Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle
Open accessAbstract
Obesity and insulin resistance in skeletal muscle are two major factors in the pathogenesis of type 2 diabetes. Mice with muscle-specific inactivation of the insulin receptor gene (MIRKO) are normoglycemic but have increased fat mass. To identify the potential mechanism for this important association, we examined insulin action in specific tissues of MIRKO and control mice under hyperinsulinemic-euglycemic conditions. We found that insulin-stimulated muscle glucose transport and glycogen synthesis were decreased by about 80% in MIRKO mice, whereas insulin-stimulated fat glucose transport was increased threefold in MIRKO mice. These data demonstrate that selective insulin resistance in muscle promotes redistribution of substrates to adipose tissue thereby contributing to increased adiposity and development of the prediabetic syndrome.
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In genetic mouse models of muscle-specific IR, by deleting the IRTK or GLUT4 genes, hepatic steatosis and adiposity were increased.
“In genetic mouse models of muscle-specific IR, by deleting the IRTK [142] or GLUT4 [143] genes, hepatic steatosis and adiposity were increased [142].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [142]
Mice with muscle-specific inactivation of the insulin receptor gene have increased plasma triglycerides and increased adiposity as a result of muscle-specific insulin resistance.
“This hypothesis is further supported by studies in mice with muscle-specific inactivation of the insulin receptor gene, which have been shown to have increased plasma triglycerides and increased adiposity as a result of muscle-specific insulin resistance (14).”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [14]
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- Authors
- Kim, J. K., Michael, M. D., Previs, S. F., Peroni, O. D., Mauvais-Jarvis, F., Neschen, S., Kahn, B. B., Kahn, C. R., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Joslin Diabetes Center (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2000-06-15
- Volume
- 105
- Issue
- 12
- Pages
- 1791-1797
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC378504
- OpenAlex
- W2120413507
- Cited by
- 331
- References
- 31
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 11 · 2022: 3 · 2021: 11 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 14 · 2016: 14 · 2015: 14 · 2014: 14 · 2013: 17 · 2012: 14
- FWCI
- 13.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01 DK43051, R01DK080756, R01DK040936, R01DK033201, R01DK043051, P30DK045735)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- skeletal muscle, adipose tissue, obesity, type 2 diabetes, insulin receptor, muscle glucose transport, glycogen synthesis, hyperinsulinemic-euglycemic clamp, prediabetes, adiposity
- MeSH terms
- Adipose Tissue, Animals, Blood Glucose, Glucose, Glycogen, Glycolysis, Hyperinsulinism, Insulin, Insulin Resistance, Male, Obesity, Receptor, Insulin, Reference Values, Glucose Clamp Technique, Mice, Knockout, Muscle, Skeletal, Mice
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