Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes

K Ueki, T Okada, J Hu, CW Liew, A Assmann… - Nature …, 2006 - nature.com
K Ueki, T Okada, J Hu, CW Liew, A Assmann, GM Dahlgren, JL Peters, JG Shackman
Nature genetics, 2006nature.com
An appropriate β cell mass is pivotal for the maintenance of glucose homeostasis. Both
insulin and IGF-1 are important in regulation of β cell growth and function (reviewed in ref.).
To define the roles of these hormones directly, we created a mouse model lacking functional
receptors for both insulin and IGF-1 only in β cells (βDKO), as the hormones have
overlapping mechanisms of action and activate common downstream proteins. Notably,
βDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they …
Abstract
An appropriate β cell mass is pivotal for the maintenance of glucose homeostasis. Both insulin and IGF-1 are important in regulation of β cell growth and function (reviewed in ref. ). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in β cells (βDKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, βDKO 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 βDKO mice manifest reduced β cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised β cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating β cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I–dependent pathways are not critical for development of β cells but that a loss of action of these hormones in β cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in β cells might protect against type 2 diabetes.
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