{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:53Z","timestamp":1785407513099,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007303","name":"University of Balamand internal research","doi-asserted-by":"publisher","award":["RGA\/FOM\/22-23-010"],"award-info":[{"award-number":["RGA\/FOM\/22-23-010"]}],"id":[{"id":"10.13039\/501100007303","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RGA\/FOM\/22-23-010"],"award-info":[{"award-number":["RGA\/FOM\/22-23-010"]}],"id":[{"id":"https:\/\/ror.org\/01xvwxv41","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Exploiting the metabolic properties of postbiotics is a novel strategy for managing metabolic disorders, including diabetes. Inactivated microorganisms, a major class of postbiotics, improve glycemic control in preclinical and clinical studies. Here, we examined whether heat-killed (HK) Mycobacterium aurum (M. aurum) exerts prophylactic or therapeutic anti-hyperglycemic effects in diabetic mice. Methods: Diabetes was induced in male BALB\/c mice by streptozotocin (STZ; 150 mg\/kg) injection. HK M. aurum (1 mg) was given orally (three prophylactic doses before STZ) or intradermally (six weekly therapeutic doses after STZ). We assessed glycemic parameters, serum C-peptide\/insulin (ELISA), and tissue protein expression (Western blot). Results: Neither route altered body weight or glucose homeostasis in non-diabetic mice. In STZ-diabetic mice, oral prophylactic treatment significantly attenuated hyperglycemia (39\u201360% reduction weeks 5\u20138 post-STZ) and showed a trend toward improved serum C-peptide, but did not affect dysregulated expression of skeletal muscle (SM), hepatic, pancreatic and renal proteins involved in glucose transport (GLUT2, GLUT4, and SGLT2), glycolysis (\u03b1-LDH), mitochondrial uncoupling (UCP2 and UCP3), and antioxidant defense (CAT). Therapeutic intradermal administration significantly decreased blood glucose (~30% at week 5, ~40% at week 6) and modestly enhanced insulin secretion. Hepatic UCP2 and \u03b1-LDH and SM UCP3 protein levels were normalized toward non-diabetic levels, whereas hepatic GLUT2 and SM GLUT4 remained largely unchanged. These correlative findings suggest effects independent of insulin-dependent glucose transport, but do not demonstrate direct functional improvement in mitochondrial or redox status. Conclusions: HK M. aurum exerts partial anti-hyperglycemic effects in STZ-induced diabetic mice, but the associated protein changes require functional validation before its role as a postbiotic in \u03b2-cell dysfunction can be established.<\/jats:p>","DOI":"10.3390\/nu18111652","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T09:17:09Z","timestamp":1779441429000},"page":"1652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prophylactic and Therapeutic Anti-Hyperglycemic Effects of Heat-Killed Mycobacterium aurum in STZ-Induced Diabetic Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5832-6142","authenticated-orcid":false,"given":"Ali","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, 33 Amioun, Al-Koura, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanin-Khaula","family":"Hakam","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, 33 Amioun, Al-Koura, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3046-7539","authenticated-orcid":false,"given":"Alaa","family":"Eter","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, 33 Amioun, Al-Koura, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samer","family":"Bazzi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, 33 Amioun, Al-Koura, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amani","family":"Chahine","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, 33 Amioun, Al-Koura, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0333-2073","authenticated-orcid":false,"given":"Charles","family":"Akle","sequence":"additional","affiliation":[{"name":"Immune Boost Clinic Limited, Shenstone Strathclyde, Bridgetown BB11078, St Michael, Barbados"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges M.","family":"Bahr","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, 33 Amioun, Al-Koura, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2134-5804","authenticated-orcid":false,"given":"Karim S.","family":"Echtay","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, 33 Amioun, Al-Koura, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee for Diabetes, Bajaj, M., McCoy, R.G., Balapattabi, K., Bannuru, R.R., Bellini, N.J., Bennett, A.K., Beverly, E.A., Briggs Early, K., and ChallaSivaKanaka, S. (2026). 