Transgenic rescue of insulin receptor-deficient mice.
The role of different tissues in insulin action and their contribution to the pathogenesis of diabetes remain unclear. To examine this question, we have used genetic reconstitution experiments in mice. Genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis. We show that combined restoration of insulin receptor function in brain, liver, and pancreatic beta cells rescues insulin receptor knockout mice from neonatal death, prevents diabetes in a majority of animals, and normalizes adipose tissue content, lifespan, and reproductive function. In contrast, mice with insulin receptor expression limited to brain or liver and pancreatic beta cells are rescued from neonatal death, but develop lipoatrophic diabetes and die prematurely. These data indicate, surprisingly, that insulin receptor signaling in noncanonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes.
Okamoto
Haruka
H
Department of Medicine, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Nakae
Jun
J
Kitamura
Tadahiro
T
Park
Byung-Chul
BC
Dragatsis
Ioannis
I
Accili
Domenico
D
D000273:Adipose Tissue / Q000033:anatomy & histology / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D001921:Brain / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014018:Tissue Distribution; D019076:Transgenes
D007328:Insulin; D011972:Receptor, Insulin; D005947:Glucose