Neuroprotective Effects of Sodium‑Glucose Cotransporter‑2 (SGLT2) Inhibitors (Gliflozins) on Diabetes‑Induced Neurodegeneration and Neurotoxicity: A Graphical Review
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Umegaki H. Neurodegeneration in diabetes mellitus.
Neurodegener Dis 2012:258‑65.
Lieth E, Gardner TW, Barber AJ, Antonetti DA. Retinal
neurodegeneration: Early pathology in diabetes. Clin Exp
Ophthalmol 2000;28:3‑8.
Moran C, Beare R, Phan TG, Bruce DG, Callisaya ML,
Srikanth V. Type 2 diabetes mellitus and biomarkers of
neurodegeneration. Neurology 2015;85:1123‑30.
Pessina AC. Target organs of individuals with diabetes caught
between arterial stiffness and damage to the microcirculation.
J Hypertension 2007;25:S13‑8.
Mohamed J, Nafizah AN, Zariyantey A, Budin S. Mechanisms of
diabetes‑induced liver damage: The role of oxidative stress and
inflammation. Sultan Qaboos Univ Med J 2016;16:e132‑41.
Levey AS, Astor BC, Stevens LA, Coresh J. Chronic kidney
disease, diabetes, and hypertension: What’s in a name? Kidney
Int 2010;78:19‑22.
Bree AJ, Puente EC, Daphna‑Iken D, Fisher SJ. Diabetes
increases brain damage caused by severe hypoglycemia. Am J
Physiol Endocrinol Metab 2009;297:E194‑201.
Kennedy JM, Zochodne DW. Impaired peripheral nerve
regeneration in diabetes mellitus. J Peripher Nerv Syst
;10:144‑57.
Obrosova IG. Diabetes and the peripheral nerve. Biochim
Biophys Acta 2009;1792:931‑40.
Adler A. Obesity and target organ damage: Diabetes. Int J Obes
;26:S11‑4.
Lynch SK, Abràmoff MD. Diabetic retinopathy is a
neurodegenerative disorder. Vis Res 2017;139:101‑7.
Tesfaye S. Neuropathy in diabetes. Medicine 2010;38:649‑55.
Omidi G, Karimi SA, Rezvani‑Kamran A, Monsef A, Shahidi S,
Komaki A. Effect of coenzyme Q10 supplementation on
diabetes induced memory deficits in rats. Metab Brain Dis
;34:833‑40.
Zhou X, Gan T, Fang G, Wang S, Mao Y, Ying C. Zeaxanthin
improved diabetes‑induced anxiety and depression through
inhibiting inflammation in hippocampus. Metab Brain Dis
;33:705‑11.
Aswar U, Chepurwar S, Shintre S, Aswar M. Telmisartan
attenuates diabetes induced depression in rats. Pharmacol Rep
;69:358‑64.
Muriach M, Flores‑Bellver M, Romero FJ, Barcia JM.
Diabetes and the brain: Oxidative stress, inflammation,
and autophagy. Oxid Med Cell Longev 2014;2014:102158.
doi: 10.1155/2014/102158.
Kahya MC, Nazıroğlu M, Övey İS. Modulation of
diabetes‑induced oxidative stress, apoptosis, and Ca2+entry
through TRPM2 and TRPV1 channels in dorsal root ganglion
and hippocampus of diabetic rats by melatonin and selenium.
Mol Neurobiol 2017;54:2345‑60.
Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol
pathway to diabetes‑induced oxidative stress. J Am Soc Nephrol
;14(Suppl 3):S233‑6.
Jangra A, Datusalia AK, Khandwe S, Sharma SS. Amelioration
of diabetes‑induced neurobehavioral and neurochemical changes
by melatonin and nicotinamide: Implication of oxidative stress–
PARP pathway. Pharmacol Biochem Behav 2013;114:43‑51.
Cinteza M. Gliflozins–a new border stone. Maedica 2019;14:3‑4.
Lee KA, Jin HY, Lee NY, Kim YJ, Park TS. Effect of
empagliflozin, a selective sodium‑glucose cotransporter 2 inhibitor,
on kidney and peripheral nerves in streptozotocin‑induced
diabetic rats. Diabetes Metab J 2018;42:338.
Jakubiak GK. Antidiabetic Drugs from Group of Gliflozins and
their Role in Pharmacotherapy of Diabetes. Medycyna Rodzinna;
;3,146-51.
Millar P, Pathak N, Parthsarathy V, Bjourson AJ, O’Kane M,
Pathak V, et al. Metabolic and neuroprotective effects of
dapagliflozin and liraglutide in diabetic mice. J Endocrinol 2017;234:255‑67.
Lee YH, Kim SH, Kang JM, Heo JH, Kim D‑J, Park SH, et al.
Empagliflozin attenuates diabetic tubulopathy by improving
mitochondrial fragmentation and autophagy. Am J Physiol Renal
Physiol 2019;317:F767‑80.
Keles R, Hazar‑Yavuz AN, Yildiz S, Cam ME, Sener G.
Dapagliflozin attenuates anxiolytic‑like behavior of rats in open
field test. Eur J Pharmacol 2019;29:201‑2.
Khan T, Khan S, Akhtar M, Ali J, Najmi AK. Empagliflozin
nanoparticles attenuates type 2 diabetes induced cognitive
impairment via oxidative stress and inflammatory pathway in
high fructose diet induced hyperglycemic mice. Neurochemistry
Int 2021;150:105158. doi: 10.1016/j.neuint. 2021.105158.
Heimke M, Lenz F, Rickert U, Lucius R, Cossais F.
Anti‑inflammatory properties of the SGLT2 inhibitor
empagliflozin in activated primary microglia. Cells 2022;11:3107.
doi: 10.3390/cells11193107.
Motawi TK, Al‑Kady RH, Abdelraouf SM, Senousy MA.
Empagliflozin alleviates endoplasmic reticulum stress and
augments autophagy in rotenone‑induced Parkinson’s disease
in rats: Targeting the GRP78/PERK/eIF2α/CHOP pathway
and miR‑211‑5p. Chem Biol Interact 2022;362:110002.
doi: 10.1016/j.cbi. 2022.110002.
De A, Chattopadhyay P, Singh M. In‑vitro antioxidant activity
and free radical scavenging potential of phlorizin derived
sodium glucose cotransporter 2 inhibitor. J Drug Deliv Ther
;257‑64.
