INSR and Hyperglycemia: Other studies show that clozapine induces insulin resistance by directly impairing insulin receptor (IR) activity and downstream signalling events (ie reduced IR substrate-1 (IRS-1) phosphorylation) in mouse skeletal muscle [11], while olanzapine was shown to upregulate mRNA expression of key gluconeogenic enzymes, leading to hyperglycemia and insulin resistance in rats [12].