Title | Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD-severe combined immunodeficiency (SCID) mice. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Levitt HE, Cyphert TJ, Pascoe JL, Hollern DA, Abraham N, Lundell RJ, Rosa T, Romano LC, Zou B, O'Donnell CP, Stewart AF, Garcia-Ocaña A, Alonso LC |
Journal | Diabetologia |
Volume | 54 |
Issue | 3 |
Pagination | 572-82 |
Date Published | 2011 Mar |
ISSN | 1432-0428 |
Keywords | Adult, Animals, Apoptosis, Blood Glucose, Cell Proliferation, Child, Female, Humans, Hyperglycemia, In Situ Nick-End Labeling, Insulin-Secreting Cells, Islets of Langerhans Transplantation, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged |
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. |
DOI | 10.1007/s00125-010-1919-1 |
Alternate Journal | Diabetologia |
PubMed ID | 20936253 |
PubMed Central ID | PMC3034833 |
Grant List | K08 DK076562 / DK / NIDDK NIH HHS / United States K08 DK076562-05 / DK / NIDDK NIH HHS / United States R01 DK077096 / DK / NIDDK NIH HHS / United States R01 DK55023 / DK / NIDDK NIH HHS / United States |