Dietary nitrite supplementation improves insulin resistance in type 2 diabetic KKA(y) mice

Nitric Oxide. 2015 Jan 30:44:31-8. doi: 10.1016/j.niox.2014.11.009. Epub 2014 Nov 13.


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.

Keywords: Dietary nitrite/nitrate; Glucose transporter 4; Insulin resistance; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology
  • Adipose Tissue / metabolism
  • Animals
  • Blood Glucose / drug effects*
  • Body Weight / drug effects
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Eating / drug effects
  • Glucose Transporter Type 4 / metabolism
  • Insulin Resistance*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nitrites / administration & dosage*
  • Nitrites / pharmacology*


  • Blood Glucose
  • Cytokines
  • Glucose Transporter Type 4
  • Nitrites
  • Slc2a4 protein, mouse