Concern about cyclosporine causing adverse effects on glucose metabolism is based mainly on in vitro studies and in vivo data in rodents. However, data on large mammals and humans are much more controversial. Because the drug is used as therapy accompanying pancreatic or isolated islet transplantations, studies in large animals are needed to assess whether cyclosporine inhibits beta-cell function and causes glucose intolerance. To address these issues, we examined intravenous glucose tolerance, islet beta-cell function, and insulin sensitivity in a group of adult mongrel dogs with intrasplenic islet autografts, with and without cyclosporine treatment. Similar fasting plasma glucose and insulin values were found before and after pancreatectomy and islet transplantation. After intravenous glucose, plasma glucose values decreased more slowly in dogs that had undergone transplantation, but no additional adverse effect as a result of cyclosporine was observed. During euglycemic clamp studies, performed at both physiologic and pharmacologic insulin concentrations, the drug had no effect on the total amount of metabolized glucose, and glucose production was unaffected by cyclosporine treatment. Thus intramuscular cyclosporine therapy does not seem to inhibit insulin secretion from heterotopic islets or to affect peripheral and hepatic insulin sensitivity in dogs with intrasplenic islet autografts.