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Cited by 51Metabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic DiseasesDiabetes, Cardiovascular Risks, and Lipoproteins

Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1

Park, So-Young, Cho, You-Ree, Kim, Hyo-Jeong, Hong, Eun-Gyoung, Higashimori, Takamasa, Lee, Sang Jun, Goldberg, Ira J., Shulman, Gerald I. +2 more·2006·American Journal of Physiology-Endocrinology and Metabolism
DOI 10.1152/ajpendo.00077.2006
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Abstract

Mice with liver-specific overexpression of dominant negative phosphorylation-defective S503A-CEACAM1 mutant (L-SACC1) developed chronic hyperinsulinemia resulting from blunted hepatic clearance of insulin, visceral obesity, and glucose intolerance. To determine the underlying mechanism of altered glucose homeostasis, a 2-h hyperinsulinemic euglycemic clamp was performed, and tissue-specific glucose and lipid metabolism was assessed in awake L-SACC1 and wild-type mice. Inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) caused insulin resistance in liver that was mostly due to increased expression of fatty acid synthase and lipid metabolism, resulting in elevated intrahepatic levels of triglyceride and long-chain acyl-CoAs. Whole body insulin resistance in the L-SACC1 mice was further attributed to defects in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Insulin resistance in peripheral tissues was associated with significantly elevated intramuscular fat contents that may be secondary to increased whole body adiposity (assessed by (1)H-MRS) in the L-SACC1 mice. Overall, these results demonstrate that L-SACC1 is a mouse model in which chronic hyperinsulinemia acts as a cause, and not a consequence, of insulin resistance. Our findings further indicate the important role of CEACAM1 and hepatic insulin clearance in the pathogenesis of obesity and insulin resistance.

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Crossref · 10.1152/ajpendo.00077.2006

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  • Fatty acid-induced reductions in insulin receptor number and function in the liver may also reduce hepatic insulin clearance, causing systemic hyperinsulinemia, itself a contributor to both insulin resistance and reduced mitochondrial function.

    “Fatty acid-induced reductions in insulin receptor number and function in the liver (211) may also reduce hepatic insulin clearance (226), causing systemic hyperinsulinemia, itself a contributor to both insulin resistance and reduced mitochondrial function (214,227,228).”

    From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [227]

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Authors
Park, S.-Y., Cho, Y.-R., Kim, H.-J., Hong, E.-G., Higashimori, T., Lee, S. J., Goldberg, I. J., Shulman, G. I., Najjar, S. M., & Kim, J. K.
Affiliations
Yale University (US)
ORCID
Venue
American Journal of Physiology-Endocrinology and Metabolism
Publisher
American Physiological Society
Published
2006-09
Volume
291
Issue
3
Pages
E517-E524
ISSN
  • 0193-1849 (ISSN-L)
  • 1522-1555
DOI
10.1152/ajpendo.00077.2006
OpenAlex
W1976197029
Cited by
51
References
45
Citations by year
2025: 1 · 2024: 2 · 2023: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2017: 3 · 2016: 3 · 2015: 4 · 2014: 3 · 2013: 2 · 2012: 6
FWCI
1.22
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Yale University
  • National Institutes of Health (5r21dk057497-02)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK54254, U24DK59635, R01DK054254, R01DK080756, DK57497, R01DK040936, U24DK059635)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
CEACAM1, impaired glucose tolerance, insulin resistance, hyperinsulinemia, hepatic insulin clearance, dominant negative mutation, visceral obesity, fatty acid synthase, hepatic lipid metabolism, triglycerides, long-chain acyl-CoA, skeletal muscle glucose uptake, adipose tissue glucose uptake, intramuscular fat, 1H NMR, hyperinsulinemic-euglycemic clamp, glucose homeostasis
MeSH terms
Acyl Coenzyme A, Animals, Blood Glucose, Carcinoembryonic Antigen, Disease Models, Animal, Glucose, Glycogen, Hyperinsulinism, Insulin, Insulin Resistance, Lipoprotein Lipase, Liver, Triglycerides, Glucose Clamp Technique, Glucose Intolerance, Mice, Knockout, Muscle, Skeletal, Glucose-6-Phosphate, Fatty Acid Transport Proteins, Mice, Fatty Acid Synthases

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