Incretin Effect and Use After Clinical Islet Transplantation

We aim to study if the administration of medications to increase the secretion of hormones from the intestines can improve glycemic control, reduce insulin use and promote β-cell regeneration/expansion in subjects with type 1 diabetes following islet transplantation who are back using small doses of insulin because of early graft dysfunction. We believe that the results will enable us to understand whether these drugs could be useful in islet transplant recipients, particularly if glycemic control deteriorates.

This is a single centre non-randomized pilot study. Subjects will be recruited from the current cohort of islet transplant recipients at the University of Alberta.

The primary objective off the study is to evaluate whether the combination of sitagliptin and pantoprazole can restore insulin independence in previously insulin independent islet transplant recipients experiencing early graft dysfunction. The study will also evaluate the safety of the combination drug therapy.

• Drug: Pantoprazole
  Starting on Day 1, Pantoprazole 80 mg daily (40 mg every morning and 40 mg every evening) administered orally at the same time each day for a period of 6 months.
  Other Name: Pantoloc
• Drug: Sitagliptin
  Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months.
  Other Name: Januvia

Inclusion Criteria

Subjects must meet the following criteria to be enrolled in this study:

1. Male or female, aged 18 to 70, inclusive, who is a previous islet transplant recipient (at least 3 months since last islet transplant) and who received their transplant at the University of Alberta.
2. Insulin independent for 3 months or longer after islet transplant.

3. Early graft dysfunction as defined by:

   1. HbA1c >6% (but less than 7.5%); or
   2. fasting glucose > 7 mmol/L (126 mg/dl); or
   3. random glucose > 10 mmol/L (180 mg/dl), and
   4. Total insulin use of < 10 units/day.
4. C-peptide positive.
5. Able to provide informed consent.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from the study:

1. Unable to provide informed consent.
2. Prior therapy with sitagliptin or a proton pump inhibitor in the preceding 2 months.
3. Vulnerable populations (i.e. cognitively impaired, pregnant women, residing in institutions, University of Alberta students or employees under the supervision of any of the investigators).

4. Children, adolescent or patients with a "contraindication" or "warning" listed in the package insert of any of the study drugs:

   1. Hypersensitivity to sitagliptin or pantoprazole for any component of the formulation.
   2. Renal disease or renal dysfunction (as suggested by serum creatinine levels ≥ 136 µmol/L (males), ≥ 124 µmol/L (females) or abnormal creatinine clearance; or estimated by GFR <50 ml/min/1.73m2).
   3. Acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).
5. Uncontrolled hyperglycemia
6. Any subject that in the opinion of the investigator would not be a good candidate for study participation.