Comment on Goldsworthy et al. Haploinsufficiency of the Insulin Receptor in the Presence of a Splice-Site Mutation in Ppp2r2a Results in a Novel Digenic Mouse Model of Type 2 Diabetes. Diabetes 2016;65:1434–1446

We have read with great interest the recently published article by Goldsworthy et al. (1), which provides novel relevant findings about the role of protein phosphatase 2A (PP2A) in diabetes development. In this elegant work, the authors showed that the presence of an alternative splicing of the Ppp2r2a gene in mice heterozygous for a null allele of the insulin receptor resulted in a digenic mouse model of type 2 diabetes. Interestingly, the alternative splicing of Ppp2r2a reduced the protein levels of this PP2A regulatory subunit, an event that correlated with decreased AKT expression and enhanced AKT phosphorylation status.

PP2A is a largely reported tumor suppressor that is functionally inactivated in a wide variety of human cancers, such as colorectal, breast, and prostate cancer. Of importance, the risk of developing these tumor types is significantly higher in patients with type 2 diabetes. Lifestyle risk factors, including diet and obesity, play relevant roles in the etiology of both diseases (2). In fact, it has been recently reported that a high-fat diet and obesity increased the development and aggressiveness of breast cancer tumors in vivo and that the oral administration of FTY720 (fingolimod) suppressed these effects (3). FTY720 is an immunosuppressant that is approved by the U.S. Food and Drug Administration and is currently used for the treatment of multiple sclerosis (4). It has shown marked anticancer properties in many tumors with reported PP2A-inhibited status (5). Moreover, FTY720 has been showing promising antidiabetes effects by preventing the development of diabetes and increasing the pancreatic β-cell mass to normoglycemic control levels (6,7).

In fact, alterations affecting PP2A represent a common event linking diabetes and cancer, and its pharmacological modulation emerges as a novel therapeutic approach for the treatment of both malignancies. Thus, the antidiabetes drug metformin has been described to induce PP2A activity and potent antitumor effects in colorectal and prostate cancer, among others (2,8). However, a recent study reported that metformin could increase the risk of tauopathies in elderly patients with diabetes (9). In conclusion, the work by Goldsworthy et al. (1) highlights the relevant role of PP2A in diabetes, further supporting the potential clinical use of the PP2A activator FTY720 to simultaneously treat diabetes and cancer and its potential benefits to decrease the risk of cancer development in patients with diabetes.