Future Prospects of Wnt-Targeted Therapy for Treatment of Type 2 Diabetes

Question
I just read a recent publication ( Experimental Diabetes Research , Volume 2008) from researchers at the University of California, San Diego concerning the role of the Wnt signaling pathway as a possible upregulator in the expression of c-myc, possibly leading to the destruction of insulin-producing beta cells. On the basis of research currently ongoing on the targeted inhibition of this pathway in various cancers, eg, breast, could you comment on the future prospects of a targeted therapy for the treatment of type 2 diabetes?

Response from George Y. Chao, MD Medical Director, Diabetes Program, Memorial Hospital, Modesto, California; Chief, Division of Endocrinology, Sutter Gould Medical Foundation, Modesto, California

Type 2 diabetes (type 2 DM) is a progressive disease with gradual deterioration of beta-cell function. Insulin resistance can be demonstrated many years before the onset of type 2 DM. Data from the United Kingdom Prospective Diabetes Study (UKPDS) showed, on average, approximately 4% of beta-cell function decline per year in patients with type 2 DM.^[1]

Currently, no pharmacologic therapy has been shown to arrest beta-cell function decline. Studies have shown that both beta-cell number and function diminish over time in patients with type 2 DM.^[2] Glucotoxicity, lipotoxicity, and other theories have been postulated to be the causes of beta-cell dysfunction, but the exact mechanisms of the decline remain elusive. The proto-oncogene, c-myc, plays an important role in cell differentiation/apoptosis, and has been reported to be upregulated in the beta cells of patients with type 2 DM.^[3] Additionally, hyperglycemia and insulin resistance have been implicated in the upregulation of c-myc. It has been postulated that the upregulation of c-myc in beta cells enhances beta-cell growth, but also leads to a loss of beta-cell differentiation and premature apoptosis.^[3]

A recent article by Lee and colleagues^[4] demonstrated that the Wnt signaling pathway is upregulated in the islet cells of patients with type 2 DM, but not in patients without diabetes. Moreover, the addition of an antagonist of Wnt prevented the overexpression of the pathway and normalized the level of c-myc, the Wnt target gene.

The above observation, if confirmed in larger studies, will provide further understanding of the pathogenesis of beta-cell dysfunction in type 2 DM. More importantly, it will allow us to search for antagonists that provide targeted, selective inhibition of the Wnt pathway to treat type 2 DM.

This activity is supported by an independent educational grant from Novo Nordisk.