Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus.
During pregnancy, maternal pancreatic islets grow to match dynamic physiological demands, but the mechanisms regulating adaptive islet growth in this setting are poorly understood. Here we show that menin, a protein previously characterized as an endocrine tumor suppressor and transcriptional regulator, controls islet growth in pregnant mice. Pregnancy stimulated proliferation of maternal pancreatic islet beta-cells that was accompanied by reduced islet levels of menin and its targets. Transgenic expression of menin in maternal beta-cells prevented islet expansion and led to hyperglycemia and impaired glucose tolerance, hallmark features of gestational diabetes. Prolactin, a hormonal regulator of pregnancy, repressed islet menin levels and stimulated beta-cell proliferation. These results expand our understanding of mechanisms underlying diabetes pathogenesis and reveal potential targets for therapy in diabetes.
Karnik
Satyajit K
SK
Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Chen
Hainan
H
McLean
Graeme W
GW
Heit
Jeremy J
JJ
Gu
Xueying
X
Zhang
Andrew Y
AY
Fontaine
Magali
M
Yen
Michael H
MH
Kim
Seung K
SK
D000818:Animals; D049109:Cell Proliferation; D016640:Diabetes, Gestational / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014407:Tumor Cells, Cultured
D007328:Insulin; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D011388:Prolactin