{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T07:02:26Z","timestamp":1785222146469,"version":"3.55.0"},"reference-count":31,"publisher":"Endocrinology Research Centre","issue":"3","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.probl-endojournals.ru\/jour\/about\/editorialPolicies#openAccessPolicy"}],"content-domain":{"domain":["www.probl-endojournals.ru"],"crossmark-restriction":true},"short-container-title":["Probl Endokrinol (Mosk)"],"abstract":"<jats:p>Gluconeogenesis, a dual-purpose pathway in type 2 diabetes mellitus (T2DM), not only synthesizes glucose but also clears metabolic waste via the Cori cycle (lactate recycling through LDH, PC, PEPCK) and Alanine cycle (nitrogen disposal via ALT, GDH, urea cycle), preventing acidosis, ROS accumulation, and ammonia toxicity. Metformin, the cornerstone T2DM therapy, inhibits gluconeogenesis by targeting mitochondrial complex I, elevating AMP\/ATP ratios, and activating AMPK-PKC\u03b9\/\u03bb signaling to repress CREB-CRTC2-driven PEPCK\/G6Pase expression, disrupting these cycles. This leads to lactate, pyruvate, and ammonia buildup, triggering pro-inflammatory cascades: HIF-1\u03b1 stabilization induces IL-6\/VEGF, ROS from pyruvate excess activates NF-\u03baB for TNF-\u03b1, and ammonia primes NLRP3 inflammasome for IL-1\u03b2\/IL-18 release, fostering chronic inflammation. Multisystem consequences include musculoskeletal fatigue from ATP deficits, cognitive fog via neuroinflammation, atherosclerosis from endothelial dysfunction, hepatic fibrosis from urea cycle stress, and immune inflammaging impairing macrophage function. Clinical evidence reveals short-term anti-inflammatory benefits (reduced IL-6, CRP) via AMPK and microbiota effects, contrasted by long-term risks like lactic acidosis and neurodegeneration in renal-impaired or elderly patients. This review integrates physiological roles, molecular mechanisms, inflammatory pathways, systemic impacts, and clinical findings, highlighting metformin\u2019s dual-edged profile glycemic efficacy versus \u201cinflammatory debt.\u201d Researchers are urged to explore precision interventions, such as antioxidants or biomarker-guided dosing, to optimize metformin\u2019s pleiotropic potential in T2DM and inflammaging-related disorders, redefining therapeutic paradigms.<\/jats:p>","DOI":"10.14341\/probl13618","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:47:35Z","timestamp":1785163655000},"page":"44-52","update-policy":"https:\/\/doi.org\/10.14341\/crossmarkpolicy2018","source":"Crossref","is-referenced-by-count":0,"title":["Metformin\u2019s disruption of gluconeogenesis in type 2 diabetes impairments of the cori and alanine cycles as hidden drivers of metabolic waste accumulation, NF-\u03baBHIF-1\u03b1\u2013mediated low-grade inflammation, and multisystem dysfunction"],"prefix":"10.14341","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-1688","authenticated-orcid":true,"given":"Maher","family":"Akl","sequence":"first","affiliation":[{"name":"National Research Lobachevsky State University of Nizhny Novgorod"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-236X","authenticated-orcid":true,"given":"Amr","family":"Ahmed","sequence":"additional","affiliation":[{"name":"The public health department, Riyadh First Health Cluster"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"5458","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Jiang S, Young JL, Wang K, Qian Y, Cai L. Diabetic-induced alterations in hepatic glucose and lipid metabolism: the role of type 1 and type 2 diabetes mellitus (Review). Mol Med Rep. 2020;22(2):603\u2013611. doi: 10.3892\/mmr.2020.11175","DOI":"10.3892\/mmr.2020.11175"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang XM, Zhang D, Camporez JG, Cline GW, Butrico GM, Kemp BE, Casals G, Steinberg GR, Vatner DF, Petersen KF, Shulman GI. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. 