Prolonged survival and improved glycemia in BioBreeding diabetic rats after early sustained exposure to glucagon-like peptide 1.
BACKGROUND
Type 1 diabetes (T1D) in both humans and BioBreeding (BB) rats is an autoimmune disease that results in complete destruction of islets and insulin dependency for life. Glucagon-like peptide 1 (GLP-1) promotes beta cell proliferation and neogenesis and has a potent insulinotropic effect. We hypothesized that the expression of GLP-1 before disease onset would increase islet mass, delay diabetes and prolong survival of BB rats.


METHODS
Vascular smooth muscle cells retrovirally transduced to secrete GLP-1 were seeded into TheraCyte encapsulation devices, implanted subcutaneously, and rats were monitored for diabetes.


RESULTS
In untreated control rats, plasma GLP-1 levels were 34.5-39.5 pmol/l, whereas, in treated rats, plasma levels were elevated, in the range 90-250.4 pmol/l. Hypoglycemia was not detected and this was anticipated from the glucose-regulated action of GLP-1. Diabetes onset (mean + or - SEM) in untreated rats occurred at 56.5 + or - 0.6 days (n = 6) and, in GLP-1-treated rats, was delayed until 76.4 + or - 3.3 days (n = 5) (p < 0.001). After disease onset, untreated control rats showed a rapid weight loss and elevated blood glucose (>650 mg/dl) and did not survive beyond 11 days. At 5 days after diabetes onset, insulin-secreting islets were absent in untreated rats. By contrast, treated rats maintained weight for up to 143 days of age and showed insulin-secreting beta cells.


CONCLUSIONS
Sustained GLP-1 expression delivered by encapsulated cells before diabetes onset in BB rats showed an improved clinical outcome, suggesting the potential for treating patients using long lasting GLP-1 analogs.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Ofer
O
Yanay
Daniel
D
Moralejo
Kelly
K
Kernan
Margaret
M
Brzezinski
Jessica M
JM
Fuller
Randall W
RW
Barton
Ake
A
Lernmark
William R
WR
Osborne
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020007:Implants, Experimental; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D017208:Rats, Wistar; D014161:Transduction, Genetic
D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D005934:Glucagon