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Aims: Resuming insulin use due to waning function is common after islet transplantation. Animal studies suggest that gastrointestinal hormones, including gastrin and incretins may increase β-cell mass. We tested the hypothesis that pantoprazole plus sitagliptin, would restore insulin independence in islet transplant recipients with early graft insufficiency and determined whether this would persist after a 3-month washout., Methods: Single-centre, uncontrolled, open label study of sitagliptin 100 mg daily plus pantoprazole 40 mg twice daily for 6 months., Results: After 6 months of treatment, two of eight participants (25%) achieved the primary endpoint, defined as HbA 1C < 42 mmol/mol (6%), fasting plasma glucose < 7.0 mmol, C-peptide > 0.5 nmol and no insulin use. There was a significant reduction in mean insulin dose, but no change in HbA 1C or weight. There were no changes in the acute insulin response to arginine, the mixed meal tolerance test or blinded continuous glucose monitoring. After the washout, no participants met the primary endpoint and HbA 1C increased from 45 ± 8 mmol/mol (6.3 ± 0.7%) to 51 ± 6 mmol/mol (6.8 ± 0.6%) (P < 0.05). Two participants had mild-moderate transient gastrointestinal side effects. There were no episodes of hypoglycaemia., Conclusions: Sitagliptin plus pantoprazole is well tolerated and safe and may restore insulin independence in some islet transplant recipients with early graft insufficiency, but this was not sustained when treatment was withdrawn. A larger, controlled trial is required to confirm the effectiveness of this combination to achieve insulin independence and to confidently exclude any persistent benefit for graft function. (Clinical Trials Registry No.: NCT00768651)., (© 2016 Diabetes UK.)