Abstract
Background
SGLT2 inhibitors increase plasma ketone concentrations. It has been suggested that insulinopenia, along with an increase in the counter-regulatory hormones epinephrine, corticosterone, glucagon and growth hormone, can induce ketoacidosis, especially in type-1 diabetes (T1DM). Dehydration precipitates SGLT2 inhibitor–induced ketoacidosis in type-2 diabetes. We studied the effects of dapagliflozin and water deprivation on the development of ketoacidosis and the associated signaling pathways in T1DM mice.
Methods
C57BL/6 mice were fed a high-fat diet. After 7 days, some mice received intraperitoneal injection of streptozocin + alloxan (STZ/ALX). The treatment groups were control + water at lib; control + dapagloflozin + water at lib; control + dapagloflozin + water deprivation; STZ/ALX + water at lib; STZ/ALX + water deprivation; STZ/ALX + dapagloflozin + water at lib; STZ/ALX + dapagloflozin + water deprivation. Dapagliflozin was given for 7 days. In the morning of day 18, food was removed, and water was removed in the water deprivation groups. ELISA, rt-PCR, and immunoblotting were used to assess blood, heart, liver, white and brown adipose tissues.
Results
The T1DM mice had ketoacidosis even without water deprivation. Water deprivation increased plasma levels of β-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1β, IL-6, IL-8, and TNFα were also increased in the T1DM mice with water deprivation. Dapagliflozin attenuated the changes in the T1DM mice without and with water deprivation. Likewise, water deprivation increased the activation of the inflammasome in the heart, liver, and white fat of the T1DM mice and dapagliflozin attenuated these changes. Dapagliflozin reduced the mRNA levels of glucagon receptors in the liver and the increase in GPR109a in white and brown fat. In the liver, dapagliflozin increased AMPK phosphorylation, and attenuated the phosphorylation of TBK1 and the activation of NFκB.
Conclusions
Dapagliflozin reduced ketone body levels and attenuated the activation of NFκB and the activation of the inflammasome in T1DM mice with ketoacidosis.
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Data Availability
Original research data will be available upon request.
References
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57. https://doi.org/10.1056/NEJMoa1812389.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. https://doi.org/10.1056/NEJMoa1504720.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57. https://doi.org/10.1056/NEJMoa1611925.
Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117–28. https://doi.org/10.1056/NEJMoa2030183.
Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129–39. https://doi.org/10.1056/NEJMoa2030186.
McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303.
Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Belohlavek J, et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA. 2020;323(14):1353–68. https://doi.org/10.1001/jama.2020.1906.
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–24. https://doi.org/10.1056/NEJMoa2022190.
Wheeler DC, Stefansson BV, Jongs N, Chertow GM, Greene T, Hou FF, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22–31. https://doi.org/10.1016/S2213-8587(20)30369-7.
Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46. https://doi.org/10.1056/NEJMoa2024816.
Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S, Cherney DZ, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41(12):2560–9. https://doi.org/10.2337/dc18-1749.
Phillip M, Mathieu C, Lind M, Araki E, di Bartolo P, Bergenstal R, et al. Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies. Diabetes Obes Metab. 2021;23(2):549–60. https://doi.org/10.1111/dom.14248.
Araki E, Watada H, Uchigata Y, Tomonaga O, Fujii H, Ohashi H, et al. Efficacy and safety of dapagliflozin in Japanese patients with inadequately controlled type 1 diabetes (DEPICT-5): 52-week results from a randomized, open-label, phase III clinical trial. Diabetes Obes Metab. 2020;22(4):540–8. https://doi.org/10.1111/dom.13922.
Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, Fulcher GR, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017;377(24):2337–48. https://doi.org/10.1056/NEJMoa1708337.
Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med. 2017;376(23):2300–2. https://doi.org/10.1056/NEJMc1701990.
Peters AL, Henry RR, Thakkar P, Tong C, Alba M. Diabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes. Diabetes Care. 2016;39(4):532–8. https://doi.org/10.2337/dc15-1995.
Musso G, Sircana A, Saba F, Cassader M, Gambino R. Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: a meta-analysis and meta-regression. PLoS Med. 2020;17(12): e1003461. https://doi.org/10.1371/journal.pmed.1003461.
Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38(12):2258–65. https://doi.org/10.2337/dc15-1730.
Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care. 2016;39(11):2036–41. https://doi.org/10.2337/dc15-2688.
Qiu H, Novikov A, Vallon V. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives. Diabetes Metab Res Rev. 2017;33(5). https://doi.org/10.1002/dmrr.2886
Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38(9):1638–42. https://doi.org/10.2337/dc15-1380.
