IRS1 and obesity due to melanocortin 4 receptor deficiency: Hyperinsulinemia can lead to downregulated insulin signaling through means such as inducing receptor degradation, altering phosphorylation patterns of insulin signaling effector molecules (e.g., IRS-1, Akt, PI3K) in target tissues or indirectly by promoting obesity (Shanik et al. 2008, Nolan & Prentki 2019, Johnson 2021).