polyethylenimine (PEI) reduced the blood glucose level effectively. However, the glucose level was not completely normalized. In the present study, the more efficient GLP-1 expression system was developed using two-step transcription amplification (TSTA). To evaluate the TSTA system, pβ-Gal4-p65 and pUAS-Luc were constructed. The pUAS-Luc/pβ-Gal4-p65 system showed the highest transfection efficiency at a 2:1 pUAS-Luc/pβ-Gal4-p65 weight ratio. In addition, the transgene expression by the TSTA system was at least 4 times higher than pβ-Luc. To apply the TSTA system to the GLP-1 expression plasmid, pUAS-GLP-1 was constructed. The pUAS-GLP-1/pβ-Gal4-p65 system showed higher mRNA level than pβ-GLP-1. In addition, the level of GLP-1 by the pUAS-GLP-1/pβ-Gal4-p65 system was more than 4 times higher than pβ-GLP-1. Therefore, the TSTA GLP-1 expression system may be useful to develop gene therapy system for type 2 diabetes. [Copyright &y& Elsevier]

Abstract: Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid hormone produced by intestinal L cells. It has been proposed that GLP-1 can be used as a new treatment for type 2 diabetes mellitus because it acts to augment insulin secretion and its effectiveness is maintained in type 2 diabetic patients. Despite its many remarkable advantages as a therapeutic agent for diabetes, GLP-1 is not immediately clinically applicable because of its extremely short half-life. One way to overcome this drawback is GLP1 gene delivery, which enables GLP-1 production in the body. In this study, the effect of GLP1 gene delivery was evaluated both in vitro and in vivo using a new plasmid constructed with a GLP1 (7–37) cDNA. The expression of the GLP1 gene was driven by a SV40 promoter/enhancer. To increase the expression level of GLP-1, nuclear factor κB binding sites were introduced. The in vitro results showed expression of GLP-1 and in vitro activity of GLP-1, which is a glucose-dependent insulinotropic action. A single systemic administration of polyethyleneimine/pSIGLP1NFκB complex into DIO mice resulted in increasing insulin secretion and decreasing blood glucose levels for a duration longer than 2 weeks. [Copyright &y& Elsevier]

Glucagon-like peptide-1 (GLP-1) is a potent insulinotrophic hormone, which makes GLP-1 an attractive candidate for the treatment of type 2 diabetes. However, the short plasma half-life of the active forms of GLP-1 poses an obstacle to the sustained delivery of this peptide. In this study, we evaluated the effect of GLP-1 gene delivery both in vitro and in vivo using a new plasmid constructed with a modified GLP-1 (7-37) cDNA. This cDNA contains a furin cleavage site between the start codon and the GLP-1 coding region. The expression of the GLP-1 gene was driven by a chicken β-actin promoter (pβGLP1). The level of the GLP-1 mRNA was evaluated by RT-PCR 24 h after transfection. The in vitro results showed a dose-dependent expression of GLP-1. Coculture assay of the GLP-1 plasmid-transfected cells with isolated rat islet cells demonstrated that GLP-1 increased insulin secretion by twofold, compared to controls during a hyperglycemic challenge. A single injection of polyethyleneimine/pβGLP1 complex into ZDF rats resulted in increasing insulin secretion and decreasing blood glucose level that was maintained for 2 weeks. This GLP-1 gene delivery system may provide an effective and safe treatment modality for type 2 diabetes. [Copyright &y& Elsevier]

Aim: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium‐glucose cotransporter‐2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). Materials and Methods: In a multicentre study, with a randomized, double‐blind, placebo‐controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24‐week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. Results: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: −0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high‐density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. Conclusions: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference. [ABSTRACT FROM AUTHOR]

