The diabetes gene Hhex maintains δ-cell differentiation and islet function

The homeodomain transcription factor HHEX (hematopoietically expressed homeobox) has been repeatedly linked to type 2 diabetes mellitus (T2DM) using genome-wide association studies. We report here that within the adult endocrine pancreas, Hhex is selectively expressed in the somatostatin-secreting delta cell. Using two mouse models with Hhex deficiency in the endocrine pancreas, we show that Hhex is required for delta-cell differentiation. Decreased somatostatin levels in Hhex-deficient islets cause disrupted paracrine inhibition of insulin release from beta cells. These findings identify Hhex as the first transcriptional regulator specifically required for islet delta cells and suggest compromised paracrine control as a contributor to T2DM.