Ala M, Khoshdel MRF, Dehpour AR. Empagliflozin enhances
autophagy, mitochondrial biogenesis, and antioxidant
defense and ameliorates renal ischemia/reperfusion in
nondiabetic rats. Oxid Med Cell Longev 2022;2022:1197061.
doi: 10.1155/2022/1197061.
Secker PF, Beneke S, Schlichenmaier N, Delp J, Gutbier S,
Leist M, et al. Canagliflozin mediated dual inhibition of
mitochondrial glutamate dehydrogenase and complex I:
An off‑target adverse effect. Cell Death Dis 2018;9:1‑13.
doi: 10.1038/s41419‑018‑0273‑y.
Bendotti G, Montefusco L, Pastore I, Lazzaroni E, Lunati M,
Fiorina P. The anti‑inflammatory and immunological properties
of SGLT‑2 inhibitors. J Endocrinol Invest 2023;46:2445‑52.
Lee N, Heo YJ, Choi S‑E, Jeon JY, Han SJ, Kim DJ, et al.
Anti‑inflammatory effects of empagliflozin and gemigliptin
on LPS‑stimulated macrophage via the IKK/NF‑κB,
MKK7/JNK, and JAK2/STAT1 signalling pathways. J Immunol
Res 2021;2021:9944880. doi: 10.1155/2021/9944880.
Sasaki M, Ozawa Y, Kurihara T, Kubota S, Yuki K, Noda K,
et al. Neurodegenerative influence of oxidative stress in the retina
of a murine model of diabetes. Diabetologia 2010;53:971‑9.
Silva KC, Rosales MA, Biswas SK, Lopes de Faria JB, Lopes
de Faria JM. Diabetic retinal neurodegeneration is associated
with mitochondrial oxidative stress and is improved by an
angiotensin receptor blocker in a model combining hypertension
and diabetes. Diabetes 2009;58:1382‑90.
Pop-Busui R, Sima A, Stevens M. Diabetic neuropathy and
oxidative stress. Diabetes Metab Res Rev 2006;22:257‑73.
Sandireddy R, Yerra VG, Areti A, Komirishetty P, Kumar A.
Neuroinflammation and oxidative stress in diabetic neuropathy:
Futuristic strategies based on these targets. Int J Endocrinol
;2014:674987. doi: 10.1155/2014/674987.
Du Y, Veenstra A, Palczewski K, Kern TS. Photoreceptor
cells are major contributors to diabetes‑induced oxidative
stress and local inflammation in the retina. Proc Natl Acad Sci
;110:16586‑91.
Yang H, Jin X, Lam CWK, Yan S‑K. Oxidative stress and
diabetes mellitus. Clin Chem Lab Med 2011;49:1773‑82.
Gandhi S, Abramov AY. Mechanism of oxidative stress in
neurodegeneration. Oxid Med Cell Longev 2012;2012:428010.
doi: 10.1155/2012/428010.
Cohen G, Riahi Y, Sunda V, Deplano S, Chatgilialoglu C,
Ferreri C, et al. Signaling properties of 4‑hydroxyalkenals
formed by lipid peroxidation in diabetes. Free Radic Biol Med
;65:978‑87.
Kumawat M, Singh N, Singh S. Status of antioxidant enzymes
and lipid peroxidation in type 2 diabetes mellitus with
neuropathy. Ann Neurosci 2010;12:49‑52.
Vincent AM, Russell JW, Low P, Feldman EL. Oxidative
stress in the pathogenesis of diabetic neuropathy. Endocr Rev
;25:612‑28.
Kowluru RA, Chan P‑S. Oxidative stress and diabetic retinopathy.
Exp Diabetes Res 2007;2007:43603. doi: 10.1155/2007/43603.
Calderon G, Juarez O, Hernandez G, Punzo S, De la Cruz Z.
Oxidative stress and diabetic retinopathy: Development and
treatment. Eye 2017;31:1122‑30.
Barber AJ. A new view of diabetic retinopathy:
A neurodegenerative disease of the eye. Prog
Neuropsychopharmacol Biol Psychiatry 2003;27:283‑90.
Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative
stress—A concise review. Saudi Pharm J 2016;24:547‑53.
Hosseini A, Abdollahi M. Diabetic neuropathy and oxidative
stress: Therapeutic perspectives. Oxid Med Cell Longev
;2013:168039. doi: 10.1155/2013/168039.
Kasznicki J, Kosmalski M, Sliwinska A, Mrowicka M,
Stanczyk M, Majsterek I, et al. Evaluation of oxidative stress
markers in pathogenesis of diabetic neuropathy. Mol Biol Rep
;39:8669‑78.
Pan H‑Z, Zhang H, Chang D, Li H, Sui H. The change of
oxidative stress products in diabetes mellitus and diabetic
retinopathy. Br J Ophthalmol 2008;92:548‑51.
Abcouwer SF, Gardner TW. Diabetic retinopathy: Loss of
neuroretinal adaptation to the diabetic metabolic environment.
Ann N Y Acad Sci 2014;1311:174‑90.
Behl T, Kaur I, Kotwani A. Implication of oxidative stress
in progression of diabetic retinopathy. Surv Ophthalmol
;61:187‑96.
West IC. Radicals and oxidative stress in diabetes. Diabet Med
;17:171‑80.
Turk Z. Glycotoxines, carbonyl stress and relevance to diabetes
and its complications. Physiological Res 2010;59:147‑56.
Naudi A, Jove M, Ayala V, Cassanye A, Serrano J, Gonzalo H,
et al. Cellular dysfunction in diabetes as maladaptive
response to mitochondrial oxidative stress. Exp Diabetes Res
;2012:696215. doi: 10.1155/2012/696215.
Mule NK, Singh JN. Diabetes mellitus to neurodegenerative
disorders: Is oxidative stress fueling the flame? CNS Neurol
Disord Drug Targets 2018;17:644‑53.
Rosales‑Corral S, Tan D‑X, Manchester L, Reiter RJ. Diabetes
and alzheimer disease, two overlapping pathologies with the
same background: Oxidative stress. Oxid Med Cell Longev
;2015:985845. doi: 10.1155/2015/985845.
Niedowicz DM, Daleke DL. The role of oxidative stress in
diabetic complications. Cell Biochem Biophys 2005;43:289‑330.