2018;24(9):1384\u20131394. doi: 10.1038\/s41591-018-0125-4","DOI":"10.1038\/s41591-018-0125-4"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Siddiqui SH, Kang D, Park J, Khan M, Belal SA, Shin D, Shim K. Altered relationship between gluconeogenesis and immunity in broilers exposed to heat stress for different durations. Poult Sci. 2021;100(8):101274. doi: 10.1016\/j.psj.2021.101274","DOI":"10.1016\/j.psj.2021.101274"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Sharabi K, Tavares CD, Rines AK, Puigserver P. Molecular pathophysiology of hepatic glucose production. Mol Aspects Med. 2015;46:21\u201333. doi: 10.1016\/j.mam.2015.09.003","DOI":"10.1016\/j.mam.2015.09.003"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017;66(6):789\u2013800. doi: 10.1016\/j.molcel.2017.05.032","DOI":"10.1016\/j.molcel.2017.05.032"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Fontaine E. Metformin-induced mitochondrial complex I inhibition: facts, uncertainties, and consequences. Front Endocrinol. 2018;9:753. doi: 10.3389\/fendo.2018.00753","DOI":"10.3389\/fendo.2018.00753"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542\u2013546. doi: 10.1038\/nature13270","DOI":"10.1038\/nature13270"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Chen Y, Meng Z, Li Y, Liu S, Hu P, Luo E. Advanced glycation end products and reactive oxygen species: uncovering the potential role of ferroptosis in diabetic complications. Mol Med. 2024;30(1):141. doi: 10.1186\/s10020-024-00905-9","DOI":"10.1186\/s10020-024-00905-9"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Sharma A, Tate M, Mathew G, Vince JE, Ritchie RH, de Haan JB. Oxidative stress and NLRP3-inflammasome activity as significant drivers of diabetic cardiovascular complications: therapeutic implications. Front Physiol. 2018;9:114. doi: 10.3389\/fphys.2018.00114","DOI":"10.3389\/fphys.2018.00114"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Gray LR, Tompkins SC, Taylor EB. Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci. 2014;71(14):2577\u20132604. doi: 10.1007\/s00018-013-1539-2","DOI":"10.1007\/s00018-013-1539-2"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Jitrapakdee S, St Maurice M, Rayment I, Cleland WW, Wallace JC, Attwood PV. Structure, mechanism and regulation of pyruvate carboxylase. Biochem J. 2008;413(3):369\u2013387. doi: 10.1042\/BJ20080709","DOI":"10.1042\/BJ20080709"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"van Schaftingen E, Gerin I. The glucose-6-phosphatase system. Biochem J. 2002;362(Pt 3):513\u2013532. doi: 10.1042\/bj3620513","DOI":"10.1042\/bj3620513"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Hole\u010dek M. Origin and roles of alanine and glutamine in gluconeogenesis in the liver, kidneys, and small intestine under physiological and pathological conditions. Int J Mol Sci. 2024;25(13):7037. doi: 10.3390\/ijms25137037","DOI":"10.3390\/ijms25137037"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Horike N, Sakoda H, Kushiyama A, Ono H, Fujishiro M, Kamata H, Nishiyama K, Uchijima Y, Kurihara Y, Kurihara H, Asano T. AMP-activated protein kinase activation increases phosphorylation of glycogen synthase kinase 3beta and thereby reduces cAMP-responsive element transcriptional activity and phosphoenolpyruvate carboxykinase C gene expression in the liver. J Biol Chem. 2008;283(49):33902\u201333910. doi: 10.1074\/jbc.M802537200","DOI":"10.1074\/jbc.M802537200"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Steinberg GR, Carling D. AMP-activated protein kinase: the current landscape for drug development. Nat Rev Drug Discov. 2019;18(7):527\u2013551. doi: 10.1038\/s41573-019-0019-2","DOI":"10.1038\/s41573-019-0019-2"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Zhang T, Chen L, Kueth G, Shao E, Wang X, Ha T, Williams DL, Li C, Fan M, Yang K. Lactate\u2019s impact on immune cells in sepsis: unraveling the complex interplay. Front Immunol. 2024;15:1483400. doi: 10.3389\/fimmu.2024.1483400","DOI":"10.3389\/fimmu.2024.1483400"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Li, Z., Hu, J., Bao, C. et al. Activation of the NLRP3 inflammasome and elevation of interleukin-1\u03b2 secretion in infection by sever fever with thrombocytopenia syndrome virus. Sci Rep 12, 2573 (2022). https:\/\/doi.org\/10.1038\/s41598-022-06229-0","DOI":"10.1038\/s41598-022-06229-0"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Tayek JA, Katz J. Glucose production, recycling, Cori cycle, and gluconeogenesis in humans: relationship to serum cortisol. Am J Physiol. 