Perry RJ, Rabin-Court A, Song JD, Cardone RL, Wang Y, Kibbey RG, et al. Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats. Nat Commun. 2019;10(1):548. https://doi.org/10.1038/s41467-019-08466-w.
Wende AR, Brahma MK, McGinnis GR, Young ME. Metabolic origins of heart failure. JACC Basic Transl Sci. 2017;2(3):297–310. https://doi.org/10.1016/j.jacbts.2016.11.009.
Bae HR, Kim DH, Park MH, Lee B, Kim MJ, Lee EK, et al. beta-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget. 2016;7(41):66444–54. https://doi.org/10.18632/oncotarget.12119.
Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263–9. https://doi.org/10.1038/nm.3804.
Wani K, AlHarthi H, Alghamdi A, Sabico S, Al-Daghri NM. Role of NLRP3 Inflammasome activation in obesity-mediated metabolic disorders. Int J Environ Res Public Health. 2021;18(2). https://doi.org/10.3390/ijerph18020511
Patel NS, Van Name MA, Cengiz E, Carria LR, Weinzimer SA, Tamborlane WV, et al. Altered patterns of early metabolic decompensation in type 1 diabetes during treatment with a SGLT2 inhibitor: an insulin pump suspension study. Diabetes Technol Ther. 2017;19(11):618–22. https://doi.org/10.1089/dia.2017.0267.
Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4(1):177–97. https://doi.org/10.1002/cphy.c130024.
Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thevenet J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512–7. https://doi.org/10.1038/nm.3828.
Pedersen MG, Ahlstedt I, El Hachmane MF, Gopel SO. Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells. Sci Rep. 2016;6:31214. https://doi.org/10.1038/srep31214.
Solini A, Sebastiani G, Nigi L, Santini E, Rossi C, Dotta F. Dapagliflozin modulates glucagon secretion in an SGLT2-independent manner in murine alpha cells. Diabetes Metab. 2017;43(6):512–20. https://doi.org/10.1016/j.diabet.2017.04.002.
Yu X, Zhang S, Zhang L. Newer perspectives of mechanisms for euglycemic diabetic ketoacidosis. Int J Endocrinol. 2018;2018:7074868. https://doi.org/10.1155/2018/7074868.
Wang MY, Yu X, Lee Y, McCorkle SK, Chen S, Li J, et al. Dapagliflozin suppresses glucagon signaling in rodent models of diabetes. Proc Natl Acad Sci U S A. 2017;114(25):6611–6. https://doi.org/10.1073/pnas.1705845114.
Capozzi ME, Coch RW, Koech J, Astapova II, Wait JB, Encisco SE, et al. The limited role of glucagon for ketogenesis during fasting or in response to SGLT2 inhibition. Diabetes. 2020;69(5):882–92. https://doi.org/10.2337/db19-1216.
Spallone V, Valensi P. SGLT2 inhibitors and the autonomic nervous system in diabetes: a promising challenge to better understand multiple target improvement. Diabetes Metab. 2021;47(4): 101224. https://doi.org/10.1016/j.diabet.2021.101224.
Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35(10):2059–68. https://doi.org/10.1097/HJH.0000000000001434.
Voss TS, Vendelbo MH, Kampmann U, Pedersen SB, Nielsen TS, Johannsen M, et al. Substrate metabolism, hormone and cytokine levels and adipose tissue signalling in individuals with type 1 diabetes after insulin withdrawal and subsequent insulin therapy to model the initiating steps of ketoacidosis. Diabetologia. 2019;62(3):494–503. https://doi.org/10.1007/s00125-018-4785-x.
Svart M, Kampmann U, Voss T, Pedersen SB, Johannsen M, Rittig N, et al. Combined insulin deficiency and endotoxin exposure stimulate lipid mobilization and alter adipose tissue signaling in an experimental model of ketoacidosis in subjects with type 1 diabetes: a randomized controlled crossover trial. Diabetes. 2016;65(5):1380–6. https://doi.org/10.2337/db15-1645.
Quarella M, Walser D, Brandle M, Fournier JY, Bilz S. Rapid onset of diabetic ketoacidosis after SGLT2 inhibition in a patient with unrecognized acromegaly. J Clin Endocrinol Metab. 2017;102(5):1451–3. https://doi.org/10.1210/jc.2017-00082.
Huang Z, Huang L, Wang C, Zhu S, Qi X, Chen Y, et al. Dapagliflozin restores insulin and growth hormone secretion in obese mice. J Endocrinol. 2020;245(1):1–12. https://doi.org/10.1530/JOE-19-0385.
