%0 Journal Article
%T Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity.
%A Cha J
%A Tong X
%A Walker EM
%A Dahan T
%A Cochrane VA
%A Ashe S
%A Russell R
%A Osipovich AB
%A Mawla AM
%A Guo M
%A Liu JH
%A Loyd ZA
%A Huising MO
%A Magnuson MA
%A Hebrok M
%A Dor Y
%A Stein R
%J JCI Insight
%V 8
%N 16
%D 2023 08 22
%M 37606041
%F 9.484
%R 10.1172/jci.insight.166386
%X Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.