1997;272(3 Pt 1):E476\u2013E484. doi: 10.1152\/ajpendo.1997.272.3.E476","DOI":"10.1152\/ajpendo.1997.272.3.E476"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Kelly B, Tannahill GM, Murphy MP, O\u2019Neill LA. Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1\u03b2 (IL-1\u03b2) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J Biol Chem. 2015;290(33):20348\u201320359. doi: 10.1074\/jbc.M115.662114","DOI":"10.1074\/jbc.M115.662114"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Zhang X, Lee W, Bian JS. Recent advances in the study of Na+\/K+-ATPase in neurodegenerative diseases. Cells. 2022;11(24):4075. doi: 10.3390\/cells11244075","DOI":"10.3390\/cells11244075"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"S\u00fcdhof TC. Calcium control of neurotransmitter release. Cold Spring Harb Perspect Biol. 2012;4(1):a011353. doi: 10.1101\/cshperspect.a011353","DOI":"10.1101\/cshperspect.a011353"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Harijith A, Ebenezer DL, Natarajan V. Reactive oxygen species at the crossroads of inflammasome and inflammation. Front Physiol. 2014;5:352. doi: 10.3389\/fphys.2014.00352","DOI":"10.3389\/fphys.2014.00352"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Lipskaia L, Chemaly ER, Hadri L, Lompre AM, Hajjar RJ. Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther. 2010;10(1):29\u201341. doi: 10.1517\/14712590903321462","DOI":"10.1517\/14712590903321462"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Inoue E, Yamauchi J. AMP-activated protein kinase regulates PEPCK gene expression by direct phosphorylation of a novel zinc finger transcription factor. Biochem Biophys Res Commun. 2006;351(4):793\u2013799. doi: 10.1016\/j.bbrc.2006.10.124","DOI":"10.1016\/j.bbrc.2006.10.124"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Mason SA, Wadley GD, Keske MA, Parker L. Effect of mitochondrial-targeted antioxidants on glycaemic control, cardiovascular health, and oxidative stress in humans: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2022;24(6):1047\u20131060. doi: 10.1111\/dom.14669","DOI":"10.1111\/dom.14669"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Katz J, Tayek JA. Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans. Am J Physiol. 1998;275(3):E537\u2013E542. doi: 10.1152\/ajpendo.1998.275.3.E537","DOI":"10.1152\/ajpendo.1998.275.3.E537"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577\u20131585. doi: 10.1007\/s00125-017-4342-z","DOI":"10.1007\/s00125-017-4342-z"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Tauffenberger A, Fiumelli H, Almustafa S, Magistretti PJ. Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling. Cell Death Dis. 2019;10(9):653. doi: 10.1038\/s41419-019-1877-6","DOI":"10.1038\/s41419-019-1877-6"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Malkov MI, Lee CT, Taylor CT. Regulation of the hypoxia-inducible factor (HIF) by pro-inflammatory cytokines. Cells. 2021;10(9):2340. doi: 10.3390\/cells10092340","DOI":"10.3390\/cells10092340"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Zhang Y, Igwe OJ. Exogenous oxidants activate nuclear factor kappa B through Toll-like receptor 4 stimulation to maintain inflammatory phenotype in macrophage. Biochem Pharmacol. 2018;147:104\u2013118. doi: 10.1016\/j.bcp.2017.11.012","DOI":"10.1016\/j.bcp.2017.11.012"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210\u2013215. doi: 10.1038\/nri2725","DOI":"10.1038\/nri2725"}],"container-title":["Problems of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.probl-endojournals.ru\/jour\/article\/viewFile\/13618\/11012","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T06:48:36Z","timestamp":1785221316000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.probl-endojournals.ru\/jour\/article\/view\/13618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":31,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,7,22]]}},"URL":"https:\/\/doi.org\/10.14341\/probl13618","relation":{},"ISSN":["2308-1430","0375-9660"],"issn-type":[{"value":"2308-1430","type":"electronic"},{"value":"0375-9660","type":"print"}],"subject":[],"published":{"date-parts":[[2026,7,22]]}}}