Past and current perspective on new therapeutic targets for Type-II diabetes

Abstract

Loss of pancreatic β-cell function is a hallmark of Type-II diabetes mellitus (DM). It is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Recently, United Kingdom Prospective Diabetes Study reported that Type-II DM is a progressive disorder. Although, DM can be treated initially by monotherapy with oral agent; eventually, it may require multiple drugs. Additionally, insulin therapy is needed in many patients to achieve glycemic control. Pharmacological approaches are unsatisfactory in improving the consequences of insulin resistance. Single therapeutic approach in the treatment of Type-II DM is unsuccessful and usually a combination therapy is adopted. Increased understanding of biochemical, cellular and pathological alterations in Type-II DM has provided new insight in the management of Type-II DM. Knowledge of underlying mechanisms of Type-II DM development is essential for the exploration of novel therapeutic targets. Present review provides an insight into therapeutic targets of Type-II DM and their role in the development of insulin resistance. An overview of important signaling pathways and mechanisms in Type-II DM is provided for the better understanding of disease pathology. This review includes case studies of drugs that are withdrawn from the market. The experience gathered from previous studies and knowledge of Type-II DM pathways can guide the anti-diabetic drug development toward the discovery of clinically viable drugs that are useful in Type-II DM.

Leptolide Improves Insulin Resistance in Diet-Induced Obese Mice

“…Glinides stimulate insulin secretion rapidly and for a short period when needed [ 9 ]. Incretins, such as glucagon-like peptide 1 (GLP-1) receptor agonists, gastric inhibitory polypeptide/glucose-dependent insulinotropic peptide (GIP) and dipeptidyl-peptidase-4 (DPP-4) inhibitors, increase insulin secretion and regulate glucose homeostasis [ 10 ]. As the disease progresses, the β-cell function declines, and insulin therapy become necessary.…”

“…Regarding new glucose-lowering therapies, sodium glucose cotransporter 2 (SGLT2) receptor inhibitors lower blood glucose levels in an insulin-independent manner by increasing renal glucose excretion [ 13 ]. Promising new pharmacological targets are currently under evaluation, such as sirtuin agonists, which enhance insulin secretion and/or insulin sensitivity; or the inhibitors of protein tyrosine phosphatase 1B, which prolong the action of insulin [ 10 ].…”

<p>A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus</p>

“…These are ertiprotafib (discontinued in Phase II), TTP814, Alexidine dihydrocloride, trivaric acid, BVT948, TCS401, ISIS-PTP1BRx (Phase II), KQ-791(Phase I), Trodusquemine (Phase I), and IONIS-PTP1BRx (Phase II). [69][70][71]…”

Netrin as a Novel Biomarker and Its Therapeutic Implications in Diabetes Mellitus and Diabetes-Associated Complications

“…It is commonly classified as type 1, type 2, gestational diabetes, and specific types of DM owing to other bases, of which type 2 diabetes is the commonest form. Diabetes has a multifaceted pathogenesis that occurs either due to impaired insulin secretion or due to development of insulin resistance at target tissues and/or wide-ranging destruction of pancreatic β -cells [ 1 , 3 ].…”

“…This unresponsiveness of insulin and pancreatic β -cell damage leads to the failure of insulin to normally regulating dietary metabolism, and the β -cell-associated modifications further induce the cellular signaling cascade. For instance, β -cell dysfunction initiates the stimulation of advanced glycation end products, diacylglycerol kinase pathway, oxidative stress, metabolic stress, and inflammation which in turn reduce the β -cell functioning, causing a sustained rise in blood glucose [ 3 , 4 ]. Once chronic hyperglycemia happens, individuals living with diabetes are highly susceptible to various forms of both short- and long-term complications.…”