Aims: The study aimed to evaluate and compare the efficacy and safety of enavogliflozin, a newly developed sodium‐glucose cotransporter 2 inhibitor, with placebo in Korean patients with type 2 diabetes mellitus. Materials and Methods: Patients with glycated haemoglobin (HbA1c) of 7.0‐10.0%, entered a 2‐week placebo run‐in period, and were randomized to receive once‐daily enavogliflozin (0.1, 0.3 or 0.5 mg) or placebo for 12 weeks. The primary efficacy endpoint was the change in HbA1c from baseline at week 12. Results: Overall, 194 patients were included in the full analysis set [placebo, n = 46; enavogliflozin (0.1 mg, n = 49; 0.3 mg, n = 50; 0.5 mg, n = 49)]. Patients receiving 0.1, 0.3 and 0.5 mg enavogliflozin showed significantly reduced HbA1c compared with those receiving placebo at week 12 (−0.79%, −0.89%, −0.92% and −0.08%, respectively; p <.001 vs. placebo). Mean changes in fasting plasma glucose from baseline at week 12 were −30.5, −31.1, −35.0 and 4.9 mg/dl in patients receiving enavogliflozin doses and placebo, respectively. The proportion of patients achieving HbA1c <7.0% at week 12 was significantly higher in the three enavogliflozin groups than in the placebo group (42.9%, 44.0%, 61.2% and 17.4%, respectively). A higher proportion of patients showed HbA1c reduction by >0.5% after receiving enavogliflozin doses than those receiving placebo (61.2%, 72.0%, 65.3% and 26.1%, respectively). There were no significant differences in incidences of adverse events of hypoglycaemia and genital infection between the groups. Conclusions: Once‐daily enavogliflozin monotherapy for 12 weeks is an effective, safe, and well‐tolerated treatment for Korean patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of a novel sodium‐glucose cotransporter 2 inhibitor, enavogliflozin 0.3 mg monotherapy, in Korean people with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. Materials and Methods: This study was a randomized, double‐blind, placebo‐controlled trial conducted in 23 hospitals. Individuals with haemoglobin A1c (HbA1c) of 7.0%‐10.0% after at least 8 weeks of diet and exercise modification were randomized to receive enavogliflozin 0.3 mg (n = 83) or placebo (n = 84) for 24 weeks. The primary outcome was a change in HbA1c at week 24 from baseline. Secondary outcomes included the proportion of participants achieving HbA1c <7.0%, change in fasting glucose, body weight and lipid levels. Adverse events were investigated throughout the study. Results: At week 24, the placebo‐adjusted mean change in HbA1c from baseline in the enavogliflozin group was −0.99% (95% confidence interval −1.24%, −0.74%). The proportions of patients achieving HbA1c <7.0% (71% vs. 24%) at week 24 was significantly higher in the enavogliflozin group (p <.0001). Placebo‐adjusted mean changes in fasting plasma glucose (−40.1 mg/dl) and body weight (−2.5 kg) at week 24 were statistically significant (p <.0001). In addition, a significant decrease in blood pressure, low‐density lipoprotein cholesterol, triglyceride, and homeostasis model assessment of insulin resistance were observed, along with a significant increase in high‐density lipoprotein cholesterol. No significant increase in treatment‐related adverse events was observed for enavogliflozin. Conclusions: Monotherapy with enavogliflozin 0.3 mg improved glycaemic control in people with T2DM. Enavogliflozin therapy also exerted beneficial effects on body weight, blood pressure and lipid profile. [ABSTRACT FROM AUTHOR]

