Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1.
Ultrasound-targeted microbubble destruction (UTMD) was used to direct betacellulin (BTC) and pancreatic duodenal homeobox-1 (PDX1) to rat pancreas 48 h after islet destruction by streptozotocin (STZ). Sprague-Dawley rats were rendered diabetic by STZ injection. Controls included normal rats, STZ only without UTMD, and UTMD with DsRed reporter gene. Blood glucose increased dramatically in all rats 48 h after STZ, and continued to rise after UTMD with BTC alone. Blood glucose declined from day 3 to day 10 after UTMD with PDX1, but remained elevated (261+/-8 mg/dl). However, in rats treated with both BTC and PDX1, blood glucose remained below 200 mg/dl throughout day 10. This was accompanied by normalization of blood insulin and C-peptide. Histology demonstrated islet-like clusters of glucagon-staining cells in the rats treated with BTC and PDX1, but these clusters disappeared by 30 days after UTMD treatment. Although regeneration of insulin-producing islets was not seen, diabetes was reversed for up to 15 days after a single UTMD treatment by ectopic insulin production by pancreatic acinar cells. These cells co-expressed amylase and insulin and demonstrated several beta-cell markers by reverse transcription-PCR. Gene therapy by UTMD can reverse diabetes in vivo in adult rats by restoring pancreatic insulin production.
Chen
S
S
Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center, Baylor Heart and Vascular Institute, Dallas, TX 75226, USA.
Ding
J
J
Yu
C
C
Yang
B
B
Wood
D R
DR
Grayburn
P A
PA
D000681:Amylases / Q000032:analysis; D000818:Animals; D066259:Betacellulin; D015415:Biomarkers / Q000032:analysis; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005934:Glucagon / Q000032:analysis; D018398:Homeodomain Proteins / Q000235:genetics*; D007328:Insulin / Q000032:analysis / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D045423:Microbubbles; D046790:Pancreas, Exocrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D014465:Ultrasonics
D066259:Betacellulin; D015415:Biomarkers; D001786:Blood Glucose; C587853:Btc protein, rat; D002096:C-Peptide; D018398:Homeodomain Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005934:Glucagon; D000681:Amylases