Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia

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Abstract
Insulin gene expression is restricted to islet β cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors1,2. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function3. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes4,5,6,7. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by ‘loss-of-function’ studies8,9,10,11. We used a ‘gain-of-function’ approach to test whether PDX-1 could endow a non-islet tissue with pancreatic β-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a β-cell phenotype, may provide a valuable approach for generating ‘self’ surrogate β cells, suitable for replacing impaired islet-cell function in diabetics.