Abstract: The relationships between insulin secretion and resistance in subjects with newly diagnosed prediabetes (preDM) and type 2 DM according to the presence of metabolic syndrome (MS) were controversial. We performed OGTT on 322 drug naive subjects with a history of hyperglycemia of ≤3 months, and divided into three groups, NGT, preDM (IFG and/or IGT), and T2DM. We also diagnosed these subjects with respect to MS according to ATP III criteria modified by Asia-Pacific guidelines and compared IGI and HOMA-IR. When compare groups stratified by the presence of MS, preDM and T2DM groups with MS showed significantly higher mean HOMA-IR and IGI than those without. When compare groups with respect to glucose tolerance, NGT, preDM, and T2DM subgroups in MS group showed significant higher HOMA-IR and lower IGI according to glucose tolerance. However, NGT, preDM, and T2DM subgroups in non-MS group showed a significant decrease in IGI but no significant difference in HOMA-IR as glucose tolerance worsened. In conclusion, deterioration in IGI and aggravation of HOMA-IR are both important in the primary pathogenesis of diabetes in those with MS. However, IGI deterioration may be the only important factor in the primary pathogenesis of T2DM in the absence of MS. [Copyright &y& Elsevier]

The combined administration of interleukin-4 (IL-4) and interleukin-10 (IL-10) expression plasmids has demonstrated synergistic effects on the prevention of autoimmune diabetes. To this end, we constructed a co-expression ‘chimeric’ plasmid, pCMV-IL4-IL10, in which the expression of IL-4 and IL-10 was driven by two separate CMV immediate early promoters by using the biodegradable polymer, poly[α-(4-aminobutyl)-l-glycolic acid] (PAGA) as a gene carrier to optimize gene delivery. In vitro transfection assays of the chimeric plasmid in 293T cells showed higher expression levels as well as dose dependence than the single gene expression plasmids. To evaluate the in vivo efficacy of the chimeric plasmid, the pCMV-IL4-IL10/PAGA complex was intravenously injected into 4-week-old non-obese diabetic (NOD) mice and compared to the co-administration group. While both groups had persistent gene expression longer than 5 weeks, the IL-4 and IL-10 serum levels of the chimeric group were higher than those in the co-administration group. Furthermore, the degree of insulitis in the chimeric group was improved over both the co-administration and non-injected control groups. These results suggest that the chimeric IL-4 and IL-10 expression plasmid can effectively reduce the incidence of autoimmune insulitis. [Copyright &y& Elsevier]

Tetrabromobisphenol A (TBBPA) is a well-known organobrominated flame retardant. TBBPA has been detected in the environment. The roles played by environmental pollutants in increasing the prevalence of metabolic syndrome are attracting increasing concern. In the present work, we investigated the effects of TBBPA on rat pancreatic β-cells (the RIN-m5F cell line). RIN-m5F cells were incubated with different concentrations of TBBPA for 48 h, and cell viability and the extent of apoptosis were determined. We also measured the levels of inflammatory cytokines, reactive oxygen species (ROS), mitochondrial adenosine triphosphate (ATP), and cardiolipin, as well as the extent of cytochrome c release from mitochondria. TBBPA reduced the ATP level, induced cardiolipin peroxidation and cytochrome c release, and triggered apoptotic cell death. Moreover, TBBPA increased the levels of inflammatory cytokines (TNF-α and IL-1β), nitric oxide, intracellular ROS, and mitochondrial superoxide. Together, our results indicate that TBBPA damages pancreatic β-cells by triggering mitochondrial dysfunction and inducing apoptosis. [ABSTRACT FROM PUBLISHER]

This study was undertaken to investigate the possible involvement of oxidative stress in tetrabromobisphenol A (TBBPA)-induced toxicity in osteoblastic MC3T3-E1 cells. To examine the potential effect of TBBPA on cultured osteoblastic cells, we measured cell viability, apoptosis, reactive oxygen species (ROS), mitochondrial superoxide, and mitochondrial parameters including adenosine triphosphate (ATP) level, cardiolipin content, cytochrome c release, cyclophilin levels, and differentiation markers in osteoblastic MC3T3-E1 cells. TBBPA exposure for 48 h caused the apoptosis and cytotoxicity of MC3T3-E1 cells. TBBPA also induced ROS and mitochondrial superoxide production in a concentration-dependent manner. These results suggest that TBBPA induces osteoblast apoptosis and ROS production, resulting in bone diseases. Moreover, TBBPA induced cardiolipin peroxidation, cytochrome c release, and decreased ATP levels which induced apoptosis or necrosis. TBBPA decreased the differentiation markers, collagen synthesis, alkaline phosphatase activity, and calcium deposition in cells. Additionally, TBBPA decreased cyclophilin A and B releases. Taken together, these data support the notion that TBBPA inhibits osteoblast function and has detrimental effects on osteoblasts through a mechanism involving oxidative stress and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid (PFOA), a stable organic perfluorinated compound, is an emerging persistent organic pollutant, found widely in human and wildlife populations. Recent evidence suggests that exposure to environmental toxicants can be associated with higher risks of osteoporosis and fractures. We studied the cellular toxicology of PFOA in MC3T3-E1osteoblast cells. To examine the effect of PFOA, we measured cell viability, reactive oxygen species (ROS), mitochondrial superoxide, and mitochondrial parameters including adenosine triphosphate (ATP) level, mitochondrial membrane potential (MMP), cardiolipin content, and cytochrome c release in MC3T3-E1 cells. Incubating MC3T3-E1 cells in different concentrations of PFOA for 48 h resulted in a concentration-dependent decrease in cell viability and significant inductions of ROS and mitochondrial superoxide. Moreover, PFOA induced MMP collapse, cardiolipin peroxidation, cytochrome c release, and decreased ATP levels, which in turn induced apoptosis or necrosis. When osteoblast differentiation markers were assessed, PFOA treatment caused a significant reduction in alkaline phosphatase activity, collagen synthesis, and mineralization in the cells. In summary, we found an ROS- and mitochondria-mediated pathway for the induction of cell damage by PFOA in MC3T3-E1 cells. Together, our results indicate that mitochondrial toxicity could be a plausible mechanism for the toxic effects of PFOA on osteoblast function. [ABSTRACT FROM PUBLISHER]

Aims/Introduction Recently, patient-tailored statin therapy was proven effective for achieving target low-density lipoprotein ( LDL) cholesterol levels. It is unclear, however, whether this therapeutic modality would be effective for atherogenic lipid profiles and inflammation in patients with type 2 diabetes. Materials and Methods The present study was an 8-week, multicenter, single-step titration trial of patient-tailored atorvastatin therapy (10, 20 and 40 mg) according to baseline LDL cholesterol levels in 440 patients with type 2 diabetes. We measured the LDL particle size by polyacrylamide gel electrophoresis, and used high-sensitivity C-reactive protein (hs CRP) and adiponectin as surrogate markers of inflammation. Results In the intention-to-treat analysis, 91% of the patients achieved their LDL cholesterol targets (<2.6 mmol/L) at week 8. There were significant reductions at week 8 in total cholesterol, triglycerides, non-high-density lipoprotein cholesterol ( HDL) cholesterol, and the total cholesterol: HDL cholesterol ratio compared with the baseline values for all of the doses. The mean LDL particle size was significantly increased, and the small, dense LDL cholesterol levels were decreased in a dose-dependent manner over the study period. In addition, the hs CRP levels were decreased in those high-risk patients with baseline hs CRP levels over 3 mg/L ( P < 0.001), and the adiponectin levels tended to increase with all of the doses ( P = 0.004) at 8 weeks. Conclusions Patient-tailored atorvastatin therapy based on LDL cholesterol at baseline was effective in ameliorating atherogenic LDL particle size and inflammation, in addition to achieving the target LDL cholesterol level without an undesirable effect on glycemic control in patients with type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT01239849). [ABSTRACT FROM AUTHOR]

Aims: It is necessary to evaluate glucose variability and postprandial hyperglycemia in patients with well-controlled type 2 diabetes mellitus because of the limitations associated with hemoglobin A1c (HbA1c) measurements. We evaluated parameters reflecting postprandial hyperglycemia and glycemic variability in patients with optimal HbA1c.Patients and Methods: Thirty-nine patients with HbA1c levels below 7% were recruited to the study. A continuous glucose monitoring system (CGMS) was applied for two 72-h periods. 1,5-Anhydroglucitol (1,5-AG) and fructosamine (FA) were measured as parameters for postprandial hyperglycemia and glucose variability. Using CGMS data, the following postprandial hyperglycemia parameters were calculated: mean postprandial maximum glucose (MPMG) and area under the curve for glucose above 180 mg/dL (AUC-180). To measure glycemic variability, we calculated mean amplitude of glucose excursion (MAGE) using a classical (MAGEc) and new method (MAGE group of sign [MAGEgos]).Results: The baseline HbA1c level was 6.3±0.3%. The mean MPMG was 10.34±1.84 mmol/L, and the mean AUC-180 was 0.17±0.23 mmol/L/day. The mean MAGEgos was 3.27±1.29 mmol/L, and MAGEc was 4.30±1.43 mmol/L, indicating glycemic variability in our patients. The mean levels of 1,5-AG and FA were 16.7±7.4 μg/mL and 273.0±22.5 μmol/L, respectively. In a correlation analysis, FA was significantly correlated with MPMG, AUC-180, MAGEgos, and MAGEc. In contrast, 1,5-AG was only correlated with AUC-180.Conclusions: This study demonstrated postprandial hyperglycemia and glycemic variability in subjects with well-controlled diabetes. FA may reflect postprandial hyperglycemia and glycemic variability, but 1,5-AG may be of limited value for assessing glucose variability in patients with well-controlled type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: The association between sarcopenia and cardiovascular disease (CVD) in elderly people has not been adequately assessed. The aim of this study was to investigate whether CVD is more prevalent in subjects with sarcopenia independent of other well-established cardiovascular risk factors in older Korean adults. Method: This study utilized the representative Korean population data from the Korea National Health and Nutrition Examination Survey (KNHANES) which was conducted in 2009. Subjects older than 65 years of age with appendicular skeletal muscle mass (ASM) determined by dual energy X-ray absorptiometry were selected. The prevalence of sarcopenia in the older Korean adults was investigated, and it was determined whether sarcopenia is associated with CVD independent of other well-known risk factors. Results: 1,578 subjects aged 65 years and older with the data for ASM were selected, and the overall prevalence of sarcopenia was 30.3% in men and 29.3% in women. Most of the risk factors for CVD such as age, waist circumference, body mass index, fasting plasma glucose and total cholesterol showed significant negative correlations with the ratio between appendicular skeletal muscle mass and body weight. Multiple logistic regression analysis demonstrated that sarcopenia was associated with CVD independent of other well-documented risk factors, renal function and medications (OR, 1.768; 95% CI, 1.075–2.909, P = 0.025). Conclusions: Sarcopenia was associated with the presence of CVD independent of other cardiovascular risk factors after adjusting renal function and medications. [ABSTRACT FROM AUTHOR]

Abstract: Both IFG and IGT are prediabetic conditions that can progress to type 2 DM. However, previous studies have shown that these are not identical. This study was conducted on 307 drug naïve prediabetic adults who did not meet the diagnostic criteria for diabetes based on the OGTT. According to the OGTT, the subjects were divided into isolated IFG (i-IFG), isolated IGT (i-IGT), and combined glucose intolerance (CGI) group. We also measured insulin resistance indices (HOMA-IR, WBISI), an insulin secretion indices (insulinogenic index [IGI], AUC I/G0–120, disposition index [DI]), and compared each of the three groups. The OGTT measurements showed that 87 subjects were diagnosed with i-IFG, 75 subjects had i-IGT, and 145 subjects had CGI. With respect to the insulin resistance indices, HOMA-IR and WBISI were not significantly different. However, insulin secretory capacity, the IGI and DI were significantly higher for the i-IFG group. Moreover, after confounders were adjusted, HOMA-IR, IGI, AUC I/G0–120, and the DI were significantly higher for the i-IFG group and WBISI was significantly higher for the i-IGT group. These results demonstrate that the pathogenesis of IFG is more closely associated with insulin resistance, and the pathogenesis of IGT is more closely associated with impaired insulin secretion. [ABSTRACT FROM AUTHOR]

