{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:45:11Z","timestamp":1787240711448,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,8]],"date-time":"2023-01-08T00:00:00Z","timestamp":1673136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006013","name":"UAE University","doi-asserted-by":"publisher","award":["31M333"],"award-info":[{"award-number":["31M333"]}],"id":[{"id":"10.13039\/501100006013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB\/c mice over 4 weeks. Balb\/c mice (4\u20136 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 \u00b5g\/g), SRL (5 \u00b5g\/g), or MET (200 \u00b5g\/g) +SRL (5 \u00b5g\/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.<\/jats:p>","DOI":"10.3390\/ijms24021223","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T02:09:39Z","timestamp":1673230179000},"page":"1223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effect of Sirolimus\/Metformin Co-Treatment on Hyperglycemia and Cellular Respiration in BALB\/c Mice"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-3891","authenticated-orcid":false,"given":"Alia","family":"Albawardi","sequence":"first","affiliation":[{"name":"Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanya","family":"Saraswathiamma","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charu","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulghani","family":"Elomami","sequence":"additional","affiliation":[{"name":"Division of Anatomy Pathology and Cytopathology, Tawam Hospital, Al Ain 15258, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul-Kader","family":"Souid","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5147-0657","authenticated-orcid":false,"given":"Saeeda","family":"Almarzooqi","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2147\/nano.2007.2.1.25","article-title":"Nanomedicines in renal transplant rejection\u2014Focus on sirolimus","volume":"2","author":"Shen","year":"2007","journal-title":"Int. J. Nanomed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1002\/j.1875-9114.1997.tb03080.x","article-title":"Sirolimus, a new, potent immunosuppressive agent","volume":"17","author":"Kelly","year":"1997","journal-title":"Pharmacotherapy"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Granata, S., Gassa, A.D., Carraro, A., Brunelli, M., Stallone, G., Lupo, A., and Zaza, G. (2016). Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050735"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3904\/kjim.2015.394","article-title":"Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats","volume":"32","author":"Jin","year":"2017","journal-title":"Korean J. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"386","DOI":"10.18632\/aging.101401","article-title":"Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice","volume":"10","author":"Weiss","year":"2018","journal-title":"Aging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.2337\/db09-1324","article-title":"Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue","volume":"59","author":"Houde","year":"2010","journal-title":"Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1007\/s40265-015-0416-8","article-title":"Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention","volume":"75","author":"Hostalek","year":"2015","journal-title":"Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/CS20110386","article-title":"Cellular and molecular mechanisms of metformin: An overview","volume":"122","author":"Viollet","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/nature11808","article-title":"Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP","volume":"494","author":"Miller","year":"2013","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.2337\/diabetes.49.12.2063","article-title":"Mechanism by which metformin reduces glucose production in type 2 diabetes","volume":"49","author":"Hundal","year":"2000","journal-title":"Diabetes"},{"key":"ref_11","first-page":"187","article-title":"Metformin-clinical pharmacology in PCOs","volume":"8","author":"Dumitrescu","year":"2015","journal-title":"J. Med. Life"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1139\/cjpp-2016-0567","article-title":"mTORC1 inhibitors rapamycin and metformin affect cardiovascular markers differentially in ZDF rats","volume":"95","author":"Nistala","year":"2017","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1002\/jnr.24050","article-title":"The antidiabetic drug metformin decreases mitochondrial respiration and tricarboxylic acid cycle activity in cultured primary rat astrocytes","volume":"95","author":"Hohnholt","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.bbrc.2017.03.036","article-title":"Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism","volume":"486","author":"Sun","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1681\/ASN.2007111202","article-title":"Sirolimus is associated with new-onset diabetes in kidney transplant recipients","volume":"19","author":"Johnston","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s10637-017-0478-4","article-title":"A phase Ib study of everolimus combined with metformin for patients with advanced cancer","volume":"36","author":"Molenaar","year":"2018","journal-title":"Investig. New Drugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3904\/kjim.2017.004","article-title":"The effects of addition of coenzyme Q10 to metformin on sirolimus-induced diabetes mellitus","volume":"34","author":"Sun","year":"2019","journal-title":"Korean J. Intern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.2337\/db12-1001","article-title":"Conversion of Mature Human \u03b2-Cells Into Glucagon-Producing \u03b1-Cells","volume":"62","author":"Spijker","year":"2013","journal-title":"Diabetes"},{"key":"ref_19","first-page":"115","article-title":"The PI3K\u03b4 inhibitor idelalisib suppresses liver and lung cellular respiration","volume":"7","author":"Hammadi","year":"2015","journal-title":"Int. J. Physiol. Pathophysiol. Pharmacol."