{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:00:27Z","timestamp":1787662827143,"version":"build-2736575974"},"reference-count":101,"publisher":"American Diabetes Association","issue":"3","license":[{"start":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:p>Secretion of insulin from pancreatic \u03b2-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of \u03b2-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.<\/jats:p>","DOI":"10.2337\/db21-0755","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T18:26:58Z","timestamp":1645640818000},"page":"367-375","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":30,"title":["ATP-Sensitive Potassium Channels in Hyperinsulinism and Type 2 Diabetes: Inconvenient Paradox or New Paradigm?"],"prefix":"10.2337","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4929-2134","authenticated-orcid":false,"given":"Colin G.","family":"Nichols","sequence":"first","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel W.","family":"York","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-472X","authenticated-orcid":false,"given":"Maria S.","family":"Remedi","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO"},{"name":"Division of Endocrinology Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, 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