Cited by 151Pancreatic function and diabetesMetabolism, Diabetes, and CancerDiabetes Management and Research

Transgenic rescue of insulin receptor–deficient mice

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Okamoto, Haruka, Nakae, Jun, Kitamura, Tadahiro, Park, Byung-Chul, Dragatsis, Ioannis, Accili, Domenico·2004·Journal of Clinical Investigation

Abstract

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 β 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 β 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.

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  • Restoring insulin signaling to the brain in addition to liver and pancreas prevents development of diabetes in insulin receptor-deficient mice.

    “restoration of insulin signaling to the brain as well prevents the development of diabetes (136).”

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Authors
Okamoto, H., Nakae, J., Kitamura, T., Park, B.-C., Dragatsis, I., & Accili, D.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Columbia University (US)
Corresponding author
Accili, Domenico
Venue
Journal of Clinical Investigation
Published
2004-07-15
Volume
114
Issue
2
Pages
214-223
ISSN
0021-9738 (ISSN-L)
OpenAlex
W1982060139
Cited by
151
References
49
Citations by year
2024: 4 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 2 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 10 · 2012: 14
FWCI
10.42
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (DK58282, DK63608)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK057539, DK63608, R01DK058282, R37DK058282, DK58282, DK 57539, P30DK063608)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
insulin receptor, transgenic rescue, diabetic ketoacidosis, neonatal lethality, lipoatrophic diabetes, fuel homeostasis, adipose tissue, pancreatic beta cells, brain insulin signaling, lifespan, reproductive function
MeSH terms
Adipose Tissue, Animals, Animals, Newborn, Body Weight, Brain, Glucose, Insulin, Islets of Langerhans, Liver, Mice, Transgenic, Receptor, Insulin, Tissue Distribution, Signal Transduction, Mice, Knockout, Transgenes, Mice

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