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Pancreatic stellate cells (PSCs) play a major role to fibrotic islet destruction observed in diabetic patients and animal model of diabetes. Exendin-4 (Ex-4) is a potent insulinotropic agent and has been approved for the treatment of type 2 diabetes. However, there have been no reports demonstrating the effects of Ex-4 on pancreatic islet fibrosis. In this study, Ex-4 treatment clearly attenuated fibrotic islet destruction and improved glucose tolerance and islet survival. GLP-1 receptor expression was upregulated during activation and proliferation of PSCs by hyperglycemia. The activation of PKA pathway by Ex-4 plays a role in ROS production and angiotensin II (Ang II) production. Exposure to high glucose stimulated ERK activation and Ang II-TGF- β1 production in PSCs. Interestingly, Ex-4 significantly reduced Ang II and TGF-β1 production by inhibition of ROS production but not ERK phosphorylation. Ex-4 may be useful not only as an anti-diabetic agent but also as an anti-fibrotic agent in type 2 diabetes due to its ability to inhibit PSC activation and proliferation and improve islet fibrosis in OLETF rats., Competing Interests: The authors have declared that no competing interests exist.

Recent epidemiologic studies clearly showed that early intensive glucose control has a legacy effect for preventing diabetic macrovascular complications. However, the cellular and molecular processes by which high glucose leads to macrovascular complications are poorly understood. Vascular smooth muscle cell (VSMC) dysfunction due to high glucose is a characteristic of diabetic vascular complications. Activation of nuclear factor-κB (NF-κB) may play a key role in the regulation of inflammation and proliferation of VSMCs. We examined whether VSMC proliferation and plasminogen activator inhibitor-1 (PAI-1) expression induced by high glucose were mediated by NF-κB activation. Also, we determined whether selective inhibition of NF-κB would inhibit proliferation and PAI-1 expression in VSMCs. VSMCs of the aorta of male SD rats were treated with various concentrations of glucose (5.6, 11.1, 16.7, and 22.2 mM) with or without an inhibitor of NF-κB or expression of a recombinant adenovirus vector encoding an IκB-α mutant (Ad-IκBαM). VSMC proliferation was examined using an MTT assay. PAI-1 expression was assayed by real-time PCR and PAI-1 protein in the media was measured by ELISA. NF-κB activation was determined by immunohistochemical staining, NF-κB reporter assay, and immunoblotting. We found that glucose stimulated VSMC proliferation and PAI-1 expression in a dose-dependent manner up to 22.2 mM. High glucose (22.2 mM) alone induced an increase in NF-κB activity. Treatment with inhibitors of NF-κB such as MG132, PDTC or expression of Ad-IκB-αM in VSMCs prevented VSMC proliferation and PAI-1 expression induced by high glucose. In conclusion, inhibition of NF-κB activity prevented high glucose-induced VSMC proliferation and PAI-1 expression.

Pancreatic stellate cells (PSCs) are involved in pancreatic inflammation and fibrosis. Recent studies have shown that blocking the renin-angiotensin system (RAS) attenuates pancreatic inflammation and fibrosis. However, there are few data about the direct effects of high glucose on extracellular matrix (ECM) protein synthesis and angiotensin II (Ang II) induction in PSCs. PSCs were isolated from male Sprague-Dawley rats and cultured in medium containing 5.5 mM (LG group) or 27 mM D-glucose (HG group). Levels of Ang II and transforming growth factor-beta (TGF-beta) in culture media were measured and Ang II-positive cells were counted. We used real-time polymerase chain reaction (PCR) to detect Ang II receptor expression and Western blot analysis for the expression of ECM proteins such as connective-tissue growth factor (CTGF) and collagen type IV. Cells were also treated with an Ang II-receptor antagonist (candesartan, 10 microM) or angiotensin-converting enzyme (ACE) inhibitor (ramiprilat, 100 nM). Thymidine uptake by PSCs increased fourfold with high glucose treatment. Ang II levels and the proportion of Ang II-positive PSCs were significantly increased after 6 h under high-glucose conditions. TGF-beta concentrations also increased significantly with high glucose. After 72 h, the expression of CTGF and collagen type IV proteins in high-glucose cultures increased significantly and this increase was effectively attenuated by the candesartan or the ramiprilat. All together, high glucose induced PSCs proliferation and ECM protein synthesis, and these effects were attenuated by an Ang II-receptor antagonist. The data suggest that pancreatic inflammation and fibrosis aggravated by hyperglycemia, and Ang II play an important role in this pathogenesis., (Copyright 2006 Wiley-Liss, Inc.)

Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add‐on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. Patients and Methods: In this multicentre, randomized, double‐blind, placebo‐controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable‐dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was −0.70% (−7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2‐h postprandial plasma glucose, fasting insulin, uric acid and gamma‐glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. Conclusion: Dapagliflozin add‐on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients. [ABSTRACT FROM AUTHOR]

