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Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic GluCreERT2;ROSA26-eYFP mice

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Sarnobat, Dipak 
Moffett, R Charlotte 
Gault, Victor A 
Tanday, Neil 


Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P<0.05 to P<0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P<0.05 and P<0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P<0.05) apoptosis and increased (P<0.05 to P<0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P<0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P<0.01 and P<0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P<0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues.



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Medical Research Council (MC_UU_12012/3)
Wellcome Trust (106262/Z/14/Z)