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S27\u2013S49.","DOI":"10.2337\/dc26-S002"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","article-title":"Global, Regional, and National Burden of Diabetes from 1990 to 2021, with Projections of Prevalence to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021","volume":"402","author":"Ong","year":"2023","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s11154-021-09635-3","article-title":"Current Treatment Options and Challenges in Patients with Type 1 Diabetes: Pharmacological, Technical Advances and Future Perspectives","volume":"22","author":"Boscari","year":"2021","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"72","DOI":"10.33590\/emjdiabet\/RKYO7834","article-title":"Treatment of Type 2 Diabetes: A Comprehensive Review of Recent Improvements, Therapeutic Strategies, Challenges, and Future Perspectives","volume":"13","author":"Islam","year":"2025","journal-title":"EMJ Diabet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cabello-Olmo, M., Ara\u00f1a, M., Urtasun, R., Encio, I.J., and Barajas, M. (2021). Role of Postbiotics in Diabetes Mellitus: Current Knowledge and Future Perspectives. Foods, 10.","DOI":"10.3390\/foods10071590"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16999","DOI":"10.1007\/s00210-025-04456-6","article-title":"Mechanistic Insights into Postbiotics as Therapeutic Agents in Type 2 Diabetes Management","volume":"398","author":"Ebadpour","year":"2025","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cofs.2019.12.003","article-title":"Paraprobiotics and Postbiotics: Concepts and Potential Applications in Dairy Products","volume":"32","author":"Barros","year":"2020","journal-title":"Curr. Opin. Food Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1039\/C6FO01147K","article-title":"A Comparative Study of the Antidiabetic Effects Exerted by Live and Dead Multi-Strain Probiotics in the Type 2 Diabetes Model of Mice","volume":"7","author":"Li","year":"2016","journal-title":"Food Funct."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"108792","DOI":"10.1016\/j.foodres.2019.108792","article-title":"Effect of Inactivated Bifidobacterium Longum Intake on Obese Diabetes Model Mice (TSOD)","volume":"129","author":"Sakamoto","year":"2020","journal-title":"Food Res. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1080\/09637486.2021.1877261","article-title":"Wheat-Durum Pasta Added of Inactivated Bifidobacterium Animalis Decreases Glucose and Total Cholesterol Levels and Modulates Gut Microbiota in Healthy Rats","volume":"72","author":"Almada","year":"2021","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/s41591-019-0495-2","article-title":"Supplementation with Akkermansia Muciniphila in Overweight and Obese Human Volunteers: A Proof-of-Concept Exploratory Study","volume":"25","author":"Depommier","year":"2019","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109905","DOI":"10.1016\/j.foodres.2020.109905","article-title":"Paraprobiotic Obtained by Ohmic Heating Added in Whey-Grape Juice Drink Is Effective to Control Postprandial Glycemia in Healthy Adults","volume":"140","author":"Barros","year":"2021","journal-title":"Food Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Abdallah, F., Bazzi, S., Akle, C., Bahr, G.M., and Echtay, K.S. (2024). Reduction of Hyperglycemia in STZ-Induced Diabetic Mice by Prophylactic Treatment with Heat-Killed Mycobacterium Aurum: Possible Effects on Glucose Utilization, Mitochondrial Uncoupling, and Oxidative Stress in Liver and Skeletal Muscle. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1427058"},{"key":"ref_14","unstructured":"(2026, February 14). Immy|Immune Support for Modern Life. Available online: https:\/\/www.immy.co\/."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4839","DOI":"10.1002\/fsn3.2413","article-title":"Heat-Killed Mycolicibacterium Aurum Aogashima: An Environmental Nonpathogenic Actinobacteria under Development as a Safe Novel Food Ingredient","volume":"9","author":"Nouioui","year":"2021","journal-title":"Food Sci. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Langgartner, D., Weiss, A.-L.J., Amoroso, M., Sterrett, J.D., Lowry, C.A., and Reber, S.O. (2024). Effects of Repeated Intragastric Administrations with Heat-Inactivated Mycobacterium Aurum DSM 33539 on the Stress-Induced Aggravation of Dextran Sulfate Sodium (DSS) Colitis in C57BL\/6N Mice. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1488603"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1002\/cpz1.78","article-title":"Streptozotocin-Induced Diabetic Models in Mice and Rats","volume":"1","author":"Furman","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wszola, M., Klak, M., Kosowska, A., Tymicki, G., Berman, A., Adamiok-Ostrowska, A., Olkowska-Truchanowicz, J., Uhrynowska-Tyszkiewicz, I., and Kaminski, A. (2021). Streptozotocin-Induced Diabetes in a Mouse Model (BALB\/c) Is Not an Effective Model for Research on Transplantation Procedures in the Treatment of Type 1 Diabetes. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121790"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S157","DOI":"10.2337\/dc09-S302","article-title":"Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes","volume":"32","author":"DeFronzo","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of Insulin Action and Insulin Resistance","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.taap.2006.01.003","article-title":"Diabetes and Mitochondrial Function: Role of Hyperglycemia and Oxidative Stress","volume":"212","author":"Rolo","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1186\/s10020-024-01027-y","article-title":"Mitochondrial Uncoupling Protein 2: A Central Player in Pancreatic Disease Pathophysiology","volume":"30","author":"Wang","year":"2024","journal-title":"Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41575-021-00440-6","article-title":"The International Scientific Association of Probiotics and Prebiotics (ISAPP) Consensus Statement on the Definition and Scope of Postbiotics","volume":"18","author":"Salminen","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Choe, H., Shin, C.Y., Lim, J.S., Park, J.