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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 | Laryngeal and oropharyngeal cancer, and alcohol dehydrogenase 3 and glutathione S-transferase M1 polymorphisms显示文摘 | Coutelle C Ward PJ Fleury B Quattrocchi P Chambrin H Iron A | 1997 | Hum Genet1997，99，3： | 3 |
| 3 | The oxidative dehydrogenation of ethane by nitrous oxide over molybdenum oxide supported on silica gel显示文摘 | M B Ward M J Lin J H Lousford | 1977 | J Catal1977，50，： | 2 |
| 4 | Factors affecting recovery and quality of oocytes for bovine embryo production in vitro using ovum pick-up technology显示文摘 | Ward F A Lonergan P Enright B P | 2000 | Theriogenology2000，54，： | 2 |
| 5 | Mammalian keratin gene families: organization for genes coding for the B2 high-sulphur proteins sheep wool 显示文摘 | Powell B C Sleigh M J Ward K A | 1983 | Nucleic Acids Res1983，11，： | 1 |
| 6 | 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 |
| 7 | Modulation of chaperone function and cochaperone interaction by novobiocin in the C- terminal domain of Hsp90 evidence that coumarin antibiotics disrupt Hsp90 dimerization显示文摘 | Allan R K Mok D Ward B K | 2006 | The Journal of Biology Chemistry2006，281，11： | 1 |
| 8 | Neurologic disease in wapiti naturally infected with meningeal worm显示文摘 | Carpenter J W Jordan H E Ward B C | 1973 | J Wildl Dis1973，9，： | 1 |
| 9 | Clinical progression and out- come of dysphagia following paediatric traumatic brain injury: a prospective study 显示文摘 | Morgan A Ward E Murdoch B | 2004 | Brain Inj2004，18，4： | 1 |
| 10 | Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions ( risk factors, screening, and treatment )to reduce future rates显示文摘 | EDWARDS B K WARD E KOHLER B A | 2010 | Cancer2010，116，3： | 1 |
| 11 | Impaired wound healing显示文摘 | Menke N B Ward K R WittenTM | 2007 | Clin Dermatol2007，25，1： | 1 |
| 12 | Comparison of memory f MRI response among normal,MCI,and Alzheimer's patients显示文摘 | Maehulda MM Ward HA Borowski B | 2003 | Neurology2003，61，4： | 1 |
| 13 | Nitrite reductase genes in halobenzoate degrading denitrifying bacteria 显示文摘 | Song B Ward B B | 2003 | FEMS Microbiology Ecology2003，43，3： | 1 |
| 14 | Primary structure of Aequorea Victoria green fluorescent protein显示文摘 | Prasher D C Eckenrode B K Ward W W | 1992 | Gene1992，111，2： | 1 |
| 15 | Ten-year follow-up of breast carcinoma in situ in connecticut显示文摘 | Ward B A Mckhann C F Ravikumar T S | 1992 | Arch Surg1992，127，： | 1 |
| 16 | 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 |
| 17 | Tests for adaptive RAPD variation in population genetic structure of wildbarley,Hordeum spontaneum Koch显示文摘 | Volis S Yakubov B Shulgina I Ward D Zur V Mendlinger S | 2001 | Biological Journal of the Linnean Society2001，，74： | 1 |
| 18 | Seeing is believing: the importance of video laryngoscopy in teaching and in managing the difficult airway显示文摘 | Kaplan M B Ward D Hagberg C A Berci G Hagiike M | 2006 | Surg Endosc2006，202，： | 1 |
| 19 | Mechanisms of Self-other Representations and Vicarious Experiences of Touchin Mirror-touch Synesthesia显示文摘 | Banissy M J Ward J Fitzgibbon B M | 2013 | Frontiers in Human Neuroscience2013，7，： | 1 |
| 20 | Aerodynamic interactions during laser cutting 显示文摘 | FIERET J TERRY M J WARD B A | 1986 | Proc SPIE1986，668，： | 1 |
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