An abstract of the article "An Efficient GLP-1 Expression System Using Two Step Transcription Amplification for Type 2 Diabetes Gene Therapy," by Kyung Soo Ko and colleagues is presented.

Block copolymers consisting of poly(ethylene glycol) (PEG) and poly(amino acid)-based random copolymers were successfully synthesized by the ring opening polymerization of the N-carboxy anhydrides (NCA) of l-lysine and l-phenylalanine. The synthesized copolymers had a molecular weight of around 30,000 and contained l-lysine and l-phenylalanine residues with molar ratios of 10/0, 9/1, 8/2, 7/3 and 6/4. The complex formation of the copolymer and pCMV-luc plasmid DNA was confirmed by the gel retardation assay and zeta potential measurement. Complete neutralization was achieved at an N/P ratio of more than 1.0 and the size of the complex was determined to be around 150 nm by dynamic light scattering. The cytotoxicity and transfection efficiency were tested on the HEK 293T cell line. The synthesized copolymers displayed negligible cytotoxicity, resulting in a cell viability of more than 95%, while those of the poly(l-lysine) (PLL) and poly(ethylenimine) (PEI) homopolymer were around 65 and 55%, respectively, under comparable conditions. The introduction of the hydrophilic PEG is believed to reduce the toxicity of the copolymer, due to its enhanced biocompatibility, and to impart improved stability to the complex under physiological conditions. The transfection efficiency at the optimized charge ratio of 7 was dramatically improved as the molar content of the l-phenylalanine residues in the copolymers increased and reached a maximum value at an l-phenylalanine content of 30 mol%. The transfection efficiency of the PEGK7/plasmid DNA complex was around 80 times higher than that of PLL, despite the presence of neutral PEG as a block segment. [ABSTRACT FROM AUTHOR]

Abstract: Gene therapy with the vascular endothelial growth factor (VEGF) gene is a potential treatment for many disorders or injuries with ischemia. However, unregulated expression of VEGF may induce pathological angiogenesis, promoting tumor growth, diabetic proliferative retinopathy and rupture of atherosclerotic plaque. Therefore, the effective regulation of the gene expression is one of the requirements for the VEGF gene therapy. In this research, we evaluated the hypoxia-inducible gene expression system with the erythropoietin (Epo) enhancer and the Epo 3′-untranslated region (UTR). The luciferase plasmids were constructed with the Epo enhancer (pEpo-SV-Luc), the Epo 3′-UTR (pSV-Luc-EpoUTR) or both (pEpo-SV-Luc-EpoUTR). The polyethylenimine/plasmid complexes were transfected to 293 or A7R5 cells and the cells were incubated under normoxia or hypoxia. The results showed that the Epo enhancer or Epo 3′-UTR increased the target gene expression under hypoxia. pEpo-SV-Luc-EpoUTR showed the highest luciferase expression. The VEGF expression plasmid with the Epo enhancer and 3′-UTR was also constructed. The VEGF expression by pEpo-SV-VEGF-EpoUTR showed the highest specificity of the gene expression in the hypoxic cells. The results suggest that the VEGF plasmid with the Epo enhancer and the Epo 3′-UTR may be useful for gene therapy for ischemic diseases. [Copyright &y& Elsevier]

Abstract: Glucose toxicity to pancreatic β-cells is defined as irreversible β-cell damage, including apoptosis, caused by chronic exposure to high glucose levels in type 2 diabetes. Oxidative stress is an important mechanism for glucose toxicity to pancreatic β-cells. Reducing sugars produce reactive oxygen species through autoxidation and protein glycosylation. 2-Deoxy-d-ribose (dRib) is a reducing sugar with high reactivity. We investigated whether cAMP-stimulating agents could protect β-cells from dRib-induced oxidative damage. HIT-T15 cells were cultured with various concentrations of dRib for 24h. We measured cell survival, intracellular cAMP and H2O2 levels, and apoptosis. dRib decreased cell survival in a dose- and time-dependent manner and markedly increased intracellular H2O2 levels and apoptosis. N-Acetyl-l-cysteine decreased dRib-induced rises in intracellular H2O2 and apoptosis to control levels. Forskolin, IBMX, and dbcAMP markedly elevated intracellular cAMP levels and significantly attenuated dRib-induced cytotoxicity and apoptosis, but had no influence on the dRib-induced rise in intracellular H2O2 levels. These results demonstrate that dRib produced oxidative stress and apoptosis in pancreatic β-cells and that elevated intracellular cAMP levels reduced dRib-induced damage, independent of reactive oxygen species metabolism. [Copyright &y& Elsevier]

Aim: Many studies suggest that the persistent organic pollutants (POPs) is a risk factor of type 2 diabetes. The relationship between dietary factors and POPs has been explored recently. POPs are fat-soluble substances that accumulate through the consumption of high fat diets, fish, meat and dairy products. Vegetables and fruits are known to prevent the accumulation of POPs. We aimed to examine the associations between dietary factors and serum cumulative bioactivity of AhR ligand mixture (AhRB) as a biomarker of POPs in subjects at high risk for type 2 diabetes. Methods: We performed a cross-sectional analysis of 304 prediabetic subjects using the Korea National Diabetes Program cohort data. AhRB was divided into quartiles according to the concentrations. (Q1 (the lowest quartile): (Q1 (the lowest quartile): 1.7±0.3, Q2: 2.4±0.2, Q3:3.1±0.2, Q4 (the highest quartile): 3.9±0.2). Socio‐demographic, health related-behaviors, and dietary factors were assessed. Dietary factors were collected from the 3-day dietary records and food frequency questionnaire. Results: Starting with the Q1 of AhRB, adjusted mean concentrations of serum triglycerides were 147.06±12.97, 151.30±12.64, 125.80±13.19 and 166.78±13.76 mg/dL for ascending quartiles, respectively (P< 0.05). In the 3Q of AhRB, the highest consumption of sugars (Q3: 13.6±11.6g, P=0.016) and dairy products (Q3: 117.0±126.6g, P=0.032) were shown compared to those of other three groups. On multiple linear regression analysis, high consumption of dairy products (P< 0.05) and fried fish with oil (P < 0.05) were significantly positive associated with serum AhRB concentration after adjusting covariates. Conclusion: This study found an association between dietary factors and AhRB level, however, further longitudinal studies are needed to clarify the effects of these dietary factors on POP levels. Disclosure: S. Chon: None. H. Lim: None. J. Kim: None. S. Oh: None. [ABSTRACT FROM AUTHOR]

Abstract: We analyzed the medical records of 884 type 2 DM patients who were taking different antiplatelet agents for more than 2 years. Based on the records, occurrences of cardiovascular events for 10 years were evaluated. The composite disease-free survival rate for cilostazol monotherapy group was similar to aspirin subgroup (p =0.133). [ABSTRACT FROM AUTHOR]

