The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Insulin Receptor Substrate 2 (IRS2) polynucleotides, in particular, by targeting natural antisense polynucleotides of Insulin Receptor Substrate 2 (IRS2) polynucleotides and Transcription factor E3 (TFE3). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of IRS2.