Novel directions for diabetes mellitus drug discovery

Abstract

Introduction: Diabetes mellitus impacts almost 200 million individuals worldwide and leads to debilitating complications. New avenues of drug discovery must target the underlying cellular processes of oxidative stress, apoptosis, autophagy, and inflammation that can mediate multi-system pathology during diabetes mellitus.

Areas covered: The authors examine the novel directions for drug discovery that involve: the β-nicotinamide adenine dinucleotide (NAD(+)) precursor nicotinamide, the cytokine erythropoietin, the NAD(+)-dependent protein histone deacetylase SIRT1, the serine/threonine-protein kinase mammalian target of rapamycin (mTOR), and the wingless pathway. Furthermore, the authors present the implications for the targeting of these pathways that oversee gluconeogenic genes, insulin signaling and resistance, fatty acid beta-oxidation, inflammation, and cellular survival.

Expert opinion: Nicotinamide, erythropoietin, and the downstream pathways of SIRT1, mTOR, forkhead transcription factors, and wingless signaling offer exciting prospects for novel directions of drug discovery for the treatment of metabolic disorders. Future investigations must dissect the complex relationship and fine modulation of these pathways for the successful translation of robust reparative and regenerative strategies against diabetes mellitus and the complications of this disorder.

Figure 1. Nicotinamide, erythropoietin, and wingless modulation of diabetes mellitus

During diabetes mellitus (DM), elevated glucose leads to oxidative stress and results in the activation of “pro-apoptotic” proteins Bad, Bax, and forkhead transcription factors (FoxOs). Activation of these pathways subsequently impairs mitochondrial (Mito) membrane potential to result in cytochrome c release and caspase activation. Nicotinamide (NIC) prevents cell injury by maintaining mitochondrial membrane potential and modulating Bad, Bax, and FoxO to prevent cytochrome c release from mitochondria and block caspase activation. NIC also may be beneficial during DM through the protection of β-cells and promoting insulin secretion. The cytokine EPO is another therapeutic target that can limit cell injury during DM. EPO can promote the activation of protein kinase B (Akt) that inhibits the activity of FoxO and glycogen synthase kinase-3β (GSK-3β) by phosphorylating (p) these entities. EPO maintains the integrity of wingless pathways, such as Wnt1, during elevated glucose and relies upon Wnt1 to inactivate GSK-3β through phosphorylation (p) that ultimately protects the “anti-apoptotic” properties of β-catenin and prevents its degradation.

Figure 2. The intimate relationship among SIRT1, mTOR, and FoxOs during diabetes mellitus

Following the induction of oxidative stress during diabetes mellitus (DM), insulin resistance can ensue. Activation of SIRT1 can alter insulin sensitivity and increase the secretion of insulin by repressing the mitochondrial uncoupling protein 2 (UCP2), promote lypolysis by mediating peroxisome proliferators-activated receptor-γ (PPAR-α), and increase gluconeogenesis and lipid homeostasis by regulating proliferators-activated receptor-γ coactivator (PGC)-1α. In addition, increased activity of forkhead transcription factors (FoxOs) can increase gene transcription of PGC-1α and also SIRT1 to regulate insulin sensitivity and glucose metabolism. Yet, FoxOs can have an inverse relationship with SIRT1 and may prevent lipolysis through inhibition of PPAR-α. During DM, the activity of the serine/threonine protein kinase mammalian target of rapamaycin (mTOR) may be blocked. Activation of mTOR and its downstream pathways of p70S6K promote the secretion of insulin and increase insulin sensitivity. If mTOR activity is inhibited, such as during rapamycin application, insulin sensitivity and glucose uptake are reduced although obesity may be averted.

Figure 3. Novel clinical pathways for drug development during diabetes mellitus

Nicotinamide (NIC) can maintain poly (ADP-ribose) polymerase-1 (PARP-1) homeostasis, restore NAD⁺ and ATP levels, enhance T-cell immune function, and lead to the prevention of diabetic neuropathy. NIC can limit reactive oxygen species (ROS) generation and oxidative stress during diabetes mellitus (DM) to assist with β-cell protection and also reduce HbA_1C levels. NIC can function as a feedback mechanism to inhibit SIRT1 and activate the mammalian target of rapamycin (mTOR) to promote insulin sensitivity and maintain β-cell function. However, high concentrations of NIC may be detrimental to cell survival by limiting the activity of SIRT1 that is necessary for food intake regulation and cellular metabolism. Erythropoietin (EPO) can limit cognitive decline, promote neurite outgrowth, and increase cardiac function during DM that may function through the ability of EPO to modulate SIRT1 activity and foster cellular protection. EPO also directly or through Wnt1 increases mTOR activity to maintain β-cell survival and insulin sensitivity. Following Wnt1 activation, Wnt1 can promote vascular protection and reduce complications of DM, such as cardiac and brain ischemic injury. Wnt1 also governs Wnt1 inducible signaling pathway protein 1 (WISP1) that may assist with β-cell regeneration and proliferation.