Target Sites of Novel Antidiabetic Agents for the Treatment of Type 2 Diabetes Mellitus

Abstract

In the last few years there have been revolutionary changes in the therapy of Diabetes mellitus. A new rapid acting insulin analog [Lys (B28), Pro (B29)] human insulin (LYSPRO) and a technique for transplantation of pancreas and /or islet cells have been developed. A number of alternatives to injecting insulin are being investigated including oral insulin, inhaled insulin, insulin pump and gene therapy. In spite of the advances in therapeutics, diabetes mellitus still remains a major cause of morbidity and mortality in the world. The understanding that the disease is a metabolic syndrome of interrelated symptoms has instigated the researchers to discover a unique solution that would effectively address these issues in one goal. The discovery of dual PPAR agonists with an unknown optimized ratio of PPAR- γ and α with lesser side effects may be a step forward to this direction. PPAR PAN agonist or partial PPAR- γ agonist concepts might also lead to discovery of novel agents with no side ceffects. Other mechanisms which target insulin secretion without excessive use of the pancreas and which effect insulin biosynthesis, may offer a better solution, including inhibition of DPP-IV or modulation of GLP-1. After the introduction of TZDs as insulin sensitizer, peptidase resistant GLP-1 peptides seem to be major breakthrough for the treatment of type 2 diabetes mellitus (T2DM). The choice of appropriate PTPases to target may be another major break through. Inhibition of HGO has not been strictly validated in the clinic since metformin has multiple actions in muscle and liver of glucose metabolism by AMPK activators may have broader impact but proof of concept is yet elusive. The hypothesis that active glucocorticoid cortisol can repair impaired glucose metabolism and that selective inhibition of 11β-HSD-1 could ameliorate excessive hepatic glucose output and improve peripheral glucose uptake by preventing the conversion of cortisone to cortisol, could take an important position in drug discovery research. The prevention or reversal of insulin resistance and glucose intolerance before the onset of overt T2DM will likely become the next target. It seems that in near future, the drugs with multiple targets will be the drugs of choice to combat the epidemic of T2DM and its associated disorders.