INS and Insulin resistance: Defects either in the insulin receptor itself, for example, changes in its expression level or activity, in its downstream substrates or molecular regulators of the signalling cascade may lead to impaired activation of the insulin signalling pathway and insulin resistance (Figure 2A).78 However, the numbers of individuals with genetic defects in the insulin receptor are rare, proposing that peripheral insulin resistance is rather caused by defects downstream of the insulin receptor.