title: Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes.
abstract: An appropriate beta cell mass is pivotal for the maintenance of glucose homeostasis. Both insulin and IGF-1 are important in regulation of beta cell growth and function (reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in beta cells (betaDKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, betaDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. Normoglycemic 2-week-old betaDKO mice manifest reduced beta cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised beta cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating beta cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in beta cells might protect against type 2 diabetes.
authors.affiliation: Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Terumasa
authors.initials: T
authors.lastname: Okada
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Anke
authors.initials: A
authors.lastname: Assmann
authors.forename: Gabriella M
authors.initials: GM
authors.lastname: Dahlgren
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Peters
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Shackman
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Isabella
authors.initials: I
authors.lastname: Artner
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kennedy
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007515:Islets of Langerhans / Q000503:physiopathology*; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin