2. Academic Validation
  3. Antihyperglycemic activity of L-norvaline and L-arginine in high-fat diet and streptozotocin-treated male rats

Antihyperglycemic activity of L-norvaline and L-arginine in high-fat diet and streptozotocin-treated male rats

  • Exp Mol Pathol. 2022 Jun:126:104763. doi: 10.1016/j.yexmp.2022.104763.
Hayarpi Javrushyan 1,  Edita Nadiryan 2,  Anna Grigoryan 3,  Nikolay Avtandilyan 4,  Alina Maloyan 5
Affiliations

Affiliations

  • 1 Research Institute of Biology, Yerevan State University, Armenia. Electronic address: hg.javrushyan@ysu.am.
  • 2 Department of Biochemistry, Microbiology and Biotechnology, Yerevan State University, Armenia. Electronic address: edita.nadiryan@ysumail.am.
  • 3 Department of Human and Animal Physiology, Yerevan State University, Armenia. Electronic address: annagrigoryan@ysu.am.
  • 4 Research Institute of Biology, Yerevan State University, Armenia; Department of Biochemistry, Microbiology and Biotechnology, Yerevan State University, Armenia. Electronic address: nv.avtandilyan@ysu.am.
  • 5 Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon 97239, USA. Electronic address: Maloyan@ohsu.edu.
PMID: 35398371 DOI: 10.1016/j.yexmp.2022.104763
Abstract

Background: A decrease in nitric oxide (NO) bioavailability has been shown to cause hyperglycemia, type II diabetes mellitus (DM), and chronic cardio-metabolic complications. In turn, hyperglycemia and hypercholesterolemia are associated with increased oxidative stress that leads to reduced nitric oxide bioavailability through disruption of L-arginine transport into cells, inactivation of nitric oxide synthase, and activation of Arginase. Upregulation of Arginase has been demonstrated in both diabetic patients and animal models of hyperglycemia and type 2 diabetes. L-norvaline is a nonselective inhibitor of Arginase that increases NO production and promotes the normal functioning of the vascular endothelium. Another means of increasing NO bioavailability in the cardiovascular system is L-arginine supplementation. Whether L-norvaline and L-arginine have antihyperglycemic effects has not been studied.

Hypothesis: We hypothesized that inhibition of Arginase will provide an antihyperglycemic effect and, as a result of the recovery of NO bioavailability, will protect against oxidative stress and hypercholesterolemia.

Methods: Rats were fed a high-fat diet (HFD) for three weeks concomitant with the two-time injection of 30 mg/kg of streptozotocin (STZ) to induce stable hyperglycemia. We studied the antihyperglycemic properties of Arginase inhibition (via L-norvaline) and its combination with NOS substrate supplementation (via L-arginine).

Results: Treatment of HFD/STZ mice with L-norvaline and L-arginine reduced fasting blood glucose levels by 27.1% vs. untreated HFD/STZ rats (p < 0.001). Blood levels of total Cholesterol, low-density lipoprotein (LDL), and malondialdehyde (MDA), a marker for oxidative stress, were significantly decreased in both L-norvaline- and L-norvaline+L-arginine-treated HFD/STZ rats when compared with untreated rats. In addition, administration of L-norvaline and L-arginine reversed the progression of pancreatic and kidney pathology in HFD/STZ rats as assessed by histology (p < 0.001).

Conclusions: Both L-norvaline and L-arginine act as potent antihyperglycemic agents and can represent alternative therapeutic tools in individuals with hyperglycemia and pre-diabetes.

Keywords

Arginase; Dyslipidemia; High fat diet; Hyperglycemia; L-norvaline; Nitric oxide; Pre-diabetes; Streptozotocin.

Figures
Products