Nishitani S, Fukuhara A, Shin J, Okuno Y, Otsuki M, Shimomura I. Metabolomic and microarray analyses of adipose tissue of dapagliflozin-treated mice, and effects of 3-hydroxybutyrate on induction of adiponectin in adipocytes. Sci Rep. 2018;8(1):8805. https://doi.org/10.1038/s41598-018-27181-y.
Bonnet F, Scheen AJ. Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: the potential contribution to diabetes complications and cardiovascular disease. Diabetes Metab. 2018;44(6):457–64. https://doi.org/10.1016/j.diabet.2018.09.005.
Okamoto A, Yokokawa H, Sanada H, Naito T. Changes in levels of biomarkers associated with adipocyte function and insulin and glucagon kinetics during treatment with dapagliflozin among obese type 2 diabetes mellitus patients. Drugs R D. 2016;16(3):255–61. https://doi.org/10.1007/s40268-016-0137-9.
Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 2005;280(29):26649–52. https://doi.org/10.1074/jbc.C500213200.
Wanders D, Graff EC, Judd RL. Effects of high fat diet on GPR109A and GPR81 gene expression. Biochem Biophys Res Commun. 2012;425(2):278–83. https://doi.org/10.1016/j.bbrc.2012.07.082.
Gambhir D, Ananth S, Veeranan-Karmegam R, Elangovan S, Hester S, Jennings E, et al. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Invest Ophthalmol Vis Sci. 2012;53(4):2208–17. https://doi.org/10.1167/iovs.11-8447.
Bradshaw PC, Seeds WA, Miller AC, Mahajan VR, Curtis WM. COVID-19: proposing a ketone-based metabolic therapy as a treatment to blunt the cytokine storm. Oxid Med Cell Longev. 2020;2020:6401341. https://doi.org/10.1155/2020/6401341.
Fu SP, Li SN, Wang JF, Li Y, Xie SS, Xue WJ, et al. BHBA suppresses LPS-induced inflammation in BV-2 cells by inhibiting NF-kappaB activation. Mediators Inflamm. 2014;2014: 983401. https://doi.org/10.1155/2014/983401.
Xu X, Lin S, Chen Y, Li X, Ma S, Fu Y, et al. The effect of metformin on the expression of GPR109A, NF-kappaB and IL-1beta in peripheral blood leukocytes from patients with type 2 diabetes mellitus. Ann Clin Lab Sci. 2017;47(5):556–62.
Digby JE, Martinez F, Jefferson A, Ruparelia N, Chai J, Wamil M, et al. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler Thromb Vasc Biol. 2012;32(3):669–76. https://doi.org/10.1161/ATVBAHA.111.241836.
Feingold KR, Moser A, Shigenaga JK, Grunfeld C. Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages. J Lipid Res. 2014;55(12):2501–8. https://doi.org/10.1194/jlr.M050955.
Liu F, Fu Y, Wei C, Chen Y, Ma S, Xu W. The expression of GPR109A, NF-kB and IL-1beta in peripheral blood leukocytes from patients with type 2 diabetes. Ann Clin Lab Sci. 2014;44(4):443–8.
Thanos D, Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995;80(4):529–32. https://doi.org/10.1016/0092-8674(95)90506-5.
Tang L, Wu Y, Tian M, Sjostrom CD, Johansson U, Peng XR, et al. Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. Am J Physiol Endocrinol Metab. 2017;313(5):E563–76. https://doi.org/10.1152/ajpendo.00086.2017.
Kang DY, Sp N, Do Park K, Lee HK, Song KD, Yang YM. Silibinin inhibits in vitro ketosis by regulating HMGCS2 and NF-kB: elucidation of signaling molecule relationship under ketotic conditions. Vitro Cell Dev Biol Anim. 2019;55(5):368–75. https://doi.org/10.1007/s11626-019-00351-6.
Savinova OV, Hoffmann A, Ghosh G. The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol Cell. 2009;34(5):591–602. https://doi.org/10.1016/j.molcel.2009.04.033.
Christian F, Smith EL, Carmody RJ. The regulation of NF-kappaB subunits by phosphorylation. Cells. 2016;5(1). https://doi.org/10.3390/cells5010012
Zhao P, Wong KI, Sun X, Reilly SM, Uhm M, Liao Z, et al. TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue. Cell. 2018;172(4):731-43e12. https://doi.org/10.1016/j.cell.2018.01.007.
Birnbaum Y, Bajaj M, Yang HC, Ye Y. Combined SGLT2 and DPP4 inhibition reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic nephropathy in mice with type 2 diabetes. Cardiovasc Drugs Ther. 2018;32(2):135–45. https://doi.org/10.1007/s10557-018-6778-x.
