The endocrine secretion of human insulin and growth hormone by exocrine glands of the gastrointestinal tract.
The exocrine pancreas, liver, and submandibular glands of the rat were used to express and secrete two exogenous, human protein hormones (growth hormone and insulin) into blood at physiological concentrations. Transfection, expression, and secretion were achieved by the in vivo retrograde injection of plasmid DNA into the secretory ducts of these glands. Pancreatic acinar cells secreted physiological concentrations of growth hormone into the circulation, and its secretion was enhanced by cholinergic stimulation. A human insulin gene was engineered to allow normal processing of insulin in non-beta cells. With this gene, the secretion of human insulin by the exocrine pancreas normalized elevated blood glucose levels in diabetic rats. These in vivo observations demonstrate the utility of retrograde ductal administration of naked DNA into exocrine organs as a novel method for the regulated systemic delivery of protein-based pharmaceuticals.
Goldfine
I D
ID
School of Medicine and Dentistry, University of California at San Francisco, USA. idg@itsa.ucsf.edu
German
M S
MS
Tseng
H C
HC
Wang
J
J
Bolaffi
J L
JL
Chen
J W
JW
Olson
D C
DC
Rothman
S S
SS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004247:DNA / Q000378:metabolism* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000628:therapy*; D016503:Drug Delivery Systems; D005818:Genetic Engineering; D015316:Genetic Therapy; D019382:Human Growth Hormone / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000078790:Insulin Secretion; D008099:Liver / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000378:metabolism; D010957:Plasmids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013363:Submandibular Gland / Q000378:metabolism; D014162:Transfection
D001786:Blood Glucose; D007328:Insulin; D019382:Human Growth Hormone; D004247:DNA