Aims: This study was designed to investigate the association between pancreatic fat content (PFC) and insulin secretory capacity as well as glucose tolerance in Korean adults. Materials: A total of 39 participants (mean age 49.9 years, 53% males) without a previous history of diabetes, or those previously diagnosed as having diabetes but with less than 10 years of disease duration and no medication history were included. They were stratified according to the results of the oral glucose tolerance test (OGTT): normal glucose tolerance, prediabetes, and diabetes. Methods: All participants underwent the proton magnetic resonance spectroscopy (1H‐MRS) to assess PFC. Insulin sensitivity and β‐cell function were measured by the frequently sampled intravenous glucose tolerance tests (FSIVGTT) and OGTT‐derived indices. Results: As glucose tolerance deteriorated, parameters such as Stumvoll index, oral glucose insulin sensitivity index, homeostatic model assessment (HOMA)‐β, insulinogenic index and oral disposition index from the OGTT, and acute insulin response to glucose (AIR) and disposition index (DI) from the FSIVGTT were decreased. PFC increased with deterioration in glucose tolerance (NGT: 12.0%, prediabetes: 23.7%, and diabetes: 31.9%). Correlation analysis indicated that glucose levels at 60 and 120 min during the OGTT were positively correlated with PFC. Also, there was a significant negative correlation between PFC and DI as well as AIR derived from the FSIVGTT. Conclusions: PFC evaluated by 1H‐MRS in Korean adults was higher in those diagnosed with diabetes than those with normal glucose tolerance status. PFC also showed a significant negative correlation with indices reflecting beta cell function. [ABSTRACT FROM AUTHOR]

Glycated hemoglobin A1c (HbA1c) is widely used for monitoring and diagnosing human diabetes mellitus, but is rarely used in veterinary clinics. The goal of our study was to validate the commercial HbA1c testing system SD A1cCare analyzer (Bionote, Gyeoggi-do, South Korea) for use in dogs. Dogs were recruited with owner's consent. Diabetic status was determined based on clinical signs, fasting hyperglycemia, and glycosuria. Intra-assay precision and linearity were evaluated with EDTA, heparin, or citrate as anticoagulants, and had excellent precision with mean coefficients of variation (CVs) of 2.47%, 2.26%, and 1.92%, respectively. Diluted anticoagulated blood samples showed excellent linear relationships with R 2 of 0.991, 0.996, and 0.994, respectively. Inter-assay precision revealed that the mean CV of the normal control was 2.18% and that of the high control was 2.01% (30 repeats). Observed total error of a normal control was 7.81%, and 6.12% for the high control. HbA1c level measured before and after removal of plasma and replacement by saline showed minimal interference by lipid contents (p = 0.929). The HbA1c concentrations of diabetic dogs were significantly higher than those of non-diabetic dogs (p < 0.001). HbA1c value >6.2% indicated canine diabetes through a classification and regression tree model. In most cases, fructosamine and HbA1c were highly correlated (r = 0.674, p < 0.001). The HbA1c testing system could be a valuable testing system to evaluate canine diabetes mellitus, providing an alternative in-house option for use by veterinary clinicians. [ABSTRACT FROM AUTHOR]

Reduced graphene oxide (RGO) is functionalized with glucose and nickel oxide for the supercapacitor application. The RGO layers intercalated by glucose create microspores inside the composite after thermal treatment at 500 °C, and the addition of nickel oxide reduces impedance of the composite, resulting in synergetic effects on the supercapacitor performance. That is, the specific capacitance of the composite is about five times higher than that of the RGO which has no glucose nor nickel oxide. The ternary composite also exhibits high performance of electric double layer capacitor (EDLC) and maintains the same specific capacitances up to 5,000 cycles, providing excellent cyclic stability. The ternary composite of the high EDLC performance, therefore, could be a good candidate of the supercapacitor electrodes. [ABSTRACT FROM AUTHOR]

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]

The commonly used relationship between HbA1c (A1c) and the mean plasma glucose (MPG) concentration is based on evidence from the DCCT. However, as the MPG is measured infrequently from capillary blood, its accuracy has some limitations. A recent study on the correlation between the A1c and the MPG measured in 12 diabetic volunteers using CGMS (Medtronic MeniMed, USA) found that the MPG estimate for an A1c of 7% was about 140 mg/dL, which is quite different from the result of the DCCT. In this study, we performed a retrospective analysis of the correlation between the A1c and the MPG from blood glucose measured using CGMS of 145 diabetic subjects. Among these patients, 74 subjects who showed no significant changes in their medication within 3 months of CGMS measurement were chosen as the final enrolled subjects, and the A1c levels of the subjects were measured within 1 month of CGMS measurement. We also investigated that the proportion of CGMS measured glucose ≥ 180 mg/dL and the proportion of CGMS measured glucose <60 mg/dL in each subject. For the study results, the study subjects mean age was 53.8±16.9 years, and the mean diabetes duration was 11.9±7.1 years, and most (91.8%) of the subjects had type 2 diabetes mellitus. The subjects mean A1c level was 8.32±1.77% and their mean MPG measured by CGMS was 185.7±54.2 mg/dL. The mean MPG value measured using a glucometer was 194.1±53.9 mg/dL and the correlation between the former and latter values were high (R=0.96). A linear regression analysis results showed that the correlation between MPG and A1c measured using CGMS could be estimated by the formula (Adjusted for R = 0.60) and accordingly a 7% A1c level would estimate a MPG concentration of 161.0 mg/dL. Furthermore, the MPG values showed a significant alteration with a change in the A1c levels. With an increasing Ale level of subjects, a significant rise was seen in the proportion of CGMS measured glucose ≥ 180 mg/dL and with a decreasing Ale level, a significant rise was seen in the proportion of CGMS measured glucose < 60 mg/dL (p<0.05). Therefore the cut off values for the A1c level and MPG concentration, where the proportion of CGMS measured value that maintained between 60∼180 mg/dL over 90%, were estimated using the ROC curve; an estimate of the A1c level at 6.25% and the MPG at 145.5 mg/dL were calculated. [ABSTRACT FROM AUTHOR]