Hassan A, Kandel RS, Mishra R, Gautam J, Alaref A,
Jahan N. Diabetes mellitus and Parkinson’s disease: Shared
pathophysiological links and possible therapeutic implications.
Cureus 2020;12:e9853. doi: 10.7759/cureus. 9853.
Domínguez R, Pagano M, Marschoff E, González S, Repetto M, Serra J. Alzheimer disease and cognitive impairment associated
with diabetes mellitus type 2: Associations and a hypothesis.
Neurología (English Edition) 2014;29:567‑72.
Magyari M, Sorensen PS. Comorbidity in multiple sclerosis.
Front Neurol 2020;11:851.
Chen R, Ovbiagele B, Feng W. Diabetes and stroke:
Epidemiology, pathophysiology, pharmaceuticals and outcomes.
Am J Med Sci 2016;351:380‑6.
Luscher TF, Creager MA, Beckman JA, Cosentino F. Diabetes
and vascular disease: Pathophysiology, clinical consequences,
and medical therapy: Part II. Circulation 2003;108:1655‑61.
Song Y, Ding W, Bei Y, Xiao Y, Tong H‑D, Wang L‑B, et al.
Insulin is a potential antioxidant for diabetes‑associated cognitive
decline via regulating Nrf2 dependent antioxidant enzymes.
Biomed Pharmacother 2018;104:474‑84.
Ceretta LB, Réus GZ, Abelaira HM, Ribeiro KF, Zappellini G,
Felisbino FF, et al. Increased oxidative stress and imbalance in
antioxidant enzymes in the brains of alloxan‑induced diabetic rats.
Exp Diabetes Res 2012;2012:302682. doi: 10.1155/2012/302682.
Kowluru RA, Kennedy A. Therapeutic potential of anti‑oxidants
and diabetic retinopathy. Expert Opin Investig Drugs
;10:1665‑76.
Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial
superoxide dismutase in the retina and the development of
diabetic retinopathy. Diabetes 2011;60:1304‑13.
Younus H. Therapeutic potentials of superoxide dismutase. Int J
Health Sci 2018;12:88.
Yorek MA. The role of oxidative stress in diabetic vascular and
neural disease. Free Radic Res 2003;37:471‑80.
Schmeichel AM, Schmelzer JD, Low PA. Oxidative injury and
apoptosis of dorsal root ganglion neurons in chronic experimental
diabetic neuropathy. Diabetes 2003;52:165‑71.
Iranzo O. Manganese complexes displaying superoxide dismutase
activity: A balance between different factors. Bioorganic Chem
;39:73‑87.
Shanmugam KR, Mallikarjuna K, Kesireddy N, Reddy KS.
Neuroprotective effect of ginger on anti‑oxidant enzymes
in streptozotocin‑induced diabetic rats. Food Chem Toxicol
;49:893‑7.
Alipour M, Salehi I, Soufi FG. Effect of exercise on
diabetes‑induced oxidative stress in the rat hippocampus. Iran
Red Crescent Med J 2012;14:222‑8.
Madsen‑Bouterse SA, Zhong Q, Mohammad G, Ho Y‑S,
Kowluru RA. Oxidative damage of mitochondrial DNA in
diabetes and its protection by manganese superoxide dismutase.
Free Radic Res 2010;44:313‑21.
Sytze van Dam P. Oxidative stress and diabetic neuropathy:
Pathophysiological mechanisms and treatment perspectives.
Diabetes Metab Res Rev 2002;18:176‑84.
Obrosova IG. Update on the pathogenesis of diabetic neuropathy.
Curr Diab Rep 2003;3:439‑45.
Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy:
A series of unfortunate metabolic events. Curr Diab Rep
;15:1‑10.
Shamsul Ola M, S Alhomida A. Neurodegeneration in diabetic
retina and its potential drug targets. Curr Neuropharmacol
;12:380‑6.
Simó R, Hernández C. Neurodegeneration in the diabetic eye:
New insights and therapeutic perspectives. Trends Endocrinol
Metab 2014;25:23‑33.
Clausen A, Doctrow S, Baudry M. Prevention of cognitive deficits
and brain oxidative stress with superoxide dismutase/catalase
mimetics in aged mice. Neurobiol Aging 2010;31:425‑33.
Infante‑Garcia C, Garcia‑Alloza M. Review of the effect of
natural compounds and extracts on neurodegeneration in animal
models of diabetes mellitus. Int J Mol Sci 2019;20:2533.
doi: 10.3390/ijms20102533.
Sofic E, Salkovic‑Petrisic M, Tahirovic I, Sapcanin A, Mandel S,
Youdim M, et al. Brain catalase in the streptozotocin‑rat
model of sporadic Alzheimer’s disease treated with the iron
chelator–monoamine oxidase inhibitor, M30. J Neural Transm
;122:559‑64.
Giordano CR, Roberts R, Krentz KA, Bissig D, Talreja D,
Kumar A, et al. Catalase therapy corrects oxidative
stress‑induced pathophysiology in incipient diabetic retinopathy.
Invest Ophthalmol Vis Sci 2015;56:3095‑102.
Kwong‑Han K, Zunaina E, Hanizasurana H, Che‑Badariah AA,
Che‑Maraina CH. Comparison of catalase, glutathione peroxidase
and malondialdehyde levels in tears among diabetic patients
with and without diabetic retinopathy. J Diabetes Metab Disord
;21:681‑8.
Djordjević GM, Djurić SS, Djordjević VB, Apostolski S,
Zivkovic M. The role of oxidative stress in pathogenesis of
diabetic neuropathy: Erythrocyte superoxide dismutase, catalase
and glutathione peroxidase level in relation to peripheral nerve
conduction in diabetic neuropathy patients. Role of the Adipocyte
in Development of Type. Vol. 2. 2011. p. 153‑72.
Tiwari BK, Pandey KB, Abidi A, Rizvi SI. Markers of
oxidative stress during diabetes mellitus. J Biomark 2013;2013.
doi: 10.1155/2013/378790.
Figueroa‑Romero C, Sadidi M, Feldman EL. Mechanisms of
disease: The oxidative stress theory of diabetic neuropathy. Rev
Endocr Metab Disord 2008;9:301‑14.
Sims‑Robinson C, Kim B, Rosko A, Feldman EL. How does
diabetes accelerate Alzheimer disease pathology? Nat Rev
Neurol 2010;6:551‑9.
