Establishment of a stringent large animal model of insulin-dependent diabetes for islet autotransplantation: combination of pancreatectomy and streptozotocin.
OBJECTIVE
A stringent porcine islet autograft diabetes model was developed to enable the assessment of autoislet safety and efficacy in either portal vein or an extrahepatic site.


METHODS
A 95% pancreatectomy was performed preserving the pancreaticoduodenal arcade; however, glycemic control was still maintained at 3.3 ± 0.3 days (mean ± SEM), shown by euglycemic fasting blood glucose levels of 4.9 ± 0.8 mmol/L (mean ± SEM, n = 3). To reduce surgical complications and eliminate remaining islets, pigs were dosed intravenously after a modified 90% pancreatectomy, with 150-mg/kg streptozotocin, producing a diabetic state (18.9 ± 1.8 mmol/L [mean ± SEM], n = 8; P < 0.001) within 2.0 ± 0.9 days (mean ± SEM).


RESULTS
Animals presented with sustained hyperglycemia, failing a glucose challenge test 12 weeks after diabetic induction, and showed no stimulated C-peptide secretion compared to nondiabetic controls (baseline: 0.479 ± 0.080 ng/mL [mean ± SEM] vs after procedure: 0.219 ± 0.055 ng/mL [mean ± SEM], P = 0.02). Diabetic animals were maintained on daily insulin. Despite an initial decline in body weight acutely after pancreatectomy and streptozotocin administration, the mean body weight increased after induction over the approximately 88-day study, indicating that the animals were in good health.


CONCLUSIONS
This stringent porcine model of diabetic induction should be used to assess autograft transplantation safety and efficacy.
Department of Pathology, University of Western Ontario, London, Ontario, Canada. apepper2@uwo.ca
Andrew R
AR
Pepper
Ian
I
Welch
Anthony
A
Bruni
Amanda
A
MacGillivary
Delfina M
DM
Mazzuca
David J G
DJ
White
William
W
Wall
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology* / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology* / Q000601:surgery*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D010180:Pancreatectomy; D013311:Streptozocin; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014182:Transplantation, Autologous
D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D013311:Streptozocin