Regulated Insulin Delivery From Human Epidermal Cells Reverses Hyperglycemia

Abstract

Alternative insulin therapies are being sought that will provide euglycemic control for people with diabetes mellitus. The epidermis is a self-renewing tissue that is easily accessible and can provide large numbers of autologous cells that can be used for generating insulin-secreting skin substitutes. Lentiviral vectors have been engineered to produce a fusion protein between the furin-cleavable proinsulin and the self-dimerization mutant of FK506-binding protein to yield bioactive insulin in keratinocytes; this insulin is released as a response to exogenous administration of a small organic molecule, rapamycin. The engineered keratinocytes retained normal morphology and grew in a manner similar to lentiviral-treated control cells. Epidermal keratinocytes in culture and in stratified bioengineered epidermis released insulin within 30 minutes after addition of rapamycin, and secretion slowed or stopped within 2-3 hours after removal of the inducing agent. When the cells were implanted into athymic mice that had been rendered diabetic with streptozotocin (STZ), insulin was detected in the plasma within 1 hour after addition of rapamycin. Concomitantly, serum glucose decreased to normal levels even in diabetic animals with severe hyperglycemia. Repeated rapamycin administration yielded similar results. These experiments provide proof-of-concept that insulin released from the skin in a regulatable manner can reverse hyperglycemia.