Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction

Insulin resistance increases patient’s risk of developing type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and germline Grb14-knockout (KO) mice have improved insulin signaling in liver and muscle tissues. Here, we show that Grb14 knockdown in the liver and the heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and decreased systolic function, effects that could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in hemodynamic function as measured by echocardiography in DIO Grb14 and DIO sham mice for a period of four months. While additional studies are needed to further establish efficacy and to de-risk potential negative cardiac effects in pre-clinical heart failure models, our data support inhibiting Grb14 to treat diabetes and related conditions. We compared 1) Metabolically healthy obese (MHO, n=15) vs metabolically unhealthy obese (MUO, n=15) people, and 2) before vs. after weight loss (n=10).