Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

Abstract

Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

Keywords: AMP activated protein kinase (AMPK); Akt; Alzheimer's disease; CCN family; FRAP1; FoxO; Wnt; Wnt1 inducible signaling pathway protein 1 (WISP1); apoptosis; autophagy; cancer; cardiovascular disease; caspase; diabetes mellitus; epidermal growth factor; erythropoietin; fibroblast growth factor; forkhead transcription factors; hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1/TSC2); insulin; mTOR Complex 1 (mT ORC1); mTOR Complex 2 (mTORC2); mechanistic target of rapamycin (mTOR); nicotinamide; nicotinamide adenine dinucleotide (NAD+); non-communicable diseases; oxidative stress; phosphoinositide 3-kinase (PI 3-K); programmed cell death; silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1); sirtuin; stem cells; wingless; β-cell.

Figure 1

mTOR controls the structure and function of mTORC1 and mTORC2 to ultimately impact programmed cell death in diabetes mellitus through apoptosis and autophagy. The mechanistic target of rapamycin (mTOR) is a critical element of both mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). mTORC1 is composed of mTOR, Raptor (Regulatory-Associated Protein of mTOR), the proline rich Akt substrate 40 kDa (PRAS40), the mammalian lethal with Sec13 protein 8 (mLST8/G L), and Deptor (DEP domain-containing mTOR interacting protein). mTORC2 consists of mTOR, Rictor (Rapamycin-Insensitive Companion of mTOR), the mammalian stress-activated protein kinase interacting protein (mSIN1), the protein observed with Rictor-1 (Protor-1), Deptor, and mLST8. Activation of mTOR can block apoptotic cell injury while inhibition of mTOR can lead to the induction of autophagy that affects insulin resistance and inflammation.

Figure 2

mTOR signaling in diabetes mellitus is intimately tied to several critical pathways that can govern cellular metabolism. The mTOR signaling axis relies upon phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and the growth factors epidermal growth factor (EGF), fibroblast growth factor (FGF), and erythropoietin (EPO) to regulate metabolic pathways. mTOR and its related signaling pathways can oversee metabolic homeostasis, stem cell maintenance and viability, insulin secretion and resistance, apoptosis, autophagy, and pancreatic β-cell mass and function.