-S., Park, J.-W., Kim, W.J., Park, Y.I., and Ree, J. (2025). Evaluation of Potential Anti-Diabetic Synbiotic Formulation of Lacticaseibacillus Rhamnosus BST.L-601 Using Db\/Db Mice. Foods, 14.","DOI":"10.3390\/foods14244230"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"108290","DOI":"10.1016\/j.fbio.2026.108290","article-title":"Lacticaseibacillus Rhamnosus SD11 Improves Gastrointestinal Functions in Multiple Low Doses of Streptozotocin-Induced Type 1 Diabetic Mice","volume":"76","author":"Nopparat","year":"2026","journal-title":"Food Biosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1111\/dme.12159","article-title":"The Clinical Utility of C-Peptide Measurement in the Care of Patients with Diabetes","volume":"30","author":"Jones","year":"2013","journal-title":"Diabet. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"739","DOI":"10.2337\/db13-0881","article-title":"Impact of C-Peptide Preservation on Metabolic and Clinical Outcomes in the Diabetes Control and Complications Trial","volume":"63","author":"Lachin","year":"2014","journal-title":"Diabetes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0168-8227(99)00079-0","article-title":"BCG Vaccine Prevents Insulitis in Low Dose Streptozotocin-Induced Diabetic Mice","volume":"46","author":"Baik","year":"1999","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41541-018-0062-8","article-title":"Long-Term Reduction in Hyperglycemia in Advanced Type 1 Diabetes: The Value of Induced Aerobic Glycolysis with BCG Vaccinations","volume":"3","author":"Tran","year":"2018","journal-title":"npj Vaccines"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cbi.2015.11.032","article-title":"Challenges and Issues with Streptozotocin-Induced Diabetes\u2014A Clinically Relevant Animal Model to Understand the Diabetes Pathogenesis and Evaluate Therapeutics","volume":"244","author":"Goyal","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/S0092-8674(01)00378-6","article-title":"Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, Beta Cell Dysfunction, and Type 2 Diabetes","volume":"105","author":"Zhang","year":"2001","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrendo.2009.21","article-title":"The Role of Inflammation in Insulitis and Beta-Cell Loss in Type 1 Diabetes","volume":"5","author":"Eizirik","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1097\/01.mjt.0000178767.67857.63","article-title":"Autoimmune Destruction of Pancreatic Beta Cells","volume":"12","author":"Yoon","year":"2005","journal-title":"Am. J. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1159\/000233249","article-title":"UCP3 Expression in Liver Modulates Gene Expression and Oxidative Metabolism in Response to Fatty Acids, and Sensitizes Mitochondria to Permeability Transition","volume":"24","author":"Camara","year":"2009","journal-title":"Cell Physiol. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.2337\/diabetes.50.12.2870","article-title":"Uncoupling Protein 3 Content Is Decreased in Skeletal Muscle of Patients with Type 2 Diabetes","volume":"50","author":"Schrauwen","year":"2001","journal-title":"Diabetes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16559","DOI":"10.1038\/s41598-024-67490-z","article-title":"Exploring Dose-Response Variability and Relative Severity Assessment in STZ-Induced Diabetes Male NSG Mice","volume":"14","author":"Talbot","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1080\/09687680110100995","article-title":"GLUT2 in Pancreatic and Extra-Pancreatic Gluco-Detection","volume":"18","author":"Thorens","year":"2001","journal-title":"Mol. Membr. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s12986-025-01037-5","article-title":"The Effect of Postbiotics Supplementation on Obesity and Metabolic Health: A Systematic Review and Meta-Analysis of Randomized Control Trials","volume":"22","author":"Li","year":"2025","journal-title":"Nutr. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101085","DOI":"10.1016\/j.isci.2020.101085","article-title":"BCG Vaccinations Upregulate Myc, a Central Switch for Improved Glucose Metabolism in Diabetes","volume":"23","author":"Takahashi","year":"2020","journal-title":"iScience"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/11\/1652\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T09:33:11Z","timestamp":1779442391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/11\/1652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["nu18111652"],"URL":"https:\/\/doi.org\/10.3390\/nu18111652","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]}}}