Hyperglycemia-Induced Proliferation of Adult Human Beta Cells Engrafted Into Spontaneously Diabetic Immunodeficient NOD-Rag1null IL2rγnull Ins2Akita Mice

1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 2Department of Pathology, University of Florida, Gainesville, FL 3Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 4The Jackson Laboratory, Bar Harbor, ME.
Pancreas (Impact Factor: 2.96). 10/2011; 40(7):1147-9. DOI: 10.1097/MPA.0b013e31821ffabe
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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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    ABSTRACT: Dipeptidyl-peptidase-4 (DPP-4) inhibitors are known to increase insulin secretion and beta cell proliferation in rodents. To investigate the effects on human beta cells in vivo, we utilize immunodeficient mice transplanted with human islets. The study goal was to determine the efficacy of alogliptin, a DPP-4 inhibitor, to enhance human beta cell function and proliferation in an in vivo context using diabetic immunodeficient mice engrafted with human pancreatic islets. Streptozotocin-induced diabetic NOD-scid IL2rγ(null) (NSG) mice were transplanted with adult human islets in three separate trials. Transplanted mice were treated daily by gavage with alogliptin (30 mg/kg/day) or vehicle control. Islet graft function was compared using glucose tolerance tests and non-fasting plasma levels of human insulin and C-peptide; beta cell proliferation was determined by bromodeoxyuridine (BrdU) incorporation. Glucose tolerance tests were significantly improved by alogliptin treatment for mice transplanted with islets from two of the three human islet donors. Islet-engrafted mice treated with alogliptin also had significantly higher plasma levels of human insulin and C-peptide compared to vehicle controls. The percentage of insulin+BrdU+ cells in human islet grafts from alogliptin-treated mice was approximately 10-fold more than from vehicle control mice, consistent with a significant increase in human beta cell proliferation. Human islet-engrafted immunodeficient mice treated with alogliptin show improved human insulin secretion and beta cell proliferation compared to control mice engrafted with the same donor islets. Immunodeficient mice transplanted with human islets provide a useful model to interrogate potential therapies to improve human islet function and survival in vivo.
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    ABSTRACT: The availability of immunodeficient mice engrafted with functional human immune systems and islets permits in vivo study of human diabetes without putting patients at risk.
    Preview · Article · Dec 2011 · Annals of the New York Academy of Sciences
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    ABSTRACT: Despite decades of studying rodent models of type 1 diabetes (T1D), no therapy capable of preventing or curing T1D has successfully been translated from rodents to humans. This inability to translate otherwise promising therapies to clinical settings likely resides, to a major degree, from significant species-specific differences between rodent and human immune systems as well as species-related variances in islets in terms of their cellular composition, function, and gene expression. Indeed, taken collectively, these differences underscore the need to define interactions between the human immune system with human β cells. Immunodeficient mice engrafted with human immune systems and human β cells represent an interesting and promising opportunity to study these components in vivo. To meet this need, years of effort have been extended to develop mice depleted of undesirable components while at the same time, allowing the introduction of constituents necessary to recapitulate physiological settings as near as possible to human T1D. With this, these so-called "humanized mice" are currently being used as a preclinical bridge to facilitate identification and translation of novel discoveries to clinical settings.
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