Signaling of reactive oxygen and nitrogen species in Diabetes mellitus

Area of Science:

• Biochemistry
• Cellular Signaling
• Diabetes Pathophysiology

Background:

• Disrupted physiological signaling of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is characteristic of type 1 and type 2 diabetes mellitus.
• Hyperglycemia elevates ROS, primarily from mitochondria and NADPH oxidase, leading to overproduction and signaling pathway deregulation, thus initiating diabetes development.
• RNS signaling deregulation typically involves decreased nitric oxide (NO) formation, causing subsequent pathological disorders.

Purpose of the Study:

• To examine pathological changes in ROS and RNS signaling pathways in diabetes.
• To investigate the role of specific enzymes and genes, including protein kinases (Akt/B, PI3-kinase, ERK1/2), p66shc, FOXO3a, and Sirt2, in ROS/RNS signaling.
• To discuss the impact of varying ROS levels and explore potential therapeutic strategies.

Main Methods:

• Review of enzyme/gene-regulated processes involving ROS and RNS signaling.
• Analysis of the roles of specific adapter proteins (p66shc, FOXO3a, Sirt2) and signaling pathways (Akt/B, PI3-kinase, ERK1/2).
• Consideration of the effects of both low and high ROS levels in diabetic conditions.

Main Results:

• Hyperglycemia-induced ROS overproduction disrupts normal cellular signaling, contributing to diabetes.
• Deregulation of RNS signaling, particularly reduced NO formation, leads to damaging effects.
• Specific proteins like p66shc, FOXO3a, and Sirt2 play crucial roles in ROS-mediated pathological changes.

Conclusions:

• Effective regulation of damaging ROS levels in diabetes is a promising therapeutic target.
• Traditional antioxidants like vitamins E and C are limited in their ability to neutralize superoxide and hydrogen peroxide.
• Novel free radical scavengers, including flavonoids, quinones, and synthetic superoxide dismutase (SOD) mimetics, require intensive investigation for diabetes treatment.