Direct genetic evidence for a role of β-cell derived insulin in the modulation of α-cell responses was provided by Kawamori et al. who demonstrated that insulin binding to its receptor on α-cells modulates glucagon secretion (but not α-cell mass), a coupling that is lost in obesity-induced insulin resistance and that contributes to the hyperglucagonemia measured in patients with T2D [32–34]. This evidence concerns the gene INS and type 2 diabetes mellitus.