Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes.
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.
Ueki
Kohjiro
K
Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Okada
Terumasa
T
Hu
Jiang
J
Liew
Chong Wee
CW
Assmann
Anke
A
Dahlgren
Gabriella M
GM
Peters
Jennifer L
JL
Shackman
Jonathan G
JG
Zhang
Min
M
Artner
Isabella
I
Satin
Leslie S
LS
Stein
Roland
R
Holzenberger
Martin
M
Kennedy
Robert T
RT
Kahn
C Ronald
CR
Kulkarni
Rohit N
RN
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
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin