Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes

Abstract

Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.

Keywords: AMP activated protein kinase (AMPK); Alzheimer's disease; SARS-CoV-2; apoptosis; autophagy; circadian rhythm; clock genes; coronavirus disease 2019 (COVID-19); dementia; diabetes mellitus; erythropoietin; mechanistic target of rapamycin (mTOR); metformin; oxidative stress; poly-ADP-ribose polymerase (PARP); silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1); sirtuin; stem cells.

Figure 1:. Downstream Nicotinamide Pathways during Metabolic Disease.

During metabolic disease and diabetes mellitus, nicotinamide employs the pathways of the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), erythropoietin (EPO), and clock genes to maintain glucose homeostasis, enhance glucose utilization, oversee pathways of autophagy, and foster mitochondrial function. These pathways have complex interactions and involve feedback mechanisms that require a fine balance in activity to enhance cellular function and survival, block oxidative stress, and limit potential detrimental outcomes.