Chowdhury SKR, Smith DR, Fernyhough P. The role of aberrant
mitochondrial bioenergetics in diabetic neuropathy. Neurobiol
Dis 2013;51:56‑65.
Srinivasan S, Stevens M, Wiley JW. Diabetic peripheral
neuropathy: Evidence for apoptosis and associated mitochondrial
dysfunction. Diabetes 2000;49:1932‑8.
Piotrowski P, Wierzbicka K, Smialek M. Neuronal death in the
rat hippocampus in experimental diabetes and cerebral ischaemia
treated with antioxidants. Folia Neuropathol 2001;39:147‑54.
Kempuraj D, Thangavel R, Natteru P, Selvakumar G, Saeed D,
Zahoor H, et al. Neuroinflammation induces neurodegeneration.
J Neurol Neurosurg Spine 2016;1:7267. doi: 10.3390/
ijms23137267.
Srodulski S, Sharma S, Bachstetter AB, Brelsfoard JM,
Pascual C, Xie XS, et al. Neuroinflammation and neurologic
deficits in diabetes linked to brain accumulation of amylin. Mol
Neurodegener 2014;9:1‑12. doi: 10.1186/1750‑1326‑9‑30.
Fletcher EL, Phipps JA, Ward MM, Puthussery T,
Wilkinson‑Berka JL. Neuronal and glial cell abnormality as
predictors of progression of diabetic retinopathy. Curr Pharm
Design 2007;13:2699‑712.
Nagayach A, Patro N, Patro I. Experimentally induced diabetes
causes glial activation, glutamate toxicity and cellular damage
leading to changes in motor function. Front Cell Neurosci
;8:355. doi: 10.3389/fncel. 2014.00355.
Zeng H‑Y, Green WR, Tso MO. Microglial activation in human
diabetic retinopathy. Arch Ophthalmol 2008;126:227‑32.
Zhang T‑T, Xue R, Fan S‑Y, Fan Q‑Y, An L, Li J, et al.
Ammoxetine attenuates diabetic neuropathic pain through
inhibiting microglial activation and neuroinflammation in the spinal cord. J Neuroinflammation 2018;15:1‑13. doi: 10.1186/
s12974‑018‑1216‑3.
Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW,
et al. Minocycline reduces proinflammatory cytokine expression,
microglial activation, and caspase‑3 activation in a rodent model
of diabetic retinopathy. Diabetes 2005;54:1559‑65.
Skundric DS, Lisak RP. Role of neuropoietic cytokines in
development and progression of diabetic polyneuropathy: From
glucose metabolism to neurodegeneration. Exp Diabesity Res
;4:303‑12.
Cheung CMG, Vania M, Ang M, Chee SP, Li J. Comparison
of aqueous humor cytokine and chemokine levels in diabetic
patients with and without retinopathy. Mol Vis 2012;18:830‑7.
Chatzigeorgiou A, Harokopos V, Mylona‑Karagianni C,
Tsouvalas E, Aidinis V, Kamper E. The pattern of inflammatory/
anti‑inflammatory cytokines and chemokines in type 1 diabetic
patients over time. Ann Med 2010;42:426‑38.
King GL. The role of inflammatory cytokines in diabetes and its
complications. J Periodontol 2008;79:1527‑34.
Saleh A, Smith DR, Balakrishnan S, Dunn L, Martens C,
Tweed CW, et al. Tumor necrosis factor‑α elevates neurite
outgrowth through an NF‑κB‑dependent pathway in cultured
adult sensory neurons: Diminished expression in diabetes may
contribute to sensory neuropathy. Brain Res 2011;1423:87‑95.
Purwata TE. High TNF‑alpha plasma levels and macrophages
iNOS and TNF‑alpha expression as risk factors for painful
diabetic neuropathy. J Pain Res 2011;4:169‑75.
Mendiola AS, Cardona AE. The IL‑1β phenomena in
neuroinflammatory diseases. J Neural Transm 2018;125:781‑95.
Andriambeloson E, Baillet C, Vitte PA, Garotta G, Dreano M,
Callizot N. Interleukin-6 attenuates the development of
experimental diabetes-related neuropathy. Neuropathology
;26:32‑42.
Herder C, Carstensen M, Ouwens D. Anti-inflammatory
cytokines and risk of type 2 diabetes. Diabetes Obes Metab
;15:39‑50.
Zhang W, Liu H, Rojas M, Caldwell RW, Caldwell RB.
Anti‑inflammatory therapy for diabetic retinopathy.
Immunotherapy 2011;3:609‑28.
Carbonetto P, Stephens M. Integrated enrichment analysis of
variants and pathways in genome‑wide association studies
indicates central role for IL‑2 signaling genes in type 1 diabetes,
and cytokine signaling genes in Crohn’s disease. PLoS Genet
;9:e1003770. doi: 10.1371/journal.pgen.1003770.
Creusot RJ, Chang P, Healey DG, Tcherepanova IY,
Nicolette CA, Fathman CG. A short pulse of IL‑4 delivered
by DCs electroporated with modified mRNA can both prevent
and treat autoimmune diabetes in NOD mice. Mol Ther
;18:2112‑20.
Akbari M, Hassan‑Zadeh V. IL‑6 signalling pathways and
the development of type 2 diabetes. Inflammopharmacology
;26:685‑98.
Rodrigues KF, Pietrani NT, Bosco AA, Campos FMF,
Sandrim VC, Gomes KB. IL‑6, TNF‑α, and IL‑10 levels/
polymorphisms and their association with type 2 diabetes
mellitus and obesity in Brazilian individuals. Arch Endocrinol
Metab 2017;61:438‑46.
Hanifi‐Moghaddam P, Kappler S, Seissler J, MüllerScholze S, Martin S, Roep B, et al. Altered chemokine levels
in individuals at risk of type 1 diabetes mellitus. Diabetic Med
;23:156‑63.
Herder C, Haastert B, Müller‑Scholze S, Koenig W, Thorand B,
Holle R, et al. Association of systemic chemokine concentrations
with impaired glucose tolerance and type 2 diabetes: Results
from the cooperative health research in the Region of Augsburg
Survey S4 (KORA S4). Diabetes 2005;54(Suppl 2):S11‑7.
Lontchi‑Yimagou E, Sobngwi E, Matsha TE, Kengne AP.
Diabetes mellitus and inflammation. Curr Diabs Rep
;13:435‑44.
