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The combination of impaired insulin-dependent glucose metabolism in skeletal muscle and impaired \u03b2-cell function causes an increase of hepatic glucose production, leading to a constellation of tissue abnormalities that has been referred to as the diabetes \u201cruling triumvirate.\u201d Targeted mutagenesis in mice has led to a critical reappraisal of the integrated physiology of insulin action. These studies indicate that insulin resistance in skeletal muscle and adipose tissue does not necessarily lead to hyperglycemia, so long as insulin sensitivity in other tissues is preserved. Additional data suggest a direct role of insulin signaling in \u03b2-cell function and regulation of \u03b2-cell mass, thus raising the possibility that insulin resistance may be the overarching feature of diabetes in all target tissues. I propose that we replace the original picture of a ruling triumvirate with that of a squabbling republic in which every tissue contributes to the onset of the disease.<\/jats:p>","DOI":"10.2337\/diabetes.53.7.1633","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"1633-1642","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":149,"title":["Lilly Lecture 2003"],"prefix":"10.2337","volume":"53","author":[{"given":"Domenico","family":"Accili","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Naomi Berrie Diabetes Center, College of Physicians & Surgeons of Columbia University, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031209425258800_R1","doi-asserted-by":"crossref","unstructured":"Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, Inzucchi S, Dresner A, Rothman DL, Shulman GI: Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. 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