{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T06:47:55Z","timestamp":1761893275078,"version":"3.41.2"},"reference-count":37,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["102820\/Z\/13\/Z"],"award-info":[{"award-number":["102820\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabet Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Glycaemic response to metformin and sulphonylureas is heritable \u2013 with ~34%\u201337% of variation explainable by common genetic variation. The premise of this review is that by understanding how genetic variation contributes to drug response we can gain insights into the mechanisms of action of diabetes drugs. Here, I focus on two old drugs, metformin and sulphonylureas, where I would suggest we still have a lot to learn about their mechanism of action or their optimal use in clinical care. The fact that reduced function variants of the key transporter that takes metformin into the liver (OCT1) do not alter glycaemic response to metformin suggests that metformin does not need to get into the liver to work. A subsequent GWAS of metformin response identifies a robust variant that alters GLUT2 expression \u2013 which may support increasing evidence that metformin works primarily in the gut. For sulphonylureas, observation from patients with neonatal diabetes due to activating K<jats:sub>ATP<\/jats:sub> channel mutations treated with sulphonylureas identified a novel role for sulphonylureas to enable \u03b2\u2010cell incretin response. This work led to recent studies of low\u2010dose sulphonylurea (20\u00a0mg gliclazide) in T2DM, which identified that at this dose sulphonylureas augment the incretin effect and increase \u03b2\u2010cell glucose sensitivity, without increasing hypoglycaemia risk. This work, prompted by studies in monogenic diabetes, suggests that we have historically been using sulphonylureas at too high a dose. With increasing availability of genetic data pharmacogenomic studies in patients with diabetes should reveal mechanistic insights into old and new diabetes drugs, with the potential for optimized use and novel therapies.<\/jats:p>","DOI":"10.1111\/dme.14726","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T21:40:18Z","timestamp":1634766018000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Dorothy Hodgkin Lecture 2021: Drugs, genes and diabetes"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9237-8585","authenticated-orcid":false,"given":"Ewan R.","family":"Pearson","sequence":"first","affiliation":[{"name":"Professor of Diabetic Medicine Head of Division, Population Health &amp; Genomics School of Medicine University of Dundee Dundee 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