Beta-cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia.
We studied the effects of hyperglycemia on beta-cell death and mass in syngeneically transplanted islets. Six groups of STZ-induced diabetic C57BL/6 mice were transplanted with 100 syngeneic islets, an insufficient beta-cell mass to restore normoglycemia. Groups 1, 2, and 3 remained hyperglycemic throughout the study. Groups 4, 5, and 6 were treated with insulin from day 7 before transplantation to day 10 after transplantation. After insulin discontinuation, group 6 mice achieved definitive normoglycemia. Grafts were harvested at 3 (groups 1 and 4), 10 (groups 2 and 5), and 30 (groups 3 and 6) days after transplantation. On day 3, the initially transplanted beta-cell mass (0.13 +/- 0.01 mg) was dramatically and similarly reduced in the hyperglycemic and insulin-treated groups (group 1: 0.048 +/- 0.002 mg; group 4: 0.046 +/- 0.007 mg; P < 0.001). Extensive islet necrosis (group 1: 30.7%; group 4: 26.8%) and increased beta-cell apoptosis (group 1: 0.30 +/- 0.05%; group 4: 0.42 +/- 0.07%) were found. On day 10, apoptosis remained increased in both hyperglycemic and insulin-treated mice (group 2: 0.44 +/- 0.09%; group 5: 0.48 +/- 0.08%) compared with normal pancreas (0.04 +/- 0.03%; P < 0.001). In contrast, on day 30, beta-cell apoptosis was increased in grafts exposed to sustained hyperglycemia (group 3: 0.37 +/- 0.03%) but not in normoglycemic mice (group 6: 0.12 +/- 0.02%); beta-cell mass was selectively reduced in islets exposed to hyperglycemia (group 3: 0.046 +/- 0.02 mg; group 6: 0.102 +/- 0.009 mg; P < 0.01). In summary, even in optimal conditions, approximately 60% of transplanted islet tissue was lost 3 days after syngeneic transplantation, and both apoptosis and necrosis contributed to beta-cell death. Increased apoptosis and reduced beta-cell mass were also found in islets exposed to chronic hyperglycemia, suggesting that sustained hyperglycemia increased apoptosis in transplanted beta-cells.
Biarnés
Montserrat
M
Laboratory of Diabetes and Experimental Endocrinology, Endocrine Unit, CSUB-Hospital de Bellvitge, University of Barcelona, Barcelona, Spain.
Montolio
Marta
M
Nacher
Victor
V
Raurell
Mercè
M
Soler
Joan
J
Montanya
Eduard
E
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D016923:Cell Death; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000601:surgery*; D006943:Hyperglycemia / Q000601:surgery*; D007328:Insulin / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology* / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014185:Transplantation, Isogeneic / Q000473:pathology / Q000502:physiology*
D001786:Blood Glucose; D007328:Insulin