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| 1 | Sodium glucose co-transporter 2 inhibition reduces succinate levels in diabetic mice显示文摘BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption in the kidney is sodium glucose co-transporter 2(SGLT2). Presently, SGLT2 inhibitors are widely used in diabetic patients to improve blood glucose levels and prevent cardiovascular and renal complications. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may exert its protective effects via alterations of the gut microbiome and tested this in a type 1 diabetic mouse model of diabetic retinopathy.AIM To determine whether the treatment with two independent SGLT2 inhibitors affects gut health in a type 1 diabetic mouse model.METHODS The SGLT2 inhibitors empagliflozin or dapagliflozin(25 mg/kg/d) or vehicle dimethylsulfoxide(DMSO) were administered to C57 BL/6 J, Akita, Kimba and Akimba mice at 10 wk of age for 8 wk via their drinking water. Serum samples were collected and the concentration of succinate and the short chain fatty acid(SCFA) butyric acid was measured using gas chromatography-mass spectrometry. Enzyme-linked immunosorbent assay(ELISA) was performed to determine the concentration of insulin and leptin. Furthermore, the norepinephrine content in kidney tissue was determined using ELISA. Pancreatic tissue was collected and stained with haematoxylin and eosin and analysed using brightfield microscopy.RESULTS Due to the presence of the Akita allele, both Akita and Akimba mice showed a reduction in insulin production compared to C57 BL/6 J and Kimba mice.Furthermore, Akita mice also showed the presence of apoptotic bodies within the pancreatic islets. The acinar cells of Akita and Akimba mice showed swelling which is indicative of acute injury or pancreatitis. After 8 wk of SGLT2 inhibition with dapagliflozin, the intermediate metabolite of gut metabolism known as succinate was significantly reduced in Akimba mice when compared to DMSO treated mice. In addition, empagliflozin resulted in suppression of succinate levels in Akimba mice. The beneficial SCFA known as butyric acid was significantly increased in Akita mice after treatment with dapagliflozin when compared to vehicle treated mice. The norepinephrine content in the kidney was significantly reduced with both dapagliflozin and empagliflozin therapy in Akita mice and was significantly reduced in Akimba mice treated with empagliflozin.In non-diabetic C57 BL/6 J and Kimba mice, serum leptin levels were significantly reduced after dapagliflozin therapy.CONCLUSION The inhibition of SGLT2 reduces the intermediate metabolite succinate, increases SCFA butyric acid levels and reduces norepinephrine content in mouse models of T1 D. Collectively, these improvements may represent an important mechanism underlying the potential benefits of SGLT2 inhibition in T1 D and its complications. | Lakshini Y Herat Natalie C Ward Aaron L Magno Elizabeth P Rakoczy Marcio G Kiuchi Markus P Schlaich Vance B Matthews | 2020 | World Journal of Gastroenterology2020，26，23： | 3 |
| 2 | Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study显示文摘 | Julia Granerod Helen E Ambrose Nicholas WS Davies Jonathan P Clewley Amanda L Walsh Dilys Morgan Richard Cunningham Mark Zuckerman Ken J Mutton Tom Solomon Katherine N Ward Michael PT Lunn Sarosh R Irani Angela Vincent David WG Brown Natasha S Crowcroft | 2010 | The Lancet Infectious Diseases2010，，12： | 2 |
| 3 | Does physical activity affect quality of life, disease symptoms and immune measures in patients with inflammatory bowel disease? A systematic review显示文摘 | Packer N Hoffman-Goetz L Ward G | 2010 | Journal of Sports Medicine and Physical Fitness2010，，： | 2 |
| 4 | Solving quadratic assignment problems by simulated annealing 显示文摘 | Wilhelm M R Ward T L | 1987 | IEEE Transactions1987，19，1： | 1 |
| 5 | Failure of spectra polyethylene fiber-reinforced composites under ballistic impact loading显示文摘 | Lee B L Song J W Ward J E | 1994 | Journal of Composite Materials1994，28，13： | 1 |
| 6 | A novel plasminogen activator from Streptococcus uberis显示文摘 | Rosey E L Lincoln R A Ward P N | 1999 | FEMS Microbiol Lett1999，178，： | 1 |
| 7 | Micro T-mixer as a rapid mixing micromixer 显示文摘 | WONG S H WARD M C L WHARTON C W | 2004 | Sensors and Actuators B-Chemical2004，100，3： | 1 |
| 8 | Rapid and sensitive colorimetric method for visualizing biotin-labeled DNA probes hybridized to DNA or RNA immobilized on nitrocellulose:bio-blots显示文摘 | Leary J L Brigati D J Ward D C | 1983 | Proc Natl Acad Sci USA1983，80，： | 1 |
| 9 | Systemic circulation of poly(L-lysine)/DNA vectors is influenced by polycation molecular weight and type of DNA:differential circulation in mice and rats and the implication for human gene therapy显示文摘 | Ward C M Read M L Seymour L W | 2001 | Blood2001，97，： | 1 |
| 10 | Brazos River bar: a study in the significance of grain size parameters显示文摘 | FOLK R L WARD W C | 1957 | Journal of Sedimentary Petrology1957，27，： | 1 |
| 11 | Pneumonia: high-resolu tion CT findings in 114 patients显示文摘 | Reittner P Ward S Heyneman L | 2003 | Eur Radiol2003，13，3： | 1 |
| 12 | Progression of chronic renal failure on substituting a ketoacid supplement for anamino acid supplement显示文摘 | Walser M Hill S Ward L | | 0，，： | 1 |
| 13 | Maternal and fetal outcome after long-term pamidronate treatment before conception:a report of two cases显示文摘 | Munns CF Rauch F Ward L | | 0，，： | 1 |
| 14 | Automated criterion-based analysis for Cole parameters assessment from cerebral neonatal electrical bioimpedance spectroscopy measurements显示文摘 | Seoane F Ward L C Lindecrantz K | | 0，，8： | 1 |
| 15 | Time-Resolved Electronic Phase Transitions in Manganites 显示文摘 | Ward T Z Zhang X G Yin L F | 2009 | Phys Rev Lett2009，102，： | 1 |
| 16 | Brazos River bar : a study in the significance of grain size parameters显示文摘 | FOLK R L WARD W C | 1957 | Journal of Sedimentary Research1957，，： | 1 |
| 17 | Hemorrhage-induced vascular hyporeactivity to norepinephrine in select vasculatures of rats and the roles of nitric oxide and endothelin显示文摘 | Liu L M Ward J A Dubick M A | 2003 | Shock2003，19，3： | 1 |
| 18 | Diferential induction and suppression of potato 3-hydroxy-3-methylglutaryl coenzyme A reductase genes in response to Phytophthora infestans and to its elicitor arachidonic acid显示文摘 | CHOI D WARD B L BOSTOCK R M | 1992 | Plant Cell1992，4，10： | 1 |
| 19 | Gray leaf spot, a disease of global importance in maize production 显示文摘 | Ward J M Stromberg E L Nowell D C | 1999 | Plant Disease1999，83，10： | 1 |
| 20 | The destruxins: Synthesis, biosynthesis, biotransformation, and biologi- cal activity 显示文摘 | Pedras M S Irina Z L Ward D E | 2002 | Phytochemistry2002，59，6： | 1 |
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