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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 δ cell. Using two mouse models with  Hhex  deficiency in the endocrine pancreas, we show that  Hhex  is required for δ-cell differentiation. Decreased somatostatin levels in  Hhex -deficient islets cause disrupted paracrine inhibition of insulin release from β cells. These findings identify Hhex as the first transcriptional regulator specifically required for islet δ cells and suggest compromised paracrine control as a contributor to T2DM.

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