Laaksonen D, Niskanen L, Nyyssönen K, Punnonen K,
Tuomainen T‑P, Valkonen V‑P, et al. C‑reactive protein and
the development of the metabolic syndrome and diabetes in
middle‑aged men. Diabetologia 2004;47:1403‑10.
Chase HP, Cooper S, Osberg I, Stene LC, Barriga K, Norris J,
et al. Elevated C‑reactive protein levels in the development of
type 1 diabetes. Diabetes 2004;53:2569‑73.
Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative
pathways in obesity, diabetes, and Alzheimer’s disease. Biochim
Biophys Acta Mol Basis Dis 2017;1863:1037‑45.
De Felice FG, Ferreira ST. Inflammation, defective insulin
signaling, and mitochondrial dysfunction as common molecular
denominators connecting type 2 diabetes to Alzheimer disease.
Diabetes 2014;63:2262‑72.
Rübsam A, Parikh S, Fort PE. Role of inflammation in
diabetic retinopathy. Int J Mol Sci 2018;19:942. doi: 10.3390/
ijms19040942.
Yu Y, Chen H, Su SB. Neuroinflammatory responses in diabetic
retinopathy. J Neuroinflammation 2015;12:1‑15. doi: 10.1186/
s12974‑015‑0368‑7.
Debnath M, Agrawal S. Diabetic neuropathy: Oxidative stress
and neuroinflammation. Med Res 2016;3:237‑41.
Madonna R, Giovannelli G, Confalone P, Renna FV, Geng
Y‑J, De Caterina R. High glucose‑induced hyperosmolarity
contributes to COX‑2 expression and angiogenesis: Implications
for diabetic retinopathy. Cardiovasc Diabetol 2016;18:15.
doi: 10.1186/s12933‑016‑0342‑4.
Wong WT, Tian XY, Huang Y. Endothelial dysfunction in
diabetes and hypertension: Cross talk in RAS, BMP4, and
ROS‑dependent COX‑2–derived prostanoids. J Cardiovasc
Pharmacol 2013;61:204‑14.
Mastrocola R, Restivo F, Vercellinatto I, Danni O,
Brignardello E, Aragno M, et al. Oxidative and nitrosative
stress in brain mitochondria of diabetic rats. J Endocrinol
;187:37‑44.
Costagliola C, Romano V, De Tollis M, Aceto F, Romano MR,
Pedicino C, et al. TNF‑alpha levels in tears: A novel biomarker
to assess the degree of diabetic retinopathy. Mediators Inflamm
;2013:629529. doi: 10.1155/2013/629529.
Serasanambati M, Chilakapati SR. Function of nuclear factor
kappa B (NF‑kB) in human diseases‑A review. South Indian J
Biol Sci. 2016;2:368‑87.
Ghanaatfar F, Ghanaatfar A, Isapour P, Farokhi N,
Bozorgniahosseini S, Javadi M, et al. Is lithium neuroprotective?
An updated mechanistic illustrated review. Fundamental &
clinical pharmacology. 2023;37:4-30.
Patel S, Santani D. Role of NF‑κB in the pathogenesis of
diabetes and its associated complications. Pharmacol Rep
;61:595‑603.
Li J, Tang Y, Cai D. IKKβ/NF‑κB disrupts adult hypothalamic
neural stem cells to mediate a neurodegenerative mechanism
of dietary obesity and pre‑diabetes. Nat Cell Biol
;14:999‑1012.
Granic I, Dolga AM, Nijholt IM, van Dijk G, Eisel UL.
Inflammation and NF‑κB in Alzheimer’s disease and diabetes.
J Alzheimer’s Dis 2009;16:809‑21.
Yun JH, Lee DH, Jeong HS, Kim HS, Ye SK, Cho CH. STAT3 activation in microglia exacerbates hippocampal neuronal
apoptosis in diabetic brains. J Cell Physiol 2021;236:7058‑70.
Chowdhury SR, Saleh A, Akude E, Smith DR, Morrow D,
Tessler L, et al. Ciliary neurotrophic factor reverses aberrant
mitochondrial bioenergetics through the JAK/STAT pathway in
cultured sensory neurons derived from streptozotocin‑induced
diabetic rodents. Cell Mol Neurobiol 2014;34:643‑9.
Cho C‑H, Roh K‑H, Lim N‑Y, Park SJ, Park S, Kim HW. Role
of the JAK/STAT pathway in a streptozotocin‑induced diabetic
retinopathy mouse model. Graefes Arch Clin Exp Ophthalmol
;260:3553‑63.
Abdul Y, Abdelsaid M, Li W, Webb RC, Sullivan JC, Dong G,
et al. Inhibition of toll‑like receptor‑4 (TLR‑4) improves
neurobehavioral outcomes after acute ischemic stroke in
diabetic rats: Possible role of vascular endothelial TLR‑4. Mol
Neurobiol 2019;56:1607‑17.
Dasu MR, Ramirez S, Isseroff RR. Toll‑like receptors and
diabetes: A therapeutic perspective. Clin Sci 2012;122:203‑14.
Wong FS, Wen L. Toll-like receptors and diabetes. Ann N Y
Acad Sci 2008;1150:123‑32.
Vincent AM, Brownlee M, Russell JW. Oxidative stress and
programmed cell death in diabetic neuropathy. Ann N Y Acad
Sci 2002;959:368‑83.
Muranyi M, Fujioka M, He Q, Han A, Yong G, Csiszar K,
et al. Diabetes activates cell death pathway after transient focal
cerebral ischemia. Diabetes 2003;52:481‑6.
Martin PM, Roon P, Van Ells TK, Ganapathy V, Smith SB.
Death of retinal neurons in streptozotocin‑induced diabetic
mice. Invest Ophthalmol Vis Sci 2004;45:3330‑6.
Li Z‑G, Zhang W, Grunberger G, Sima AA. Hippocampal
neuronal apoptosis in type 1 diabetes. Brain Res
;946:221‑31.
Barber AJ, Gardner TW, Abcouwer SF. The significance of
vascular and neural apoptosis to the pathology of diabetic
retinopathy. Invest Ophthalmol Vis Sci 2011;52:1156‑63.
Sadeghi A, Hami J, Razavi S, Esfandiary E, Hejazi Z. The
effect of diabetes mellitus on apoptosis in hippocampus:
Cellular and molecular aspects. Int J Prev Med 2016;7:57. doi:
4103/2008‑7802.178531.
