Regulated Insulin Delivery From Human Epidermal Cells Reverses Hyperglycemia

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.