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Cardiovascular Drugs and Therapy

Erschienen in:

27.08.2021 | Original Article

SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes

verfasst von: Huan Chen, Yochai Birnbaum, Regina Ye, Hsiu-Chiung Yang, Mandeep Bajaj, Yumei Ye

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 6/2022

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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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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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

10.

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.CrossRefPubMed

11.

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.CrossRefPubMed

12.

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.CrossRefPubMed

13.

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.CrossRefPubMed

14.

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.CrossRefPubMed

15.

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.CrossRefPubMed

16.

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.CrossRefPubMed

17.

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.CrossRefPubMedPubMedCentral

18.

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.CrossRefPubMed

19.

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.CrossRefPubMedPubMedCentral

20.

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

21.

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.CrossRefPubMed

22.

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.CrossRefPubMedPubMedCentral

23.

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.CrossRefPubMedPubMedCentral

24.

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.CrossRefPubMedPubMedCentral

25.

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.CrossRefPubMedPubMedCentral

26.

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

27.

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.CrossRefPubMedPubMedCentral

28.

Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4(1):177–97. https://doi.org/10.1002/cphy.c130024.CrossRefPubMedPubMedCentral

29.

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.CrossRefPubMed

30.

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.CrossRefPubMedPubMedCentral

31.

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.CrossRefPubMed

32.

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.CrossRefPubMedPubMedCentral

33.

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.CrossRefPubMedPubMedCentral

34.

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.CrossRefPubMedPubMedCentral

35.

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.CrossRefPubMed

36.

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.CrossRefPubMed

37.

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.CrossRefPubMed

38.

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.CrossRefPubMed

39.

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.CrossRefPubMed

40.

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.CrossRefPubMed

41.

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.CrossRefPubMedPubMedCentral

42.

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.CrossRefPubMed

43.

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.CrossRefPubMedPubMedCentral

44.

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.CrossRefPubMed

45.

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.CrossRefPubMed

46.

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.CrossRefPubMedPubMedCentral

47.

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.CrossRefPubMedPubMedCentral

48.

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.CrossRefPubMedPubMedCentral

49.

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.PubMed

50.

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.CrossRefPubMedPubMedCentral

51.

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.CrossRefPubMedPubMedCentral

52.

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.PubMed

53.

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.CrossRefPubMed

54.

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.CrossRefPubMed

55.

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.CrossRef

56.

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.CrossRefPubMedPubMedCentral

57.

Christian F, Smith EL, Carmody RJ. The regulation of NF-kappaB subunits by phosphorylation. Cells. 2016;5(1). https://doi.org/10.3390/cells5010012

58.

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.CrossRefPubMedPubMedCentral

59.

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.CrossRefPubMed

60.

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.CrossRefPubMed

61.

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.CrossRefPubMed

62.

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.CrossRefPubMed

63.

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.CrossRefPubMed

64.

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.CrossRefPubMed

65.

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.CrossRefPubMed

66.

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.CrossRefPubMedPubMedCentral

67.

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.CrossRefPubMed

68.

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.CrossRefPubMed

69.

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.CrossRefPubMed

70.

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.CrossRefPubMedPubMedCentral

Titel: SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes
verfasst von: Huan Chen
Yochai Birnbaum
Regina Ye
Hsiu-Chiung Yang
Mandeep Bajaj
Yumei Ye
Publikationsdatum: 27.08.2021
Verlag: Springer US
Erschienen in: Cardiovascular Drugs and Therapy / Ausgabe 6/2022
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI: https://doi.org/10.1007/s10557-021-07243-6

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