{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:09:04Z","timestamp":1791900544109,"version":"4.3.4"},"reference-count":89,"publisher":"American Diabetes Association","issue":"3","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":8,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,3,1]]},"abstract":"<jats:p>Since the UK Prospective Diabetes Study (UKPDS), metformin has been considered the first-line medication for patients with newly diagnosed type 2 diabetes. Though direct evidence from specific trials is still lacking, several studies have suggested that metformin may protect from diabetes- and nondiabetes-related comorbidities, including cardiovascular, renal, neurological, and neoplastic diseases. In the past few decades, several mechanisms of action have been proposed to explain metformin\u2019s protective effects, none being final. It is certain, however, that metformin increases lactate production, concentration, and, possibly, oxidation. Once considered a mere waste product of exercising skeletal muscle or anaerobiosis, lactate is now known to act as a major energy shuttle, redistributed from production sites to where it is needed. Through the direct uptake and oxidation of lactate produced elsewhere, all end organs can be rapidly supplied with fundamental energy, skipping glycolysis and its possible byproducts. Increased lactate production (and consequent oxidation) could therefore be considered a positive mechanism of action of metformin, except when, under specific circumstances, metformin and lactate become excessive, increasing the risk of lactic acidosis. We are proposing that, rather than considering metformin-induced lactate production as dangerous, it could be considered a mechanism through which metformin exerts its possible protective effect on the heart, kidneys, and brain and, to some extent, its antineoplastic action.<\/jats:p>","DOI":"10.2337\/dc20-1964","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T21:19:10Z","timestamp":1613769550000},"page":"647-654","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":47,"title":["Metformin Benefits: Another Example for Alternative Energy Substrate Mechanism?"],"prefix":"10.2337","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-7792","authenticated-orcid":false,"given":"Andrea","family":"Giaccari","sequence":"first","affiliation":[{"name":"Center for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7855-8253","authenticated-orcid":false,"given":"Anna","family":"Solini","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-7552","authenticated-orcid":false,"given":"Simona","family":"Frontoni","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Diabetes and Metabolism, San Giovanni Calibita Fatebenefratelli Hospital, Rome, Italy"},{"name":"Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5388-0270","authenticated-orcid":false,"given":"Stefano","family":"Del Prato","sequence":"additional","affiliation":[{"name":"Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"2022031309513163900_B1","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/S0140-6736(98)07037-8","article-title":"Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)","volume":"352","author":"UK Prospective Diabetes Study (UKPDS) Group","year":"1998","journal-title":"Lancet"},{"key":"2022031309513163900_B2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00125-019-05039-w","article-title":"2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. 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