Novel targets for potential therapeutic use in Diabetes mellitus

Abstract

Future targets are a promising prospect to overcome the limitation of conventional and current approaches by providing secure and effective treatment without compromising patient compliance. Diabetes mellitus is a fast-growing problem that has been raised worldwide, from 4% to 6.4% (around 285 million people) in past 30 years. This number may increase to 430 million people in the coming years if there is no better treatment or cure is available. Ageing, obesity and sedentary lifestyle are the key reasons for the worsening of this disease. It always had been a vital challenge, to explore new treatment which could safely and effectively manage diabetes mellitus without compromising patient compliance. Researchers are regularly trying to find out the permanent treatment of this chronic and life threatening disease. In this journey, there are various treatments available in market to manage diabetes mellitus such as insulin, GLP-1 agonist, biguanides, sulphonyl ureas, glinides, thiazolidinediones targeting the receptors which are discovered decade before. PPAR, GIP, FFA1, melatonin are the recent targets that already in the focus for developing new therapies in the treatment of diabetes. Inspite of numerous preclinical studies very few clinical data available due to which this process is in its initial phase. The review also focuses on the receptors like GPCR 119, GPER, Vaspin, Metrnl, Fetuin-A that have role in insulin regulation and have potential to become future targets in treatment for diabetes that may be effective and safer as compared to the conventional and current treatment approaches.

Keywords: Diabetes mellitus; New drug molecules; Novel targets; Unexplored targets.

Fig. 1

Roles of different conventional targets in diabetes mellitus

Fig. 2

Mechanism of PPAR

Fig. 3

Role of GIP in diabetes

Fig. 4

GIP mediated mechanism for insulin secreation from β-cells

Fig. 5

Mechanism of GPR119

Fig. 6

Pharmacological effects of FFA-1 receptors

Fig. 7

Incretin release is stimulated by the glucose present in the small intestine, then incretins are passed to their target tissue is the pancreas, to stimulate the β- cells lead them to release additional insulin in action to the equal volume of blood glucose [47]

Fig. 8

There is an increased production of Melatonin in T1DM (Type-1 diabetes mellitus) due to the activation of enzyme cascade which causes reduced β- cell function which then reduces the formation of insulin and rises the amount of glucagon in cells resulting in high blood glucose. Then in T2DM, the decreased production of Melatonin causes the increase in mRNA expression of melatonin membrane receptor which leads to the impaired insulin signaling that causes a upsurge in the insulin level leading to beta-cell exhaustion with high glucagon concentration leading to hyperglycemia

Fig. 9

Working of 11β- HSD1

Fig. 10

Role of ARCP30 in diabetes

Fig. 11

Role of Fetuin-A diabetes and other metabolic disorders

Fig. 12

Mechanism of Fetuin-A in diabetes

Fig. 13

Role of visfatin in glucose homeostasis

Fig. 14

Metrnl is involved in various pharmacological pathways through intracellular signalling between the cells. In nerve cells, it promotes the neurite outgrowth via the JAKSTAT3 and MEK-ERK signalling pathway. In fat cells due to upregulation of the Metrnl increases the lipid metabolism, relieves from the high-fat diet-induced inflammation and improves adipose remodeling through upregulation of PPARγ, due to which the insulin resistance is also improved. In muscle cells or myocytes it increases the PPARγ signalling which increases the phosphorylation of AMPK due to increased intracellular calcium and also encourages the phosphorylation of TBC1D1, HDAC5, and p38 MAPK in an AMPK-mediated manner, then promotes the expression and translocation of GLUT4, which thus improves the insulin sensitivity and reduces the inflammation [103]

Fig. 15

FFA: free fatty acids, INSR: Insulin receptor, IRS: insulin receptor substrate, JAK2: Janus kinase, LeptinR: Leptin receptor, NFκB: nuclear factor κ B, SOCS3: suppressor of cytokine signalling 3, TLR: toll-like receptor

Fig. 16

Role of vaspin in different organs linked to diabetes mellitus

Fig. 17

Role of GPER in different body organs affecting diabetes mellitus

Fig. 18

Systemic representation of the characteristics of cell-based gene therapy procedures in diabetes treatment [128]