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Gene Transfer of Constitutively Active Akt Markedly Improves Human Islet Transplant Outcomes in Diabetic Severe Combined Immunodeficient Mice

¹ Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, Rangos Research Center, Pittsburgh, Pennsylvania
³ Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Akt is an important intracellular mediator of ß-cell growth and survival in rodents. However, whether constitutive activation of Akt in human ß-cells enhances the survival and function of transplanted islets is unknown. In the current study, we examined the efficacy of constitutive activation of Akt in improving human islet transplant outcomes using a marginal mass model in diabetic severe combined immunodeficient (SCID) mice. Human islets transduced with adenoviruses encoding constitutively active Akt1 (Adv-CA-Akt) displayed increased total and phosphorylated Akt and Akt kinase activity compared with control islets. Expression of CA-Akt in human islets induced a significant increase in ß-cell replication and a significant decrease in ß-cell death induced by serum and glucose deprivation or chronic hyperglycemia. Two control groups of islets (1,500 uninfected or adenovirus LacZ [Adv-LacZ]–transduced human islet equivalents [IEQs]) transplanted under the kidney capsule of streptozotocin-induced diabetic SCID mice were insufficient to correct hyperglycemia. Importantly and in marked contrast to these controls, 1,500 Adv-CA-Akt–transduced IEQs were capable of restoring euglycemia in diabetic SCID mice. Moreover, blood glucose normalization persisted for at least 6 months. Human plasma insulin at day 54 after transplant was 10-fold higher in Adv-CA-Akt islet recipients (2.4 ± 0.4 ng/ml) compared with those receiving Adv-LacZ islets (0.25 ± 0.08 ng/ml) (P < 0.05). In summary, expression of CA-Akt in human islets improves islet transplant outcomes in a subcapsular renal graft model in SCID mice. Akt is an attractive target for future strategies aimed at reducing the number of islets required for successful islet transplantation in humans.

Abbreviations: Adv-CA-Akt; adenovirus encoding constitutively active Akt1; Adv-LacZ, adenovirus LacZ; BrdU, bromodeoxyuridine; CK-19, cytokeratin-19; FBS, fetal bovine serum; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; GSIS, glucose-stimulated insulin secretion; GSK, glycogen synthase kinase; HGF, hepatocyte growth factor; IEQ, islet equivalent; IPGTT, intraperitoneal glucose tolerance test; MOI, multiplicity of infection; PI3K, phosphatidylinositol 3'-kinase; STZ, streptozotocin; TRITC, tetramethylrhodamine isothiocyanate; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling

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