Rapid Determination of Dapagliflozin in Rat Plasma by UHPLC-Q-Orbitrap MS and Its Application to a Pharmacokinetic Study.

Dapagliflozin (DAPA), sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is used to treat Type 2 diabetes. In this study, a highly sensitive and selective analytical method based on ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was established and validated for the determination of DAPA in rat plasma. The separation of DAPA and internal standard (DAPA-d5) were performed on a reversed-phase ACQUITY UPLC® BEH C18 column (100 × 3.0 mm, 1.7 µm). The mobile phase is composed of 0.1% formic acid in water (solvent A) and methanol (solvent B) in gradient elution. Under the negative ion mode, full MS/dd-MS2 was adopted to collect data via Q-Orbitrap. DAPA was effectively separated from matrix backgrounds within 10 min, and DAPA in plasma showed a good linear relationship in the range of 10-10000 µg/L. The determination coefficient (R2) was 0.9987, and the lower limit of quantification (LLOQ) was 10 µg/L. The precision and accuracy were all less than 10%, and the extraction recovery of DAPA was 86.16-96.06% from plasma. This study offered an efficient separation and quantification method for DAPA. The improved and validated method succeeded in evaluating the pharmacokinetics of DAPA in rat plasma samples after a single oral administration of 1 mg/kg.

γ-Glutamyltranspeptidase and pH based "AND" logic gate fluorescent probe for orthotopic breast tumor imaging.

An "AND" logic gate-based NIR fluorescent probe Si-NH2-Glu was developed based on novel meso-amine Si-Rhodamine, which combined γ-glutamyl transpeptidase and pH dual-responsive sites. The features of Si-NH2-Glu enable it to be applied in orthotopic tumor imaging and fluorescence-guided surgery.

A new phenylpropanoic acid congener from Zanthoxylum nitidum.

One new phenylpropanoic acid congener, 2R-(5'-methoxy) pandanusphenol B (1), along with 26 known isolates, were isolated from Zanthoxylum nitidum. Their structures were elucidated by comprehensive spectroscopic data and circular dichroism analyses. All compounds, except 4, 7-10, 15, 17, 19 and 25, were reported from Z. nitidum for the first time. Among them, 16 compounds (1-3, 5-6, 12-14, 16, 20-24 and 26-27) were discovered from genus Zanthoxylum for the first time, while 15 compounds (1-3, 5-6, 12-14, 20-24 and 26-27) were isolated from the Rutaceae family for the first time. All isolates were evaluated for their cytotoxicity against five human cancer cell lines and the results showed that compound 27 exhibited significant cytotoxicity toward HepG2 and T24, with IC50 values of 2.49 and 7.0 µM, respectively.

Down-regulation of HuR inhibits pathological angiogenesis in oxygen-induced retinopathy.

HuR (also known as ELAV1), a ubiquitous RNA-binding protein, is implicated in the pathogenesis of diverse diseases via the mechanism of post-transcriptional regulation. Whether it is involved in pathological angiogenesis in oxygen-induced retinopathy is not clear. In this study, we detected HuR expression was increased in the retina of mouse model of oxygen-induced retinopathy (OIR) as well as in vascular endothelial cells exposed to hypoxia. With gain-of-function and loss-of-function studies using adenovirus infection, we found HuR over-expression promoted while HuR knockdown inhibited the migration, proliferation and tube formation of vascular endothelial cells. Moreover, HuR regulated the expression of VEGFA in vascular endothelial cells. We also found the retinal pathological angiogenesis in mouse OIR model was greatly reduced with HuR knockdown using recombinant AAV expressing HuR specific shRNA which was administered by intravitreal injection. The results of this study suggest HuR is involved in pathological angiogenesis via regulating angiogenic behaviors of endothelial cells, providing a potential target for the treatment of retinopathy of prematurity.

Effects of Se-enriched Chrysanthemum morifolium on lifespan and antioxidant defense-related gene expression of Drosophila melanogaster model.

