Oxidative stress biology and cell injury during type 1 and type 2 diabetes mellitus

Abstract

Diabetes mellitus (DM) affects approximately 170 million individuals worldwide and is expected to alter the lives of at least 366 million individuals within a future span of 25 years. Of even greater concern is the premise that these projections are underestimated since they assume obesity levels will remain constant. Type 1 insulin-dependent DM accounts for only 5-10 percent of all diabetics but represents a highly significant health concern, since this disorder begins early in life and leads to long-term complications. In contrast, Type 2 DM is recognized as the etiology of over 80 percent of all diabetics and is dramatically increasing in incidence as a result of changes in human behavior and increased body mass index. Yet, the pathological consequences of these disorders that involve the both the neuronal and vascular systems are intimately linked through the pathways that mediate oxidative stress. Here we highlight some of the relevant oxidative pathways that determine insulin resistance through reactive oxygen species, mitochondrial dysfunction, uncoupling proteins, and endoplasmic reticulum stress. These pathways are ultimately linked to protein kinase B (Akt) and the insulin signaling pathways that determine the initial onset of glucose intolerance and the subsequent course to apoptotic cell injury. Through the elucidation of these targets, improvement in current strategies as well as the development of future clinical applications can move forward for both the prevention and treatment of Type 1 and Type 2 DM.

Fig. 1. Acute hyperglycemia leads to neuronal injury

Representative hippocampal neurons obtained from E-19 Sprague-Dawley rat pups were incubated in L-15 growth medium with free serum containing elevated D-glucose of 50 mM for 24 hours at 37°C in a humidified atmosphere of 5% CO₂ and 95% room air. Neuronal cell survival was determined by trypan blue exclusion method and reveals significantly increased dye uptake in injured neurons during hyperglycemia (right panel), but not in untreated control neurons (left panel). Note: Acute neuronal injury with elevated glucose can occur at significantly lower glucose concentrations of 20 mM, but a glucose concentration of 50 mM was chosen for dramatic visualization of cell injury.