Sankyo and Metabasis reached clinical proof of concept with its first-in-class fructose 1,6-bisphosphatase inhibitor. Leaders in the arena of glycogen phsophorylase inhibitors are Pfizer and Sanofi-Aventis with clinical stage projects. Isis is ahead in the field of protein tyrosine phosphatase 1B inhibitors with its 2nd generation antisense project.

Glucokinase activators (GKA) enhance glucose-stimulated insulin release from pancreatic islet cells and glucose disposition by the liver, thus reducing blood glucose and reducing weight as shown by Innodia's ID1101 in phase I. The compound had an excellent safety profile and now serves as an anti-obesity drug candidate.

The stimulation of insulin secretion by GKAs is glucose-dependent which should make it less likely that GKAs cause hypoglycemia. Inhibition of glycogenolysis by glycogen phosphorylase inhibitors (GPI) is another strategy to reduce blood glucose and has attracted the interest of many companies with drug discovery activities. The opposite approach is to inhibit gluconeogenesis by antagonizing the activity of fructose 1,6-bisphosphatase. Sankyo's and Metabasis' CS-917 was shown to cause a clinically significant reduction in blood glucose.

Protein tyrosine phosphatase 1B (PTP-1B) downregulates the insulin receptor. Inhibition of PTP-1B should prevent downregulation of the insulin receptor, thus improving insulin action. Isis showed clinically that its antisense compound could induce insulin sensitizing activity in healthy volunteers. Results of 12-weeks treatment of diabetes patients with ISIS 113715 are expected this year. Small molecule PTP-1B inhibitors are in the pipeline, but do not lead the field after failure of Wyeth's phase II compound. Further novel approaches include a beta3 adrenergic agonist in phase II, a phosphodiesterease 11A inhibitor and a dually acting small molecule in preparation for phase I which increases insulin secretion and peripheral insulin sensitivity.