Kong F‑J, Ma L‑L, Guo J‑J, Xu L‑H, Li Y, Qu S. Endoplasmic
reticulum stress/autophagy pathway is involved in
diabetes‑induced neuronal apoptosis and cognitive decline in
mice. Clin Sci 2018;132:111‑25.
Liu Y‑P, Shao S‑J, Guo H‑D. Schwann cells apoptosis is
induced by high glucose in diabetic peripheral neuropathy. Life
Sci 2020;248:117459. doi: 10.1016/j.lfs. 2020.117459.
Hengartner MO. The biochemistry of apoptosis. Nature
;407:770‑6.
Cheng H, Gang X, Liu Y, Wang G, Zhao X, Wang G.
Mitochondrial dysfunction plays a key role in the development
of neurodegenerative diseases in diabetes. Am J Physiol
Endocrinol Metab 2020;318:E750‑E64.
Nazarnezhad S, Rahmati M, Shayannia A, Abbasi Z, Salehi M,
Khaksari M. Nesfatin‑1 protects PC12 cells against high
glucose‑induced cytotoxicity via inhibiting oxidative stress,
autophagy and apoptosis. Neurotoxicology 2019;74:196‑202.
Bhattacharya D, Mukhopadhyay M, Bhattacharyya M,
Karmakar P. Is autophagy associated with diabetes mellitus and
its complications? A review. EXCLI J 2018;17:709‑20.
Wang X, Zhang B, Xia R, Jia Q. Inflammation, apoptosis and
autophagy as critical players in vascular dementia. Eur Rev
Med Pharmacol Sci 2020;24:9601‑14.
Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D,
et al. Role for neuronal insulin resistance in neurodegenerative
diseases. Proc Natl Acad Sci 2004;101:3100‑5.
Liu J, Liu L, Han YS, Yi J, Guo C, Zhao HQ, et al. The
molecular mechanism underlying mitophagy‐mediated
hippocampal neuron apoptosis in diabetes‐related depression.
J Cell Mol Med 2021;25:7342‑53.
Zhang X, Xu L, He D, Ling S. Endoplasmic reticulum
stress‑mediated hippocampal neuron apoptosis involved
in diabetic cognitive impairment. Biomed Res Int
;2013:924327. doi: 10.1155/2013/924327.
Lavrik IN. Systems biology of apoptosis signaling networks.
Curr Opin Biotechnol 2010;21:551‑5.
Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X. Pyroptosis:
Mechanisms and diseases. Signal Transduct Target Ther
;6:1‑21. doi: 10.1038/s41392‑021‑00507‑5.
Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: Host cell
death and inflammation. Nat Rev Microbiol 2009;7:99‑109.
Zhang X, Wang N, Barile GR, Bao S, Gillies M. Diabetic
retinopathy: Neuron protection as a therapeutic target. Int J
Biochem Cell Biol 2013;45:1525‑9.
Chen X, Famurewa AC, Tang J, Olatunde OO, Olatunji OJ.
Hyperoside attenuates neuroinflammation, cognitive
impairment and oxidative stress via suppressing TNF‑α/NF‑κB/
caspase‑3 signaling in type 2 diabetes rats. Nutr Neurosci
;25:1774‑84.
Park S‑H, Park J‑W, Park S‑J, Kim K‑Y, Chung J‑W,
Chun M‑H, et al. Apoptotic death of photoreceptors in the
streptozotocin‑induced diabetic rat retina. Diabetologia
;46:1260‑8.
Shamsaei N, Abdi H, Shamsi M. The Effect of a continuous
training on necrosis and apoptosis changes in the hippocampus
of diabetic rats. J Ilam Univ Med Sci 2017;25:1. doi: 10.29252/
sjimu. 25.1.1.
Yang J‑S, Lu C‑C, Kuo S‑C, Hsu Y‑M, Tsai S‑C, Chen S‑Y,
et al. Autophagy and its link to type II diabetes mellitus.
Biomedicine 2017;7:8. doi: 10.1051/bmdcn/2017070201.
Kimura N. Diabetes mellitus induces Alzheimer’s disease
pathology: Histopathological evidence from animal models. Int
J Mol Sci 2016;17:503.
Martins IJ. Nutritional and genotoxic stress contributes to
diabetes and neurodegenerative diseases such as Parkinson’s and
Alzheimer’s diseases. Front Endocrinol (Lausanne) 2018;9:196.
doi: 10.3389/fendo.2018.00196.
Pagano G, Polychronis S, Wilson H, Giordano B, Ferrara N,
Niccolini F, et al. Diabetes mellitus and Parkinson disease.
Neurology 2018;90:e1654‑62.
Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis
induced by SGLT2 inhibitors: Possible mechanism and
contributing factors. J Diabetes Investig 2016;7:135‑8.
Sha W, Wen S, Chen L, Xu B, Lei T, Zhou L. The role of
SGLT2 inhibitor on the treatment of diabetic retinopathy.
J Diabetes Res 2020;2020:8867875. doi: 10.1155/2020/8867875.
Karami F, Jamaati H, Coleman‑Fuller N, Zeini MS, Hayes AW,
Gholami M, et al. Is metformin neuroprotective against diabetes
mellitus‑induced neurodegeneration? An updated graphical
review of molecular basis. Pharmacol Rep 2023;75:511‑43.
Hsia DS, Grove O, Cefalu WT. An update on SGLT2 inhibitors
for the treatment of diabetes mellitus. Curr Opin Endocrinol
Diabetes Obes 2017;24:73.
Dong D, Lou P, Wang J, Zhang P, Sun J, Chang G, et al.
Interaction of sleep quality and anxiety on quality of life in
individuals with type 2 diabetes mellitus. Health Qual Life
Outcomes. 2020;18:1‑7.
Shinkov A, Borissova A‑M, Kovatcheva R, Vlahov J,
Dakovska L, Atanassova I, et al. Increased prevalence of
depression and anxiety among subjects with metabolic syndrome
and known type 2 diabetes mellitus–A population‑based study.
Postgrad Med 2018;130:251‑7.
Muscatello M, Troili GM, Pandolfo G, Mento C, Gallo G,
Lanza G, et al. Depression, anxiety and anger in patients with
type 1 diabetes mellitus. Recenti Prog Med 2017;108:77‑82.
