P-228 Poster of distinction

Metabolic function of a minimal transplanted islet mass in non-human primates on rapamycin monotherapy

S. Soleimanpour¹, B. Hirshberg², D. Bunnell², A. Sumner², M. Ader³, A. Remaley², K. Rother², M. Rickels¹, D. Harlan^4
1 University of Pennsylvania School of Medicine, Philadelphia, PA, USA; ² National Institutes of Health, Besthesda, MD, USA; ³ University of Southern California, Los Angles, CA, USA; ⁴ University of Massachusetts, Worcester, MA, USA

Objective: Although islet transplantation may restore insulin independence to individuals with type 1 diabetes, most do not achieve normal glucose tolerance. We asked whether the defective glucose tolerance is due to inadequate ?-cell mass or to impaired insulin sensitivity.

Methods: We performed metabolic studies on four Cynomolgus primates before inducing diabetes with streptozotocin, then again 1 month after restoring insulin-independence via intrahepatic islet transplantation utilizing a calcineurin inhibitor-free immunosuppressive regimen, i.e. induction with rabbit anti-thymocyte globulin, and maintenance therapy with rapamycin. Engrafted ?-cell mass was assessed by acute insulin and C-peptide responses to glucose (AIR_glu & ACR_glu) and arginine (AIR_arg & ACR_arg). The primates’ insulin sensitivity (S_I) was determined by intravenous glucose tolerance testing and analyzed using the minimal model. Alpha-cell function was determined by the acute glucagon response to arginine (AGR_arg).

Results: S_I did not differ from naïve to post-transplant states, but as shown in Table 1, all parameters reflecting islet mass did differ.

In the post-streptozotocin diabetic primates, AGR_arg was 1020 ± 440 pg/mL (p<0.01 relative to post-transplant).

Conclusions: These data suggest that impaired glucose tolerance observed in islet transplant recipients is secondary to low functional ?-cell mass and not to insulin resistance. Further, our data suggest that improved glycemic control achieved via islet transplantation over the diabetic state might be attained, in part, via suppressed glucagon secretion.

P-228 Poster of distinction

Metabolic function of a minimal transplanted islet mass in non-human primates on rapamycin monotherapy

S. Soleimanpour¹, B. Hirshberg², D. Bunnell², A. Sumner², M. Ader³, A. Remaley², K. Rother², M. Rickels¹, D. Harlan^4
1 University of Pennsylvania School of Medicine, Philadelphia, PA, USA; ² National Institutes of Health, Besthesda, MD, USA; ³ University of Southern California, Los Angles, CA, USA; ⁴ University of Massachusetts, Worcester, MA, USA

Objective: Although islet transplantation may restore insulin independence to individuals with type 1 diabetes, most do not achieve normal glucose tolerance. We asked whether the defective glucose tolerance is due to inadequate ?-cell mass or to impaired insulin sensitivity.

Methods: We performed metabolic studies on four Cynomolgus primates before inducing diabetes with streptozotocin, then again 1 month after restoring insulin-independence via intrahepatic islet transplantation utilizing a calcineurin inhibitor-free immunosuppressive regimen, i.e. induction with rabbit anti-thymocyte globulin, and maintenance therapy with rapamycin. Engrafted ?-cell mass was assessed by acute insulin and C-peptide responses to glucose (AIR_glu & ACR_glu) and arginine (AIR_arg & ACR_arg). The primates’ insulin sensitivity (S_I) was determined by intravenous glucose tolerance testing and analyzed using the minimal model. Alpha-cell function was determined by the acute glucagon response to arginine (AGR_arg).

Results: S_I did not differ from naïve to post-transplant states, but as shown in Table 1, all parameters reflecting islet mass did differ.

In the post-streptozotocin diabetic primates, AGR_arg was 1020 ± 440 pg/mL (p<0.01 relative to post-transplant).

Conclusions: These data suggest that impaired glucose tolerance observed in islet transplant recipients is secondary to low functional ?-cell mass and not to insulin resistance. Further, our data suggest that improved glycemic control achieved via islet transplantation over the diabetic state might be attained, in part, via suppressed glucagon secretion.