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

Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, 200 Lothrop St, BST E1140, Pittsburgh, PA 15261, USA.
Diabetologia (Impact Factor: 6.67). 10/2010; 54(3):572-82. DOI: 10.1007/s00125-010-1919-1
Source: PubMed


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

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    • "As such, strategies that simultaneously enhance b cell mass and glucose signaling can be of great therapeutic utility. Beyond stimulating insulin secretion, increased b cell glucose metabolism stimulates b cell mass, at least in part, through mitogenic effects (Levitt et al., 2011; Porat et al., 2011; Terauchi et al., 2007). These observations suggest shared molecular control of both b cell mass and function by glucose. "
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    • "In rodents, DPP-4 inhibitors were reported to increase the proliferation of beta cells.1,2,24 In our study, alogliptin treatment also stimulated human beta cell proliferation within the islet grafts by approximately 10-fold, a similar magnitude of induction that we and others have reported for engrafted human beta cells in response to hyperglycemia.25,26 Together these data may suggest that human beta cells, even from older individuals, can be induced to proliferate in vivo in response to certain inductive stimuli, albeit at a much lower level than observed in rodents. "
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