Amiri S, Behnezhad S. Diabetes and anxiety symptoms:
A systematic review and meta‑analysis. Int J Psychiatry Med
:0091217419837407. doi: 10.1177/0091217419837407.
Tang Y, Yu C, Wu J, Chen H, Zeng Y, Wang X, et al. Lychee
seed extract protects against neuronal injury and improves
cognitive function in rats with type II diabetes mellitus with
cognitive impairment. Int J Mol Med 2018;41:251‑63.
Li W, Huang E, Gao S. Type 1 diabetes mellitus and
cognitive impairments: A systematic review. J Alzheimer’s Dis
;57:29‑36.
Clar C, Gill JA, Waugh N. Systematic review of SGLT2 receptor
inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open
;2:e001007. doi: 10.1136/bmjopen‑2012‑001007.
Herat LY, Matthews VB, Rakoczy PE, Carnagarin R,
Schlaich M. Focusing on sodium glucose cotransporter‑2
and the sympathetic nervous system: Potential impact in
diabetic retinopathy. Int J Endocrinol. 2018;2018:9254126.
doi: 10.1155/2018/9254126.
Hemmingsen B, Krogh J, Metzendorf MI, Richter B. Sodiumglucose cotransporter (SGLT) 2 inhibitors for prevention or
delay of type 2 diabetes mellitus and its associated complications
in people at risk for the development of type 2 diabetes
mellitus. Cochrane Database Syst Rev 2016;4:CD012106. doi:
1002/14651858.CD012106.pub2.
Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus:
Rationale and clinical prospects. Nat Rev Endocrinol
;8:495‑502.
Chao EC, Henry RR. SGLT2 inhibition — A novel strategy for
diabetes treatment. Nat Rev Drug Discov 2010;9:551‑9.
Filippas‑Ntekouan S, Filippatos TD, Elisaf MS. SGLT2
inhibitors: Are they safe? Postgrad Med 2018;130:72‑82.
Feinkohl I, Price JF, Strachan MW, Frier BM. The impact of
diabetes on cognitive decline: Potential vascular, metabolic, and
psychosocial risk factors. Alzheimers Res Ther 2015;7:1‑22.
Oelze M, Kröller‑Schön S, Welschof P, Jansen T, Hausding M,
Mikhed Y, et al. The sodium‑glucose co‑transporter 2 inhibitor
empagliflozin improves diabetes‑induced vascular dysfunction
in the streptozotocin diabetes rat model by interfering with
oxidative stress and glucotoxicity. PloS One 2014;9:e112394.
doi: 10.1371/journal.pone.0112394.
Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K,
Uekawa K, et al. Glycemic control with empagliflozin, a
novel selective SGLT2 inhibitor, ameliorates cardiovascular
injury and cognitive dysfunction in obese and type 2 diabetic
mice. Cardiovasc Diabetol 2014;13:1‑15. doi: 10.1186/
s12933‑014‑0148‑1.
Amin EF, Rifaai RA, Abdel‐latif RG. Empagliflozin attenuates
transient cerebral ischemia/reperfusion injury in hyperglycemic
rats via repressing oxidative–inflammatory–apoptotic pathway.
Fundam Clin Pharmacol 2020;34:548‑58.
Sa‑Nguanmoo P, Tanajak P, Kerdphoo S, Jaiwongkam T,
Pratchayasakul W, Chattipakorn N, et al. SGLT2‑inhibitor
and DPP‑4 inhibitor improve brain function via attenuating
mitochondrial dysfunction, insulin resistance, inflammation, and
apoptosis in HFD‑induced obese rats. Toxicol Appl Pharmacol
;333:43‑50.
Chen C, Turnbull DM, Reeve AK. Mitochondrial dysfunction in
Parkinson’s disease—cause or consequence? Biology 2019;8:38.
Arab HH, Safar MM, Shahin NN. Targeting ROS‑dependent
AKT/GSK‑3β/NF‑κB and DJ‑1/Nrf2 pathways by dapagliflozin
attenuates neuronal injury and motor dysfunction in
rotenone‑induced Parkinson’s disease rat model. ACS Chem
Neurosci 2021;12:689‑703.
El Mouhayyar C, Riachy R, Khalil AB, Eid A, Azar S. SGLT2
inhibitors, GLP‑1 agonists, and DPP‑4 inhibitors in diabetes
and microvascular complications: A review. Int J Endocrinol
;2020:1762164. doi: 10.1155/2020/1762164.
Lin K‑J, Wang T‑J, Chen S‑D, Lin K‑L, Liou C‑W,
Lan M‑Y, et al. Two birds one stone: The neuroprotective
effect of antidiabetic agents on Parkinson disease—focus on
sodium‑glucose cotransporter 2 (SGLT2) inhibitors. Antioxidants
;10:1935. doi: 10.3390/antiox10121935.
Rizzo MR, Di Meo I, Polito R, Auriemma MC, Gambardella A,
di Mauro G, et al. Cognitive impairment and type 2 diabetes
mellitus: Focus of SGLT2 inhibitors treatment. Pharmacol Res
;176:106062. doi: 10.1016/j.phrs.2022.106062.
Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS,
Siasos G, Tsioufis K, et al. The impact of SGLT2 inhibitors
on inflammation: A systematic review and meta‑analysis of
studies in rodents. Int Immunopharmacol 2022;111:109080.
doi: 10.1016/j.intimp.2022.109080.
Naznin F, Sakoda H, Okada T, Tsubouchi H, Waise TZ,
Arakawa K, et al. Canagliflozin, a sodium glucose cotransporter
inhibitor, attenuates obesity‑induced inflammation in the
nodose ganglion, hypothalamus, and skeletal muscle of mice.
Eur J Pharmacol 2017;794:37‑44.
Steven S, Oelze M, Hanf A, Kröller‑Schön S, Kashani F,
Roohani S, et al. The SGLT2 inhibitor empagliflozin improves
the primary diabetic complications in ZDF rats. Redox Biol
;13:370‑85.
Pirklbauer M, Sallaberger S, Staudinger P, Corazza U, Leierer J,
Mayer G, et al. Empagliflozin inhibits IL‑1β‑mediated
inflammatory response in human proximal tubular cells. Int J
Mol Sci 2021;22:5089. doi: 10.3390/ijms22105089.
