Prevention of primary nonfunction of canine islet autografts by treatment with pravastatin.
BACKGROUND
Nonspecific inflammation is the primary cause of early islet graft loss. We have shown in mice that pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, prevents primary nonfunction of islet isografts by reducing inflammatory reactions at the graft site. This study was designed to test the effectiveness of this agent in a large animal model, dogs, by transplanting autologous islets.


METHODS
After total pancreatectomy, islets were isolated by using a two-step digestion method, followed by discontinuous gradient centrifugation on EuroFicoll. A known number of freshly isolated islets were immediately transplanted back into the same dog via the portal vein.


RESULTS
First, we determined the minimal islet number required to reverse diabetes by transplanting 3,000-10,000 IEQ/kg with no additional treatment. The number was found to be 4,000 IEQ/kg, and islets less than 4,000 IEQ/kg consistently failed. To test the effect of pravastatin, 3,000 IEQ/kg were transplanted into dogs that either received no further treatment or were treated daily with 20 mg/kg of pravastatin from days -2 to 14. Without pravastatin, this number of islets lowered blood glucose only transiently, and all four of these dogs became hyperglycemic within 1 week. In contrast, four of the five dogs treated with pravastatin became normoglycemic (<150 mg/dL) and maintained this level during the observation period of 12 weeks (P<0.05). Postprandial plasma glucose and insulin levels returned to normal, and K values of intravenous glucose tolerance tests were significantly higher in pravastatin-treated dogs than in controls (P<0.04 at week 2 and P<0.01 at week 4).


CONCLUSIONS
Peritransplant pravastatin treatment reduced the number of autologous islets required to reverse diabetes in totally pancreatectomized dogs. These results suggest that pravastatin may also facilitate better islet graft survival and function in clinical transplantation.
Arita
Seiji
S
Islet Transplant Program, Department of Surgery, UCLA School of Medicine and Veterans Affairs Medical Center/West Los Angeles, California 90073, USA.
Nagai
Tetsu
T
Ochiai
Mari
M
Sakamoto
Yoshimasa
Y
Shevlin
Linda A
LA
Smith
Craig V
CV
Mullen
Yoko
Y
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002469:Cell Separation / Q000379:methods; D004285:Dogs; D005215:Fasting; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D008297:Male; D010180:Pancreatectomy; D019518:Postprandial Period; D017035:Pravastatin / Q000627:therapeutic use*; D014182:Transplantation, Autologous; D014185:Transplantation, Isogeneic
D001786:Blood Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D017035:Pravastatin