Open Access Metabolic Function of a Suboptimal Transplanted Islet Mass in Nonhuman Primates on Rapamycin Monotherapy

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Abstract:

Although islet transplantation may restore insulin independence to individuals with type 1 diabetes mellitus, most have abnormal glucose tolerance. We asked whether the defective glucose tolerance is due to inadequate β-cell mass or to impaired insulin sensitivity. We performed metabolic studies on four cynomolgus primates before inducing diabetes with streptozotocin (STZ), then again 2‐3 weeks after restoring insulin independence via intrahepatic islet transplantation utilizing a calcineurin inhibitor-free immunosuppressive regimen (induction with rabbit antithymocyte globulin and maintenance therapy with rapamycin). Engrafted β-cell mass was assessed by acute insulin and C-peptide responses to glucose (AIRglu and ACRglu) and arginine (AIRarg and ACRarg). Insulin sensitivity (SI) was determined in naive and transplanted primates from an intravenous glucose tolerance test using the minimal model. α-Cell function was determined by the acute glucagon response to arginine (AGRarg). Glucose tolerance (Kg ) decreased from 4.1 ± 0.5%/min in naive primates to 1.8 ± 0.3%/min in transplanted primates (p < 0.01). Following transplantation, AIRglu was 28.7 ± 13.1 μU/ml compared to 169.9 ± 43.1 μU/ml (p < 0.03) in the naive condition, ACRglu was 14.5 ± 6.0 ng/ml compared to 96.5 ± 17.0 ng/ml naive (p < 0.01), AIRarg was 29.1 ± 13.1 μU/ml compared to 91.4 ± 28.2 μU/ml naive (p < 0.05), and ACRarg was 1.11 ± 0.51 ng/ml compared to 2.79 ± 0.77 ng/ml naive (p < 0.05). SI did not differ from naive to posttransplant states. AGRarg was reduced in transplanted primates (349 ± 118 pg/ml) when compared to both naive (827 ± 354 pg/ml) and post-STZ diabetic primates (1020 ± 440 pg/ml) (p < 0.01 for both comparisons). These data suggest that impaired glucose tolerance observed in islet transplant recipients is secondary to low functional β-cell mass and not to insulin resistance shortly after transplant. Furthermore, improved glycemic control achieved via islet transplantation over the diabetic state might be attained, in part, via reduced glucagon secretion.

Keywords: Islet transplantation; Metabolic function; Nonhuman primates

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368911X603620

Affiliations: 1: Islet and Autoimmunity Branch, NIDDK, NIH, Bethesda, MD, USA 2: Diabetes, Endocrinology, and Obesity Branch, NIDDK, NIH, Bethesda, MD, USA 3: Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA, USA 4: Department of Laboratory Medicine, NIH, Bethesda, MD, USA 5: Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Publication date: June 1, 2012

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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