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.
Tian
Jun
J
1Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, New York, USA.
Lei
Pedro
P
Laychock
Suzanne G
SG
Andreadis
Stelios T
ST
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D019281:Dimerization; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000627:therapeutic use*; D015603:Keratinocytes / Q000166:cytology; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D020123:Sirolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods
D007328:Insulin; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus