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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 | 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 |
| 3 | 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 |
| 4 | 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 |
| 5 | 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 |
| 6 | 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 |
| 7 | 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 |
| 8 | 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 |
| 9 | Micro Tmixer 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 |
| 10 | Exploratory spatial data analysis of regional seroprevalence of antibodies against epizootic hemorrhagic disease virus in cattle from Illinois and Indiana 显示文摘 | BOYER T C WARD M P WALLACE R L | 2008 | American Journal of Veterinary Research2008，69，： | 1 |
| 11 | 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 |
| 12 | Brazos river bar: A study in the signi fication of grain size parameters显示文摘 | Folk R L Ward W C | 1957 | Journal of Sedimentary Petrology1957，27，： | 1 |
| 13 | Grey leaf spot: A disease of global importance in maize production 显示文摘 | Ward J M J Stromberg E L Nowell D C | 1999 | Plant Disease1999，83，10： | 1 |
| 14 | Coordinate gene activity in response to agents that in- duce systemic acquired resistance显示文摘 | WARD E R UKNESS S J WILLIAMS S C DINCHER S S WIEDER- HOLD D L ALEXANDER D C AHL-GOY P METRAUX J P RYALS J A | 1991 | Plant Cell1991，3，10： | 1 |
| 15 | Brazos River Bar:A study in the signification of grain size parameters显示文摘 | FOLK R L Ward W C | 1957 | Journal of Sedimentary Petrology1957，，27： | 1 |
| 16 | Brazos river bar: a study in the signifi- cation of grain size parameters 显示文摘 | Folk R L Ward W C | 1957 | Journal of Sedimentary Pe- trology1957，27，： | 1 |
| 17 | Effect of cancer pain on performance status, mood states, and level of hope among Taiwanese cancer patients显示文摘 | Lin C C Lai Y L Ward S E | 2003 | Journal of Pain and Symptom Management2003，25，1： | 1 |
| 18 | Brazos river bar:A study in the significance of grain size parameters显示文摘 | Folk R L Ward W C | | 0，，： | 1 |
| 19 | Brazos River bar:a study in the significance of grain size parameters显示文摘 | Folk R L Ward W C | | 0，，： | 1 |
| 20 | Identification and molec- ular characterization of GRA8, a novel, proline-rich, dense granule protein of Toxoplasma gondii显示文摘 | Carey K L Donahue C G Ward G E | 2000 | Mol Biochem Para sitol2000，105，： | 1 |
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