},{"key":"ref_20","first-page":"4678","article-title":"Sirolimus treatment induces dose-dependent involution of the thymus with elevated cellular respiration in BALB\/c mice","volume":"14","author":"Almarzooqi","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/agm2.12135","article-title":"Clinical perspectives and concerns of metformin as an anti-aging drug","volume":"3","author":"Wang","year":"2020","journal-title":"Aging Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1021\/jp710176z","article-title":"Oxygen measurement via phosphorescence: Reaction of sodium dithionite with dissolved oxygen","volume":"112","author":"Tao","year":"2008","journal-title":"J. Phys. Chem. A."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Alfazari, A.S., Al-Dabbagh, B., Almarzooqi, S., Albawardi, A., and Souid, A.K. (2013). A preparation of murine liver fragments for in vitro studies: Liver preparation for toxicological studies. BMC Res. Notes, 6.","DOI":"10.1186\/1756-0500-6-70"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1000203","DOI":"10.4172\/2161-0495.1000203","article-title":"Modulation of Cardiomyocyte and Hepatocyte Bioenergetics by Biguanides","volume":"4","author":"Almarzooqi","year":"2014","journal-title":"J. Clin. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.brainres.2012.01.028","article-title":"The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats","volume":"1444","author":"Lv","year":"2012","journal-title":"Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1093\/gerona\/glq033","article-title":"Metformin supplementation and life span in Fischer-344 rats","volume":"65","author":"Smith","year":"2010","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1038\/s41467-022-29714-6","article-title":"Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle","volume":"13","author":"Ham","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.neuron.2012.03.043","article-title":"Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons","volume":"75","author":"Yang","year":"2012","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature13270","article-title":"Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase","volume":"510","author":"Madiraju","year":"2014","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/acel.12405","article-title":"Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system","volume":"15","author":"Neuman","year":"2016","journal-title":"Aging Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E1046","DOI":"10.1152\/ajpendo.00683.2013","article-title":"PPAR\u03b3 activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats","volume":"306","author":"Festuccia","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e13666","DOI":"10.1111\/acel.13666","article-title":"Rapamycin\/metformin co-treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice","volume":"21","author":"Reifsnyder","year":"2022","journal-title":"Aging Cell"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rahman, M.S., Hossain, K.S., Das, S., Kundu, S., Adegoke, E.O., Rahman, M.A., Hannan, M.A., Uddin, M.J., and Pang, M.-G. (2021). Role of Insulin in Health and Disease: An Update. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126403"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1016\/j.bbadis.2016.09.019","article-title":"Metformin, beyond an insulin sensitizer, targeting heart and pancreatic \u03b2 cells","volume":"1863","author":"Yang","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lundquist, I., Mohammed Al-Amily, I., Meidute Abaraviciene, S., and Salehi, A. (2016). Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165668"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.2337\/diabetes.54.8.2404","article-title":"Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: Effects of lifestyle intervention and metformin","volume":"54","author":"Kitabchi","year":"2005","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.diabres.2013.12.031","article-title":"Prevention by metformin of alterations induced by chronic exposure to high glucose in human islet beta cells is associated with preserved ATP\/ADP ratio","volume":"104","author":"Masini","year":"2014","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1080\/13880209.2016.1268635","article-title":"Metformin attenuates hepatic insulin resistance in type-2 diabetic rats through PI3K\/Akt\/GLUT-4 signalling independent to bicuculline-sensitive GABAA receptor stimulation","volume":"55","author":"Garabadu","year":"2017","journal-title":"Pharm. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e130770","DOI":"10.1172\/jci.insight.130770","article-title":"Tacrolimus- and sirolimus-induced human \u03b2 cell dysfunction is reversible and preventable","volume":"5","author":"Dai","year":"2020","journal-title":"JCI Insight"},{"key":"ref_40","first-page":"54","article-title":"The mTOR inhibitor sirolimus suppresses renal, hepatic, and cardiac tissue cellular respiration","volume":"7","author":"Albawardi","year":"2015","journal-title":"Int. J. Physiol. Pathophysiol. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Grubelnik, V., Zmazek, J., Markovi\u010d, R., Gosak, M., and Marhl, M. (2020). Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus. Life, 10.","DOI":"10.3390\/life10120348"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1089\/ars.2016.6755","article-title":"The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus","volume":"26","author":"Gerber","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12931-017-0618-6","article-title":"Sirolimus alters lung pathology and viral load following influenza A virus infection","volume":"18","author":"Alsuwaidi","year":"2017","journal-title":"Respir. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1223\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:03:10Z","timestamp":1760119390000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,8]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021223"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021223","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,8]]}}}