Native pancreatic α‐cell adaptation in streptozotocin‐induced diabetic primates: importance for pig islet xenotransplantation

Abstract

Metabolic compatibility between donor and recipient species is an important matter for pig islet xenotransplantation. Glucagon is a key hormone for the function of pig islets as well as control of hypoglycemia in the recipients of the islets. Because a discrepancy exists in the composition of glucagon cells of pig and human/primate islets, the present study was designed to determine the role of native recipient glucagon cells in the treatment of diabetes by islet transplantation in a "pig-to-primate" model. Streptozotocin-treated (50 mg/kg) monkeys (n = 12, follow-up of 6 to 231 days) were compared with non-diabetic animals (n = 5; follow-up, 180 days). Metabolic [fasting and intravenous glucose tolerance tests (IVGTTs) for serum levels of glucose, insulin, glucagon] and morphologic (endocrine volume density and cell mass for insulin and glucagon) were compared between non-diabetic and diabetic animals. Six additional diabetic primates were given transplants of 15 000 adult pig islet equivalents without immunosuppression to monitor glucose, glucagon, insulin, and porcine C-peptide levels until 48 h after transplantation. Elevated fasting blood glucose, pathologic IVGTT, destruction of 95% of beta-cell mass, and glycosylated hemoglobin (>13%) were assessed in diabetic monkeys. The serum glucagon levels and glucagon cell mass correlated significantly with diabetes time course of diabetes (R = 0.940, p = 0.005; R = 0.663, p = 0.019, respectively). A mean increase of 89% in glucagon cell mass was observed for primates suffering from diabetes >53 days. No response of glucagon secretion was observed for diabetic animals during IVGTT, because no increase of serum insulin levels followed glucose loading. Blood glucose levels dropped after pig islet xenografts in diabetic primates. This reduction was maintained by an insulin level >20 microU/ml over the period of time of xenograft function (porcine C-peptide >0.1 ng/ml). A total restoration of native primate glucagon sensitivity to insulin was found after pig islets xenotransplantation as revealed by a reduction of 80% of the glucagon level. When graft dysfunction (>24 h post-transplantation), the insulin level dropped and glucagon levels rose again (>50 pg/ml). Native glucagon cells provide morphologic and functional plasticity to diabetes. Adult pig islet xenotransplantation can restore the sensitivity of primate glucagon to insulin but cannot protect the diabetic recipient against hypoglycemia.