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A Role for iNOS in Fasting Hyperglycemia and Impaired Insulin Signaling in the Liver of Obese Diabetic Mice
Open accessAbstract
Chronic inflammation has been postulated to play an important role in the pathogenesis of insulin resistance. Inducible nitric oxide synthase (iNOS) has been implicated in many human diseases associated with inflammation. iNOS deficiency was shown to prevent high-fat diet-induced insulin resistance in skeletal muscle but not in the liver. A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. To address this issue, we examined the effects of a specific inhibitor for iNOS, L-NIL, in obese diabetic (ob/ob) mice. iNOS expression was increased in the liver of ob/ob mice compared with wild-type mice. Treatment with iNOS inhibitor reversed fasting hyperglycemia with concomitant amelioration of hyperinsulinemia and improved insulin sensitivity in ob/ob mice. iNOS inhibitor also increased the protein expression of insulin receptor substrate (IRS)-1 and -2 1.5- and 2-fold, respectively, and enhanced IRS-1- and IRS-2-mediated insulin signaling in the liver of ob/ob mice. Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice.
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“and the use of an NOS2-specific inhibitor (L-NIL) reversed hyperglycemia, hyperinsulinemia, and insulin resistance in ob/ob mice [150].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [150]
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“Similarly, 5 improved insulin sensitivity and fasting hyperglycemia in obese and diabetic mice, which have iNOS overexpressed in the liver, muscle, and adipose tissue.(211) Obesity can also impair lymphatic function (possibly via the accumulation of perilymphatic inflammatory cells that produce iNOS), and treatment of…”
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“In genetically obese and diabetic rodent models, such as ob/ob mice and ZDF rats, iNOS protein expression in both adipose tissue and skeletal muscle was higher in comparison with the lean nonobese wild-types [118,119].”
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“iNOS was also proposed to play a role in hepatic insulin resistance in ob/ob mice (120).”
BackgroundDavis, B. J., Xie, Z., Viollet, B., & Zou, M. (2006) · Diabetes · doi:10.2337/diabetes.55.02.06.db05-1064 · Cited by 465
“In particular, elevated levels of NO caused by upregulation of high-output inducible NOS-II have been reported to occur in diabetes (41,42).”
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Metadata
- Authors
- Fujimoto, M., Shimizu, N., Kunii, K., Martyn, J. A. J., Ueki, K., & Kaneki, M.
- Affiliations
- Harvard University (US)
- The University of Tokyo (JP)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-05-01
- Volume
- 54
- Issue
- 5
- Pages
- 1340-1348
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2138266804
- Cited by
- 209
- References
- 47
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 9 · 2019: 15 · 2018: 12 · 2017: 10 · 2016: 10 · 2015: 24 · 2014: 14 · 2013: 7 · 2012: 15
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shriners Hospitals for Children
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM055082, R01GM031569, R01GM061411)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058127)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- inducible nitric oxide synthase, fasting hyperglycemia, hepatic insulin resistance, insulin signaling, IRS-1, insulin receptor substrate 2, L-NIL, ob/ob mice, obesity, type 2 diabetes, nitric oxide, chronic inflammation, hepatocytes
- MeSH terms
- Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Enzyme Inhibitors, Fasting, Hyperglycemia, Insulin, Insulin Resistance, Liver, Lysine, Male, Mice, Obese, Signal Transduction, Nitric Oxide Synthase, Phosphatidylinositol 3-Kinases, Nitric Oxide Donors, Hepatocytes, Mice, Nitric Oxide Synthase Type II
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