Ye Y, Bajaj M, Yang HC, Perez-Polo JR, Birnbaum Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther. 2017;31(2):119–32. https://doi.org/10.1007/s10557-017-6725-2.
Chen H, Tran D, Yang HC, Nylander S, Birnbaum Y, Ye Y. Dapagliflozin and ticagrelor have additive effects on the attenuation of the activation of the NLRP3 inflammasome and the progression of diabetic cardiomyopathy: an AMPK-mTOR interplay. Cardiovasc Drugs Ther. 2020;34(4):443–61. https://doi.org/10.1007/s10557-020-06978-y.
Park JH, Seo I, Shim HM, Cho H. Melatonin ameliorates SGLT2 inhibitor-induced diabetic ketoacidosis by inhibiting lipolysis and hepatic ketogenesis in type 2 diabetic mice. J Pineal Res. 2020;68(2): e12623. https://doi.org/10.1111/jpi.12623.
Xu Q, Fan Y, Loor JJ, Liang Y, Sun X, Jia H, et al. Adenosine 5’-monophosphate-activated protein kinase ameliorates bovine adipocyte oxidative stress by inducing antioxidant responses and autophagy. J Dairy Sci. 2021. https://doi.org/10.3168/jds.2020-18728.
Karavanaki K, Karanika E, Georga S, Bartzeliotou A, Tsouvalas M, Konstantopoulos I, et al. Cytokine response to diabetic ketoacidosis (DKA) in children with type 1 diabetes (T1DM). Endocr J. 2011;58(12):1045–53. https://doi.org/10.1507/endocrj.ej11-0024.
Close TE, Cepinskas G, Omatsu T, Rose KL, Summers K, Patterson EK, et al. Diabetic ketoacidosis elicits systemic inflammation associated with cerebrovascular endothelial cell dysfunction. Microcirculation. 2013;20(6):534–43. https://doi.org/10.1111/micc.12053.
Hoffman WH, Casanova MF, Cudrici CD, Zakranskaia E, Venugopalan R, Nag S, et al. Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis. Exp Mol Pathol. 2007;83(1):65–72. https://doi.org/10.1016/j.yexmp.2007.01.006.
Niu J, Gilliland MG, Jin Z, Kolattukudy PE, Hoffman WH. MCP-1and IL-1beta expression in the myocardia of two young patients with Type 1 diabetes mellitus and fatal diabetic ketoacidosis. Exp Mol Pathol. 2014;96(1):71–9. https://doi.org/10.1016/j.yexmp.2013.11.001.
Li J, Huang M, Shen X. The association of oxidative stress and pro-inflammatory cytokines in diabetic patients with hyperglycemic crisis. J Diabetes Complications. 2014;28(5):662–6. https://doi.org/10.1016/j.jdiacomp.2014.06.008.
Jain SK, Kannan K, Lim G, McVie R, Bocchini JA Jr. Hyperketonemia increases tumor necrosis factor-alpha secretion in cultured U937 monocytes and Type 1 diabetic patients and is apparently mediated by oxidative stress and cAMP deficiency. Diabetes. 2002;51(7):2287–93. https://doi.org/10.2337/diabetes.51.7.2287.
Prasun P. Role of mitochondria in pathogenesis of type 2 diabetes mellitus. J Diabetes Metab Disord. 2020;19(2):2017–22. https://doi.org/10.1007/s40200-020-00679-x.
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The study was funded by an investigator-initiated grant from AstraZeneca and the John S. Dunn Chair in Cardiology Research and Education.
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All authors contributed to the study conception and design. Material preparation, experiments, and data collection were performed by Huan Chen and Yumei Ye. Data analysis was performed by Yumei Ye and Yochai Birnbaum. Figures were made by Yochai Birnbaum. The first draft of the manuscript was written by Yochai Birnbaum and all authors read and edited the manuscript. All authors read and approved the final manuscript.
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The experimental designs and animal care were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH Publication No. 85–23, revised 1996) and approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch.
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Huan Chen, Regina Ye—none. Yochai Birnbaum and Yumei Ye—research grant from AstraZeneca. Mandeep Bajaj—research grants: Novo Nordisk and AstraZeneca; Advisory Board: AstraZeneca; consulting fees: Genentech. At the time of publication, Hsiu-Chiung Yang was previously an employee of AstraZeneca.
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Chen, H., Birnbaum, Y., Ye, R. et al. SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes. Cardiovasc Drugs Ther 36, 1091–1108 (2022). https://doi.org/10.1007/s10557-021-07243-6
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DOI: https://doi.org/10.1007/s10557-021-07243-6