Novel pharmacological approaches to the treatment of type 2 diabetes.

The huge increase in type 2 diabetes is a burden worldwide. Many marketed compounds do not address relevant aspects of the disease; they may already compensate for defects in insulin secretion and insulin action, but loss of secreting cells (β-cell destruction), hyperglucagonemia, gastric emptying, enzyme activation/inhibition in insulin-sensitive cells, substitution or antagonizing of physiological hormones and pathways, finally leading to secondary complications of diabetes, are not sufficiently addressed. In addition, side effects for established therapies such as hypoglycemias and weight gain have to be diminished. At present, nearly 1000 compounds have been described, and approximately 180 of these are going to be developed (already in clinical studies), some of them directly influencing enzyme activity, influencing pathophysiological pathways, and some using G-protein-coupled receptors. In addition, immunological approaches and antisense strategies are going to be developed. Many compounds are derived from physiological compounds (hormones) aiming at improving their kinetics and selectivity, and others are chemical compounds that were obtained by screening for a newly identified target in the physiological or pathophysiological machinery. In some areas, great progress is observed (e.g., incretin area); in others, no great progress is obvious (e.g., glucokinase activators), and other areas are not recommended for further research. For all scientific areas, conclusions with respect to their impact on diabetes are given. Potential targets for which no chemical compound has yet been identified as a ligand (agonist or antagonist) are also described.