Chrysanthemum morifolium is a well-known edible medicinal plant in Asia and some other regions. Content of selenium in Se-enriched C. morifolium (SeCM) is significantly higher than that in traditional C. morifolium (non-Se-enriched C. morifolium, TCM). In order to understand health effects of SeCM, its chemical composition, lifespan-prolonging activities, and impacts on antioxidant defense-related gene expressions of model organism D. melanogaster were systematically studied. A total of eight phenols, including luteolin-7-O-glucoside, linarin, luteolin, apigenin, diosmetin, acacetin, 3-caffeoylquinic acid and 4,5-dicaffeoylquinic acid, were identified in SeCM extract. Compared with TCM, SeCM exhibited superior antioxidant properties. Intake of SeCM dramatically reduced malondialdehyde level and increased activities of endogenous antioxidant enzymes in fruit flies. SeCM was able to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase and hydrogen peroxide catalase, and extend lifespans of fruit flies. Comparatively high antioxidant capacities and lifespan-prolonging activities of SeCM might be attributed to its abundant phenols and selenium, which probably ameliorated accumulation of free radicals and susceptibility to oxidative stress. These findings provide clues on further exploitation and utilization of Se-enriched C. morifolium. PRACTICAL APPLICATIONS: Chrysanthemum morifolium has been used for nutraceutical and curative purposes in China for thousands of years. Se-enriched C. morifolium typically contains more selenium than traditional C. morifolium, and is widely consumed in Asia and some other regions. Selenium is an essential micronutrient for humans, and selenium deficiency may result in several diseases such as myocardial infarction. SeCM is one of important selenium supplements. In this study, SeCM was found to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and hydrogen peroxide catalase, and extend lifespans of experimental animals. These results provide supporting information for developing SeCM-based functional foods with distinct health benefits.

General Carbon-Supporting Strategy to Boost the Oxygen Reduction Activity of Zeolitic-Imidazolate-Framework-Derived Fe/N/Carbon Catalysts in Proton Exchange Membrane Fuel Cells.

The oxygen reduction reaction (ORR) activity of the Fe/N/Carbon catalysts derived from the pyrolysis of zeolitic-imidazolate-framework-8 (ZIF-8) has been still lower than that of commercial Pt-based catalysts utilized in the proton exchange membrane fuel cells (PEMFCs) due to low density of accessible active sites. In this study, an efficient carbon-supporting strategy is developed to enhance the ORR efficiency of the ZIF-derived Fe/N/Carbon catalysts by increasing the accessible active site density. The enhancement lies in (i) improving the accessibility of active sites via converting dodecahedral particles to graphene-like layered materials and (ii) enhancing the density of FeNx active sites via suppressing the formation of nanoparticles as well as providing extra spaces to host active sites. The optimized and efficient Fe/N/Carbon catalyst shows a half-wave potential (E1/2) of 0.834 V versus reversible hydrogen electrode in acidic media and produces a peak power density of 0.66 W cm-2 in an air-fed PEMFC at 2 bar backpressure, outperforming most previously reported Pt-free ORR catalysts. Finally, the general applicability of the carbon-supporting strategy is confirmed using five different commercial carbon blacks. This work provides an effective route to derive Fe/N/Carbon catalysts exhibiting a higher power density in PEMFCs.

Chemical Structure, Hypoglycemic Activity, and Mechanism of Action of Selenium Polysaccharides.

Selenium polysaccharides (Se-polysaccharides) are one of important forms of organic Se, in which selenium (Se) and polysaccharides are joined by covalent bonds. In the present review, recent progress in chemical structure and hypoglycemic activity of Se-polysaccharides is summarized. In particular, the mechanism underlying hypoglycemic capacity of Se-polysaccharides is discussed, and the relationship between hypoglycemic activity and chemical structure is analyzed. Besides, strategies for further research into chemical structure and hypoglycemic activity of Se-polysaccharides are proposed. Hypoglycemic activity of Se-polysaccharides is closely related to their inhibitory effect on α-amylase and α-glucosidase, influence on insulin signal pathway especially IRS-PI3K-Akt signaling pathway, and protection capacity against oxidative stress.

Changes in Conjunctival Microbiota Associated With HIV Infection and Antiretroviral Therapy.

Purpose: HIV infection is associated with a variety of ocular surface diseases. Understanding the difference of the ocular microbiota between HIV-infected and healthy individuals as well as the influence of antiretroviral therapy will help to investigate the pathogenesis of these conditions. Methods: A cross-sectional study was conducted on subjects including HIV-negative individuals, untreated HIV-infected individuals, and HIV-infected individuals with antiretroviral therapy. Conjunctival microbiota was assessed by bacterial 16S rRNA sequencing of the samples obtained from the conjunctival swab. Results: The microbial richness in ocular surface was similar in HIV-negative, untreated HIV-positive, and highly active antiretroviral therapy (HAART) subjects. The bacterial compositions were similar in the two HIV infection groups but were significantly different from the HIV-negative group. HAART changed the beta diversity of bacterial community as determined by Shannon index. CD4+ T cell count had no significant influence on the diversity of ocular microbiota in HIV-infected individuals. Conclusions: The data revealed the compositional and structural difference in conjunctival microbial community in subjects with and without HIV infection, indicating that HIV infection or its treatment, may contribute to ocular surface dysbiosis.

Rapid diagnosis of disseminated Mycobacterium mucogenicum infection in formalin-fixed, paraffin-embedded specimen using next-generation sequencing: A case report.

BACKGROUND: Mycobacterium mucogenicum (M. mucogenicum) belongs to the group of rapidly growing Nontuberculous mycobacteria. This microorganism is associated with a wide spectrum of infectious diseases. Due to a low detection rate or the time required for conventional culture methodology, a rapid and broad-spectrum method is necessary to identify rare pathogens. CASE SUMMARY: A 12-year-old immunocompetent girl presented with painful masses for five months. The first mass was found in the right upper quadrant of the abdomen, and was about 1 cm × 1.5 cm in size, tough but pliable in texture, with an irregular margin and tenderness. An abscess gradually formed and ulcerated with suppuration of the mass. Three new masses appeared on the back one by one. Chest computed tomography showed patchy and streaky cloudy opacities in both lungs. Needle aspiration of the abscess was performed, but the smear and conventional culture were negative, and the pathological examination showed no pathogens. We then performed next-generation sequencing using a formalin-fixed, paraffin-embedded specimen to identify the pathogen. A significantly high abundance of M. mucogenicum was detected. The patient's abscesses gradually decreased in size, while inflammation in both lungs improved following 12-wk of treatment. No recurrence was observed four months after the end of the one-year treatment period. CONCLUSION: Next-generation sequencing is a promising tool for the rapid and accurate diagnosis of rare pathogens, even when using a formalin-fixed, paraffin-embedded specimen.

Gut microbiota as prognosis markers for patients with HBV-related acute-on-chronic liver failure.

The gut microbiota in the hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is poorly defined. We aim to uncover the characteristics of the gut microbiota in HBV-ACLF and in other HBV associated pathologies. We analyzed the gut microbiome in patients with HBV-ACLF or other HBV associated pathologies and healthy individuals by 16S rRNA sequencing and metagenomic sequencing of fecal samples. 212 patients with HBV-ACLF, 252 with chronic hepatitis B (CHB), 162 with HBV-associated cirrhosis (HBV-LC) and 877 healthy individuals were recruited for the study. CHB and HBV-LC patients are grouped as HBV-Other. We discovered striking differences in the microbiome diversity between the HBV-ACLF, HBV-Other and healthy groups using 16S rRNA sequencing. The ratio of cocci to bacilli was significantly elevated in the HBV-ACLF group compared with healthy group. Further analysis within the HBV-ACLF group identified 52 genera showing distinct richness within the group where Enterococcus was enriched in the progression group whilst Faecalibacterium was enriched in the regression group. Metagenomic sequencing validated these findings and further uncovered an enrichment of Lactobacillus casei paracasei in progression group, while Alistipes senegalensis, Faecalibacterium prausnitzii and Parabacteroides merdae dominated the regression group. Importantly, our analysis revealed that there was a rapid increase of Enterococcus faecium during the progression of HBV-ACLF. The gut microbiota displayed distinct composition at different phases of HBV-ACLF. High abundance of Enterococcus is associated with progression while that of Faecalibacterium is associated with regression of HBV-ACLF. Therefore, the microbiota features hold promising potential as prognostic markers for HBV-ACLF.

Changes of cytokine levels and T cell surface molecules in patients with chronic hepatitis B and the association with functional cure.

This study aimed to examine changes in levels of cytokine and T cell surface molecules in chronic hepatitis B (CHB) patients receiving sequential interferon therapy following 1-year nucleos(t)ide analogs (NAs) treatment. Cytokine levels were measured in 30 patients, and T cell surface molecule expression was measured in 48 patients receiving sequential interferon therapy and 24 patients only receiving NA mono-therapy. An HBsAg titer of <0.05 IU/ml was defined as a "functional cure." In the cured group (HBsAg < 0.05 IU/ml), a decreasing probability was observed in IFN-γ (after Week 0), and IL-22 and IP-10 (after Week 12). In the non-cured group (HBsAg ≥ 0.05 IU/ml), a probability of slightly decreasing was observed for IFN-γ (after Week 12), and a probability of increasing IP-10 concentration (after Week 0) was observed. Generalized estimating equation (GEE) analyses showed significant differences in the levels of IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70 between the two groups. In GEE analysis, there were significant differences in expressions of CD45RO+ between the cured group and the non-cured group. The frequencies of T cells expressing Tim-3, CD62L, and CD152 were significantly lower in the sequential interferon therapy group than in the NA mono-therapy group. Changes in cytokine levels (IFN-γ, IP-10, IL-10, IL-23, CCL-3, IL-1ß, IL-2, and IL-12P70) and T cell surface molecules (CD45RO+ ) may predict HBsAg seroconversion in CHB patients receiving sequential interferon therapy. The period from Weeks 12 to 24 during sequential interferon therapy may be a critical time of immune status change.

Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection in ß cells.

BACKGROUND: Long noncoding RNAs (lncRNAs) and mRNAs are widely involved in various physiological and pathological processes. The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is a novel therapeutic strategy that could promote insulin secretion and decrease the rate of ß-cell apoptosis in type 2 diabetes mellitus (T2DM) patients. However, the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated. AIM: To identify the lncRNAs and mRNAs that are involved in the protective effect of GLP-1RA in ß cells, and their roles. METHODS: Rat gene microarray was used to screen differentially expressed (DE) lncRNAs and mRNAs in ß cells treated with geniposide, a GLP-1RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs. Hub mRNAs were filtered using the STRING database and the Cytoscape plugin, CytoHubba. In order to reveal the regulatory relationship between lncRNAs and hub mRNAs, their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs, and competing endogenous RNA (ceRNA) mechanism was explored through miRanda and TargetScan databases. RESULTS: We identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of ≥ 1.5 and P value < 0.05. GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway, inflammatory response, calcium signaling pathway, positive regulation of cell proliferation, and ERK1 and ERK2 cascade. Pomc, Htr2a, and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin, CytoHubba. This result was further verified using SwissTargetPrediction tool. Through the co-expression network and competing endogenous (ceRNA) mechanism, we identified seven lncRNAs (NONRATT027738, NONRATT027888, NONRATT030038, etc.) co-expressed with the three hub mRNAs (Pomc, Htr2a, and Agtr1a) based on the Pearson coefficient of the expression levels. These lncRNAs regulated hub mRNA functions by competing with six miRNAs (rno-miR-5132-3p, rno-miR-344g, rno-miR-3075, etc.) via the ceRNA mechanism. Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs, suggesting that it is at a core position within the ceRNA network. CONCLUSION: We have identified key lncRNAs and mRNAs, and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA in ß cells.

Flavonoids from Epimedium pubescens: extraction and mechanism, antioxidant capacity and effects on CAT and GSH-Px of Drosophila melanogaster.

BACKGROUND: Epimedium is a famous medicinal plant in China, Southeast Asian and some other regions. Flavonoids are regarded as its supremely important active constituents used in phytomedicines and/or functional foods. It is of theoretical and applied significance to optimize the procedure for extraction of flavonoids with high bioactivity from Epimedium, to unveil extraction mechanism, to identify chemical composition of flavonoids, to analyze free radical-scavenging ability of flavonoids, and to investigate their effects on the model organism Drosophila melanogaster. METHODS: Box-Behnken design was applied to optimization of extraction procedure. Laser diffraction particle size analysis was used to clarify extraction mechanism. Chemical composition of flavonoids was analyzed using high-performance liquid chromatography. Antiradical capacities of flavonoids were determined by chemical-based assay. Then, effects of flavonoids on catalase (CAT) and glutathione peroxidase (GSH-Px) in D. melanogaster were investigated for the first time. RESULTS: The optimal condition for ultrasonic extraction of antioxidant flavonoids from Epimedium pubescens was achieved and extraction mechanism was discussed. Epimedium flavonoids contained icariin, epimedin A, epimedin B and epimedin C. Epimedium flavonoids exhibited the ability to scavenge ABTS+ and DPPH⋅ radicals with EC50 values of 55.8 and 52.1 µg/ml, respectively. Moreover, Epimedium flavonoids were able to increase activities of CAT and GSH-Px in D. melanogaster. For females, oral administration of flavonoids improved CAT and GSH-Px activities by 13.58% and 5.18%, respectively. For males, oral administration of flavonoids increased CAT and GSH-Px activities by 13.90% and 5.65%, respectively. CONCLUSION: Flavonoids ultrasonically extracted from E. pubescens considerably affected antioxidant defense system in D. melanogaster. Flavonoids of E. pubescens showed great potential for becoming a natural antioxidant because of their antiradical ability and effects on CAT and GSH-Px of the model organism.

An anterior neurovascular interval approach to coronal shear fractures of the distal humerus: a prospective clinical study with short- to mid-term follow-up.

OBJECT: To explore the treatment effect of the anterior medial neurovascular interval approach to coronal shear fractures of the distal humerus. METHODS: This prospective study included two female patients who were 30-64 years old, with a mean age of 47 years. Fractures were caused by falling from a bicycle. The time between the injury and operation was 1-2 days, with a mean time interval of 1.5 days. Two patients with coronal shear fracture of the distal humerus were treated with open reduction and internal fixation using anterior neurovascular interval approach. RESULTS: There were no intraoperative and postoperative neurological and vascular complications or infections, and the fracture was united. At 12 months after the surgery, the patient returned to work without pain, and with a normal range of motion for elbow and forearm rotation. The X-rays revealed excellent fracture union, no signs of heterotopic ossification, and no traumatic arthritis. According to Mayo's evaluation standards for elbow function, a score of 100 is excellent. CONCLUSIONS: The application of the anterior neurovascular interval approach of the elbow in the treatment of shear fracture of the articular surface of the distal humerus, particularly the trochlea of the humerus, can reduce the stripping of the soft tissue.

An anterior neurovascular interval approach to coronal shear fractures of the distal humerus: a prospective clinical study with short- to mid-term follow-up

SUMMARY OBJECT: To explore the treatment effect of the anterior medial neurovascular interval approach to coronal shear fractures of the distal humerus. METHODS: This prospective study included two female patients who were 30-64 years old, with a mean age of 47 years. Fractures were caused by falling from a bicycle. The time between the injury and operation was 1-2 days, with a mean time interval of 1.5 days. Two patients with coronal shear fracture of the distal humerus were treated with open reduction and internal fixation using anterior neurovascular interval approach. RESULTS: There were no intraoperative and postoperative neurological and vascular complications or infections, and the fracture was united. At 12 months after the surgery, the patient returned to work without pain, and with a normal range of motion for elbow and forearm rotation. The X-rays revealed excellent fracture union, no signs of heterotopic ossification, and no traumatic arthritis. According to Mayo's evaluation standards for elbow function, a score of 100 is excellent. CONCLUSIONS: The application of the anterior neurovascular interval approach of the elbow in the treatment of shear fracture of the articular surface of the distal humerus, particularly the trochlea of the humerus, can reduce the stripping of the soft tissue.

RESUMO OBJETIVO: Explorar o efeito do tratamento com uma abordagem anterior do intervalo neurovascular médio para fraturas de cisalhamento coronal da porção distal do úmero. METODOLOGIA: Este estudo prospectivo incluiu duas pacientes do sexo feminino de 30-64 anos de idade, com idade média de 47 anos. As fraturas foram causadas por quedas de bicicleta. O tempo entre a lesão e a operação foi de 1-2 dias, com um intervalo de tempo médio de 1,5 dias. Duas pacientes com cisalhamento coronal da porção distal do úmero foram tratadas com redução aberta e fixação interna utilizando a abordagem anterior do intervalo neurovascular. RESULTADOS: Não houve complicações neurológicas e vasculares intra e pós-operatórias, nem complicações ou infecções, e a fratura foi unida. Após 12 meses da cirurgia, as pacientes retornaram ao trabalho sem dor e com uma amplitude normal de movimento de rotação do antebraço e cotovelo. Os raios-X revelaram excelente união das fraturas, sem sinais de ossificação heterotópica e sem artrite traumática. De acordo com as diretrizes da clínica Mayo para avaliação da função do cotovelo, uma pontuação de 100 é considerada excelente. CONCLUSÃO: A aplicação da abordagem anterior do intervalo neurovascular do cotovelo no tratamento de uma fratura de cisalhamento da superfície articular da porção distal do úmero, especificamente da tróclea do úmero, pode reduzir o desgaste do tecido mole.

Contents of Heavy Metals in Chinese Edible Herbs: Evidence from a Case Study of Epimedii Folium.

Toxic heavy metal contamination in Chinese edible herbs has raised a worldwide concern. In this study, heavy metals in Epimedii Folium, an edible medicinal plant in China, were quantitatively analyzed. Variations of heavy metals in different species, in various organs (i.e., leaves, stems, and roots), in wild-growing and cultivated plants, and in 35 market samples of Epimedii Folium, were systematically investigated. In all of Epimedium samples, Hg (mercury) was not detectable (0.00 µg/g). Four species, Epimedium pubescens, Epimedium sagittatum, Epimedium brevicornu, and Epimedium wushanense, were found to contain Cu (copper) and Pb (lead). And contents of Cu and Pb in E. brevicornu were significantly higher than those in other species (P < 0.01). In wild-growing and cultivated Epimedium plants, Cd (cadmium) and As (arsenic) were not detectable, and concentrations of Cu and Pb in wild-growing plants were significantly higher than those in cultivated plants (P < 0.01). Cd was not detectable in leaves, roots, and stems, while organ specificity was apparent in the distribution of Cu, As, and Pb. And the highest levels of Cu and Pb were observed in roots and leaves, respectively. In Chinese markets, several samples of Epimedii Folium contained excessive Cu, Cd, As, and Pb beyond the national permissible limits. In summary, there was a large variation of heavy metals among Epimedii Folium samples, and Cu and Pb were the most important heavy metals contaminating the edible medicinal plant. Application of Epimedii Folium to drug and food industries will need to focus more on toxic heavy metal contamination.

The relationship between insulin sensitivity and heart rate-corrected QT interval in patients with type 2 diabetes.

BACKGROUND: Reduced insulin sensitivity not only contributes to the pathogenesis of type 2 diabetes but is also linked to multiple metabolic risk factors and cardiovascular diseases (CVD). A prolonged heart rate-corrected QT interval (QTc interval) is related to ventricular arrhythmias and CVD mortality and exhibits a high prevalence among type 2 diabetes patients. The aim of the study was to investigate the relationship between insulin sensitivity and the QTc interval in patients with type 2 diabetes. METHODS: This cross-sectional observational study recruited 2927 patients with type 2 diabetes who visited the Affiliated Haian Hospital and Second Affiliated Hospital of Nantong University. The insulin sensitivity index (Matsuda index, ISIMatsuda) derived from 75-g OGTT and other metabolic risk factors were examined in all patients. The QTc interval was estimated using a resting 12-lead electrocardiogram, and an interval longer than 440 ms was considered abnormally prolonged. RESULTS: The QTc interval was significantly and negatively correlated with the ISIMatsuda (r = -0.296, p < 0.001), and when the multiple linear regression analysis was adjusted for anthropometric parameters, metabolic risk factors, and current antidiabetic treatments, the QTc interval remained significantly correlated with the ISIMatsuda (ß = -0.23, t = -12.63, p < 0.001). The proportion of patients with prolonged QTc interval significantly increased from 12.1% to 17.9%, 25.6% and 37.9% from the fourth to third, second and first quartile of the ISIMatsuda, respectively. After adjusting for anthropometric parameters by multiple logistic regression analysis, the corresponding odd ratios (ORs) for prolonged QTc interval of the first, second and third quartiles versus the fourth quartile of ISIMatsuda were 3.11 (95% CI 2.23-4.34), 2.09 (1.51-2.88) and 1.53 (1.09-2.14), respectively, and p for trend was <0.001. CONCLUSIONS: Reduced insulin sensitivity is associated with an increase in the QTc interval in patients with type 2 diabetes.

The association of long-term glycaemic variability versus sustained chronic hyperglycaemia with heart rate-corrected QT interval in patients with type 2 diabetes.

OBJECTIVES: Prolonged heart rate-corrected QT(QTc) interval is related to ventricular arrhythmia and cardiovascular mortality, with considerably high prevalence of type 2 diabetes. Additionally, long-term glycaemic variability could be a significant risk factor for diabetic complications in addition to chronic hyperglycaemia. We compared the associations of long-term glycaemic variability versus sustained chronic hyperglycaemia with the QTc interval among type 2 diabetes patients. METHODS: In this cross-sectional study, 2904 type 2 diabetes patients were recruited who had undergone at least four fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPG) measurements (at least once for every 3 months, respectively) during the preceding year. Long-term glycaemic variabilities of FPG and 2-hour PPG were assessed by their standard deviations (SD-FPG and SD-PPG, respectively), and chronic fasting and postprandial hyperglycaemia were assessed by their means (M-FPG and M-PPG, respectively). HbA1c was also determined upon enrolment to assess current overall glycaemic control. QTc interval was estimated from resting 12-lead electrocardiograms, and more than 440 ms was considered abnormally prolonged. RESULTS: Patients with prolonged QTc interval (≥440 ms) had greater M-FPG, M-PPG, SD-PPG and HbA1c than those with normal QTc interval but comparable SD-FPG. QTc interval was correlated with M-FPG, M-PPG, SD-PPG and HbA1c (r = 0.133, 0.153, 0.245 and 0.207, respectively, p = 0.000) but not with SD-FPG (r = 0.024, p = 0.189). After adjusting for metabolic risk factors via multiple linear regression analysis, SD-PPG, M-PPG and HbA1c (t = 12.16, 2.69 and 10.16, respectively, p = 0.000) were the major independent contributors to the increased QTc interval. The proportion of prolonged QTc interval increased significantly from 10.9% to 14.2% to 26.6% for the first (T1) to second (T2) to third (T3) tertiles of SD-PPG. After adjusting via multiple logistic regression analysis, the odd ratios of prolonged QTc interval of the T2 and T3 versus the T1 of SD-PPG were 1.15 (95% CI, 0.82-1.60) and 2.62 (1.92-3.57), respectively. CONCLUSIONS: Increased long-term variability of PPG is a strong independent risk factor for prolonged QTc interval in type 2 diabetes patients, in addition to long-term postprandial hyperglycaemia and current HbA1c.