Novel Avenues of Drug Discovery and Biomarkers for Diabetes Mellitus

Abstract

Globally, developed nations spend a significant amount of their resources on healthcare initiatives that poorly translate into increased population life expectancy. As an example, the United States devotes sixteen percent of its gross domestic product to healthcare, the highest level in the world, but falls behind other nations that enjoy greater individual life expectancy. These observations point to the need for pioneering avenues of drug discovery to increase lifespan with controlled costs. In particular, innovative drug development for metabolic disorders such as diabetes mellitus (DM) becomes increasingly critical given that the number of diabetic individuals will increase exponentially over the next twenty years. Here we discuss the elucidation and targeting of novel cellular pathways that are intimately tied to oxidative stress in DM for new treatment strategies. Pathways that involve wingless, NAD + precursors, and cytokines govern complex biological pathways that determine both cell survival and longevity during DM and its complications. Furthermore, the role of these entities as biomarkers for disease can further enhance their utility irrespective of their treatment potential. Greater understanding of the intricacies of these unique cellular mechanisms will shape future drug discovery for DM to provide focused clinical care with limited or absent long-term complications. Keywords biomarkers; diabetes; oxidative stress Healthcare and metabolic diseaseCompared with other nations throughout the world, the United States devotes 16% of the gross domestic product to healthcare and spending for each individual equal to $7,290, the highest levels in the world 1 . Total spending on pharmaceuticals is also the highest in the world with $878 per individual. Yet, life expectancy in years in the United States equals 78.1 years and trails behind other countries such as Japan that allots 8% of the gross domestic product on healthcare, spends $2,514 for each individual, and has a life expectancy of 82.6 years. Furthermore, the United States is ranked as having the highest level of obesity in the population at 34.3% while countries such as Japan have a 3.4% level of obesity 1 . These statistics are the results of multiple factors, but also can support the arguments for not only improved preventive health measures, but also new directions to treat multiple disorders that can lead to improved lifespan while minimizing economic burden.In particular, one can consider diabetes mellitus (DM), a metabolic disorder closely associated with increased weight gain 2,3 . DM reaches approximately 20 million individuals in the United States and more than 165 million individuals worldwide 4 . By 2030, DM may affect more than 360 million individuals. Additionally, a significant portion of the population has undiagnosed diabetes, illustrating the need for improved early diagnosis 5 . The incidence of impaired glucose tolerance in the young also raises further concerns 6 . Individuals with impaired glucose tolerance have a greate...

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus

“…At the cellular level, a significant mediator that leads to injury during DM involves oxidative stress and the release of reactive oxygen species (ROS) (8, 13, 77-80). Several genetic polymorphisms in oxidative stress pathways have recently been linked to the complications of DM (81).…”

Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus

“…As a result, recent investigations have concentrated upon pathways that involve anti-oxidant therapies (3, 23, 27, 30, 53, 71, 75), mammalian forkhead transcription factors (9, 37, 47, 150, 151), protein tyrosine phosphatases (6, 15, 152), and growth factors (11–13, 50, 65, 70, 104). In addition, new therapeutic strategies are now focusing upon the role of extracellular matrix associated proteins such as the CCN family of proteins (153, 154).…”

“…AMPK that phosphorylates TSC2 and inhibits mTORC1 activity (21, 199) can increase the cellular NAD + /NADH ratio leading to the deacetylation of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1α), FoxO1 (37), and FoxO3a (253). AMPK also can increase NAMPT during glucose restriction that results in increased NAD + and decreased levels of nicotinamide (254), an inhibitor of SIRT1 (3). SIRT1 activators, such as resveratrol, also can activate AMPK through SIRT1 dependent and independent mechanisms (253, 255).…”

“…A strong case can be made for clinical programs that assist with the early diagnosis of DM given that a significant portion of the population currently remains undiagnosed with DM (10, 19). Furthermore, the incidence of impaired glucose tolerance in the young also raises additional concerns (3). Individuals with impaired glucose tolerance have more than twice the risk for the onset of diabetic complications than individuals with normal glucose tolerance (20).…”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…Another eight million individuals also have metabolic disorders but remain undiagnosed at present (23–25). Impaired glucose tolerance in the young (5, 26) and the presence of obesity increases the risk of developing DM in these individuals (19). …”