Dietary nitrite supplementation improves insulin resistance in type 2 diabetic KKAy mice
Abstract
Background Because insulin signaling is essential for endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production, the loss of bioavailable NO might be a common molecular mechanism underlying the development of insulin resistance and endothelial dysfunction. Although dietary nitrite acts as a substrate for systemic NO generation, thereby serving as a physiological alternative source of NO for signaling, it is not precisely known how dietary nitrite affects type 2 diabetes mellitus. Here we report the therapeutic effects of dietary nitrite on the metabolic and histological features of KKA(y) diabetic mice.Methods KKA(y) mice were divided into three groups (without nitrite, and with 50 mg/L and 150 mg/L nitrite in drinking water), and two groups of C57BL/6J mice served as controls (without nitrite and with 150 mg/L nitrite in drinking water). After 10 weeks, blood samples, visceral adipose tissues, and gastrocnemius muscles were collected after a 16-hour fast to assess the homeostasis model assessment of insulin resistance (HOMA-IR) levels, the histology of the adipose tissue, insulin-stimulated sequential signaling to glucose transporter 4 (GLUT4), and nitrite and nitrate contents in the muscle using an HPLC system.Results KKA(y) mice developed obesity with enhanced fasting plasma levels of glucose and insulin and exhibited increased HOMA-IR scores compared with the C57BL/6J control mice. Dietary nitrite dose-dependently reduced the size of the hypertrophic adipocytes and TNF-α transcription in the adipose tissue of KKA(y) diabetic mice, which also restored the insulin-mediated signal transduction, including p85 and Akt phosphorylation, and subsequently restored the GLUT4 expression in the skeletal muscles.Conclusions These results suggest that dietary nitrite provides an alternative source of NO, and subsequently improves the insulin-mediated signaling and the metabolic and histological features in KKA(y) diabetic mice.
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Recent studies demonstrate improvements of insulin resistance in humans and animals as a result of dietary nitrate/nitrite enhancing NO availability in plasma and tissues.
“the therapeutic potential of dietary nitrate/nitrite has been supported by recent studies demonstrating the improvements of insulin resistance in humans and animals as a result of its enhancing the NO availability in plasma and tissues [65,66,67,68].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [67]
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- Authors
- Ohtake, K., Nakano, G., Ehara, N., Sonoda, K., Ito, J., Uchida, H., & Kobayashi, J.
- Affiliations
- Josai University (JP)
- Kinjo Gakuin University (JP)
- Meikai University (JP)
- Corresponding author
- Kobayashi, Jun
- Venue
- Nitric Oxide
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 44
- Pages
- 31-38
- ISSN
- 1089-8603 (ISSN-L)
- OpenAlex
- W2065063113
- Cited by
- 63
- References
- 39
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 2 · 2015: 7
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nitric Oxide (publishedVersion)
- PubMed (publishedVersion)
- Josai University Repository of Academia (Josai University) (submittedVersion)
- Funders
- Japan Food Chemical Research Foundation
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- dietary nitrite, insulin resistance, type 2 diabetes, KK-Ay mice, endothelial nitric oxide synthase, adipose tissue hypertrophy, TNF-α, insulin signaling, Akt phosphorylation, GLUT4, skeletal muscle, obesity
- MeSH terms
- Adipose Tissue, Animals, Blood Glucose, Body Weight, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Eating, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Transgenic, Nitrites, Cytokines, Glucose Transporter Type 4, Mice
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