Muhammad RN, Ahmed LA, Abdul Salam RM, Ahmed KA,
Attia AS. Crosstalk among NLRP3 inflammasome, ET BR
signaling, and miRNAs in stress‑induced depression‑like
behavior: A modulatory role for SGLT2 inhibitors.
Neurotherapeutics 2021;18:2664‑2681.
Wiciński M, Wódkiewicz E, Górski K, Walczak M,
Malinowski B. Perspective of SGLT2 inhibition in treatment
of conditions connected to neuronal loss: Focus on Alzheimer’s
disease and ischemia‑related brain injury. Pharmaceuticals
;13:379. doi: 10.3390/ph 13110379.
Pawlos A, Broncel M, Woźniak E, Gorzelak‑Pabiś P.
Neuroprotective effect of SGLT2 inhibitors. Molecules
;26:7213. doi: 10.3390/molecules26237213.
Hierro‑Bujalance C, Infante‑Garcia C, Del Marco A, Herrera M,
Carranza‑Naval MJ, Suarez J, et al. Empagliflozin reduces
vascular damage and cognitive impairment in a mixed murine
model of Alzheimer’s disease and type 2 diabetes. Alzheimers
Res Ther 2020;12:1‑13.
Abdel‑Latif RG, Rifaai RA, Amin EF. Empagliflozin alleviates
neuronal apoptosis induced by cerebral ischemia/reperfusion
injury through HIF‑1α/VEGF signaling pathway. Arch Pharm
Res 2020;43:514‑25.
Freeman LR, Haley‑Zitlin V, Rosenberger DS, Granholm A‑C.
Damaging effects of a high‑fat diet to the brain and cognition: A review of proposed mechanisms. Nutr Neurosci
;17:241‑51.
Palaiodimou L, Lioutas V‑A, Lambadiari V, Paraskevas GP,
Voumvourakis K, Tsivgoulis G. Glycemia management in acute
ischemic stroke: Current concepts and novel therapeutic targets.
Postgrad Med 2019;131:423‑37.
El‑Sahar AE, Rastanawi AA, El‑Yamany MF, Saad MA.
Dapagliflozin improves behavioral dysfunction of Huntington’s
disease in rats via inhibiting apoptosis‑related glycolysis. Life
Sci 2020;257:118076.
Ibrahim WW, Kamel AS, Wahid A, Abdelkader NF.
Dapagliflozin as an autophagic enhancer via LKB1/AMPK/
SIRT1 pathway in ovariectomized/d‑galactose Alzheimer’s rat
model. Inflammopharmacology 2022;30:2505‑20.
Madhusudhanan J, Suresh G, Devanathan V. Neurodegeneration
in type 2 diabetes: Alzheimer’s as a case study. Brain Behav
;10:e01577. doi: 10.1002/brb3.1577.
Panahi Y, Khalili N, Sahebi E, Namazi S, Karimian MS,
Majeed M, et al. Antioxidant effects of curcuminoids in patients
with type 2 diabetes mellitus: A randomized controlled trial.
Inflammopharmacology 2017;25:25‑31.
Hamed SA. Brain injury with diabetes mellitus: Evidence,
mechanisms and treatment implications. Expert Rev Clin
Pharmacol 2017;10:409‑28.
Dobi A, Rosanaly S, Devin A, Baret P, Meilhac O, Harry GJ,
et al. Advanced glycation end‑products disrupt brain
microvascular endothelial cell barrier: The role of mitochondria
and oxidative stress. Microvasc Res 2021;133:104098.
doi: 10.1016/j.mvr. 2020.104098.
Venkat P, Chopp M, Chen J. Blood–brain barrier disruption,
vascular impairment, and ischemia/reperfusion damage
in diabetic stroke. J Am Heart Assoc 2017;6:e005819.
doi: 10.1161/JAHA.117.005819.
Hasan R, Lasker S, Hasan A, Zerin F, Zamila M, Parvez F,
et al. Canagliflozin ameliorates renal oxidative stress and
inflammation by stimulating AMPK–Akt–eNOS pathway
in the isoprenaline‑induced oxidative stress model. Sci Rep
;10:14659. doi: 10.1038/s41598‑020‑71599‑2.
Zhong Y, Zhu Y, He T, Li W, Li Q, Miao Y. Brain‑derived
neurotrophic factor inhibits hyperglycemia‑induced apoptosis
and downregulation of synaptic plasticity‑related proteins in
hippocampal neurons via the PI3K/Akt pathway. Int J Mol Med
;43:294‑304.
Moreira PI, Santos MS, Seiça R, Oliveira CR. Brain
mitochondrial dysfunction as a link between Alzheimer’s
disease and diabetes. J Neurol Sci 2007;257:206‑14.
Shibusawa R, Yamada E, Okada S, Nakajima Y, Bastie CC,
Maeshima A, et al. Dapagliflozin rescues endoplasmic reticulum
stress‑mediated cell death. Sci Rep 2019;9:9887.
Faridvand Y, Kazemzadeh H, Vahedian V, Mirzajanzadeh P,
Nejabati HR, Safaie N, et al. Dapagliflozin attenuates high
glucose-induced endothelial cell apoptosis and inflammation
through AMPK/SIRT1 activation. Clin Exp Pharmacol Physiol
;49:643‑51.
Avgerinos KI, Mullins RJ, Vreones M, Mustapic M,
Chen Q, Melvin D, et al. Empagliflozin induced ketosis,
upregulated IGF‑1/insulin receptors and the canonical insulin
signaling pathway in neurons, and decreased the excitatory
neurotransmitter glutamate in the brain of non‑diabetics. Cells
;11:3372. doi: 10.3390/cells11213372.
Larsen EL, Andersen A, Kjær LK, Eickhoff MK,
Frimodt‑Møller M, Persson F, et al. Effects of two‑and
twelve‑weeks sodium‑glucose cotransporter 2 inhibition on
DNA and RNA oxidation: Two randomized, placebo‑controlled
trials. Free Radic Res 2023;57:140‑51.
Guerrero‑Castillo AP, Sigfrido Benitez‑Renteria A,
Cuevas‑Ramos D, López‑Carrasco G, Silva A, Brito GX,
et al. 885‑P: Impact on glycaemic variability in newly onset
T2DM patients initiating dapagliflozin plus metformin vs.
metformin alone, a randomized open label clinical study—The
MAGNNIFY trial. Diabetes 2023;72(Suppl 1). doi: 10.2337/
db23‑885‑P