INSR and Hyperglycemia: However, studies with 6-month old global insulin receptor knockout mice (IRKO-L1) that were made euglycemic by the expression of the human insulin receptor transgene in the pancreas, liver and brain, thereby allowing to distinguish the effects of reduced insulin receptor signaling from those of hyperglycemia on the bone, demonstrated that reduced insulin receptor signaling is not a major factor contributing to reduced bone density in T1D [62].