Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice

Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth.