Mechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice
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Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may be related to alterations in fat metabolism. Fatless mice have been created using dominant-negative protein (A-ZIP/F-1) targeted gene expression in the adipocyte and shown to develop diabetes. To understand the mechanism responsible for the insulin resistance in these mice, we conducted hyperinsulinemic-euglycemic clamps in awake fatless and wild type littermates before the development of diabetes and examined insulin action and signaling in muscle and liver. We found the fatless mice to be severely insulin-resistant, which could be attributed to defects in insulin action in muscle and liver. Both of these abnormalities were associated with defects in insulin activation of insulin receptor substrate-1 and -2-associated phosphatidylinositol 3-kinase activity and a 2-fold increase in muscle and liver triglyceride content. We also show that upon transplantation of fat tissue into these mice, triglyceride content in muscle and liver returned to normal as does insulin signaling and action. In conclusion, these results suggest that the development of insulin resistance in type 2 diabetes may be due to alterations in the partitioning of fat between the adipocyte and muscle/liver leading to accumulation of triglyceride in the latter tissues with subsequent impairment of insulin signaling and action.
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Previous studies by our group and others have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.
“Previous studies by our group (9, 17-20) and others (7, 21, 22) have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [19]
NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM.
“recent studies have demonstrated that NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM (18–23).”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [18]
NAFLD is strongly linked to hepatic insulin resistance.
“NAFLD is strongly linked to hepatic insulin resistance”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [18]
There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance in rodent models and in patients with nonalcoholic fatty liver disease.
“There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance both in rodent models with hepatic steatosis and in patients with nonalcoholic fatty liver disease (4, 18-25).”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [24]
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- Authors
- Kim, J. K., Gavrilova, O., Chen, Y., Reitman, M. L., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institutes of Health (US)
- Corresponding author
- Shulman, Gerald I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-03
- Volume
- 275
- Issue
- 12
- Pages
- 8456-8460
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2111445543
- Cited by
- 443
- References
- 30
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 8 · 2021: 13 · 2020: 12 · 2019: 15 · 2018: 10 · 2017: 19 · 2016: 18 · 2015: 18 · 2014: 14 · 2013: 19 · 2012: 17
- FWCI
- 25.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, 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
- insulin resistance, type 2 diabetes, IRS-1, insulin receptor substrate 2, phosphatidylinositol 3-kinase, insulin signaling, liver triglyceride accumulation, fat partitioning, fat transplantation, hyperinsulinemic-euglycemic clamp
- MeSH terms
- Adipose Tissue, Animals, Body Composition, Insulin, Insulin Resistance, Liver, Mice, Mutant Strains, Mice, Transgenic, Muscles, Phosphoproteins, Transcription Factors, Glucose Clamp Technique, Phosphatidylinositol 3-Kinases, Intracellular Signaling Peptides and Proteins, Mice, Insulin Receptor Substrate Proteins
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