Insights on effects of Wnt pathway modulation on insulin signaling and glucose homeostasis for the treatment of type 2 diabetes mellitus: Wnt activation or Wnt inhibition?

Type 2 diabetes mellitus (T2DM) is a major worldwide chronic disease and can lead to serious diabetic complications. Despite the availability of many anti-diabetic agents in the market, they are unable to meet the long-term treatment goals. Also, they cause many side effects which justify the need for novel class of anti-diabetic drugs with newer mechanism of action. Wnt signaling is one of such novel target pathways which can be explored for metabolic disorders. Many key components of the Wnt signaling are involved in the regulation of glucose homeostasis. Polymorphism in the Transcription factor 7-like 2 (TCF7L2) gene, and mutations in the LRP5 (LDL Receptor Related Protein 5) gene lead to disturbed glucose metabolism and obesity. Despite of several years of research in this field, there is no concrete proof of concept available on whether Wnt activation or Wnt inhibition is the beneficial approach for the treatment of T2DM. Here, we have summarized the conclusions of relevant published research studies to give structured insights into possibilities to explore Wnt modulation as a novel target pathway for the treatment of T2DM. The review also highlights the present challenges and future opportunities towards the development of anti-diabetic small molecules targeting the Wnt signaling pathway.