Abstract: Introduction: In recent studies, apolipoprotein E (apo E) genetic polymorphism in association with dyslipidemia have been proposed as the one of the risk factors for the development of diabetic nephropathy. We found that type 2 diabetic patients with microalbuminuria (MA) had higher plasma triglyceride levels than those with normoalbuminuria (NA) in our previous study. Therefore, we aimed for investigating the association among apo E genetic polymorphism, dyslipidemia and the development of diabetic nephropathy in type 2 diabetic patients. Method: We included 58 subjects with normoalbuminuria and 36 subjects with microalbuminuria in analysis. They were all Korean and type 2 diabetic patients who had normal renal function, history of diabetes longer than 10 years and the data of urine albumin excretion rate at 10th year diabetes duration. Mean HbA1c, plasma total cholesterol and triglyceride levels for 10 years and several clinical characteristics were examined. Apo E genotypes were confirmed by real time PCR. Results: The frequency of e3/e4 genotype (20.7% versus 5.6%, p =0.045) and E4 carrier (22.8% versus 5.9%, p =0.035) was significantly higher in NA group than in MA group. On logistic regression analysis, crude odds ratio of E2 carrier and E4 carrier were 0.833 (95% CI: 0.245–2.833) and 0.205 (95% CI: 0.043–0.986), respectively. However, after adjusted by HbA1c, hypertension, total cholesterol and triglyceride, odds ratio of E2 carrier and E4 carrier were 0.664 (95% CI: 0.134–3.289) and 0.365 (95% CI: 0.061–2.187) and the association became weak. There were no correlation between apo E carrier and lipid profile. HbA1c (7.6±1.3% versus 7.0±0.9%, p =0.012) and mean creatinine (1.2±0.7mg/dL versus 1.0±0.2mg/dL, p =0.004) levels were significantly higher in MA group than in NA group as expected. Conclusions: These data suggest that E4 carrier might be associated with the protection for the development of diabetic nephropathy in type 2 diabetic patients without respect to dyslipidemia. [Copyright &y& Elsevier]

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are pre-diabetes states that can progress to type 2 diabetes mellitus. However, it has been shown that only 29 - 76% of pre-diabetic subjects diagnosed satisfy the definition of IFG and IGT simultaneously, and it appears that a significant difference between them is also present. We performed an oral glucose tolerance test (OGTT) on 528 subjects who had no history of the medication that affect on glucose tolerance, and the patients were classified into four groups: the normal glucose tolerance, the isolated IFG, the isolated IGT, and the combined glucose intolerance (CGI) group satisfying IFG and IGT conditions simultaneously. The characteristics of each group were compared. In addition, for all subjects, the insulin resistance indices HOMA-IR, WBISI, and the insulin secretion indices insulinogenic index (IGI), and AUC insulin[sub 0-120]/AUC glucose[sub 0-120] (AUC I/G 120) were determined. The OGTT measurements showed that 87 subjects were diagnosed as having isolated IFG, 75 subjects as having isolated IGT, and 145 subjects as having CGI, and 43.2% of the pre-diabetes subjects were placed in the CGI group. Comparing the isolated IFG and the isolated IGT group, the isolated IFG group was relatively young (49.9±11.3 years vs. 51.4±14.4 years, p=0.038), the percentage of male was higher (56.3% vs. 40%, p=0.028), and the isolated IFG group subjects showed a trend to be leaner. In addition, the HOMA-IR of the isolated IFG group was significantly higher (2.30±0.12 vs. 1.89±0.13, p=0.028), the WBISI between two groups was not different (10.8±0.67 vs. 12.4±0.78, p=0.123), and these findings suggest that the difference in insulin resistance between two groups was mainly caused by hepatic resistance. For the insulin secretory indices, the IGI (140.3±10.6 vs. 91.0±11.5, p=0.002) and the AUC I/G 120 (65.2±3.4 vs. 54.0±4.0, p=0.037) were significantly higher for the isolated IFG group. This significance of the insulin secretory capacity between each group did not change after an adjustment for insulin resistance (IGI/WBISI) or the disposition index (IGI X WBISI). In conclusion, following the use of the OGTT, it was found that significant metabolic differences in insulin sensitivity and insulin the secretory capacity between the isolated IFG group and the isolated IGT group exist. [ABSTRACT FROM AUTHOR]