Article

Diabetologia

, Volume 54, Issue 3, pp 572-582

Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD–severe combined immunodeficiency (SCID) mice

  • H. E. LevittAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
  • , T. J. CyphertAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
  • , J. L. PascoeAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
  • , D. A. HollernAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
  • , N. AbrahamAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
  • , R. J. LundellAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
  • , T. RosaAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
  • , L. C. RomanoAffiliated withDivision of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh
  • , B. ZouAffiliated withDivision of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh
    • , C. P. O’DonnellAffiliated withDivision of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh
    • , A. F. StewartAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
    • , A. Garcia-OcañaAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine
    • , L. C. AlonsoAffiliated withDivision of Endocrinology and Metabolism, University of Pittsburgh School of Medicine Email author 

Abstract

Aims/hypothesis

We determined whether hyperglycaemia stimulates human beta cell replication in vivo in an islet transplant model

Methods

Human islets were transplanted into streptozotocin-induced diabetic NOD–severe combined immunodeficiency mice. Blood glucose was measured serially during a 2 week graft revascularisation period. Engrafted mice were then catheterised in the femoral artery and vein, and infused intravenously with BrdU for 4 days to label replicating beta cells. Mice with restored normoglycaemia were co-infused with either 0.9% (wt/vol.) saline or 50% (wt/vol.) glucose to generate glycaemic differences among grafts from the same donors. During infusions, blood glucose was measured daily. After infusion, human beta cell replication and apoptosis were measured in graft sections using immunofluorescence for insulin, and BrdU or TUNEL.

Results

Human islet grafts corrected diabetes in the majority of cases. Among grafts from the same donor, human beta cell proliferation doubled in those exposed to higher glucose relative to lower glucose. Across the entire cohort of grafts, higher blood glucose was strongly correlated with increased beta cell replication. Beta cell replication rates were unrelated to circulating human insulin levels or donor age, but tended to correlate with donor BMI. Beta cell TUNEL reactivity was not measurably increased in grafts exposed to elevated blood glucose.

Conclusions/interpretation

Glucose is a mitogenic stimulus for transplanted human beta cells in vivo. Investigating the underlying pathways may point to mechanisms capable of expanding human beta cell mass in vivo.

Keywords

Glucose Human islets Hyperglycaemia Insulin Mitosis NOD-SCID mice Proliferation Replication Transplantation