title: Dietary nitrite supplementation improves insulin resistance in type 2 diabetic KKA(y) 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.
authors.affiliation: Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohtake
authors.affiliation: Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama, Japan.
authors.forename: Genya
authors.initials: G
authors.lastname: Nakano
authors.affiliation: Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ehara
authors.affiliation: Department of Food and Nutritional Environment, College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Sonoda
authors.affiliation: Division of Oral Anatomy, Department of Human Development and Fostering, Meikai University School of Dentistry, Saitama, Japan.
authors.forename: Junta
authors.initials: J
authors.lastname: Ito
authors.affiliation: Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Division of Pathophysiology, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, Saitama, Japan. Electronic address: junkoba@josai.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Kobayashi
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009573:Nitrites / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D051275:Glucose Transporter Type 4; D009573:Nitrites; C495693:Slc2a4 protein, mouse
keywords: Dietary nitrite/nitrate; Glucose transporter 4; Insulin resistance; Type 2 diabetes mellitus