Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice.
Hyperglycemia-induced beta-cell dysfunction may be an important component in the pathogenesis of non-insulin-dependent diabetes mellitus. However, most available data in this field were obtained from rodent islets. To investigate the relevance of this hypothesis for human beta-cells in vivo, human pancreatic islets were transplanted under the renal capsule of nude mice. Experimental groups were chosen so that grafted islets were exposed to either hyper- or normoglycemia or combinations of these for 4 or 6 wk. Grafts of normoglycemic recipients responded with an increased insulin release to a glucose stimulus during perfusion, whereas grafts of hyperglycemic recipients failed to respond to glucose. The insulin content of the grafts in the latter groups was only 10% of those observed in controls. Recipients initially hyperglycemic (4 wk), followed by 2 wk of normoglycemia regained a normal graft insulin content, but a decreased insulin response to glucose remained. No ultrastructural signs of beta-cell damage were observed, with the exception of increased glycogen deposits in animals hyperglycemic at the time of killing. It is concluded that prolonged exposure to a diabetic environment induces a long-term secretory defect in human beta-cells, which is not dependent on the size of the islet insulin stores.
Jansson
L
L
Department of Medical Cell Biology, Uppsala University, Sweden.
Eizirik
D L
DL
Pipeleers
D G
DG
Borg
L A
LA
Hellerström
C
C
Andersson
A
A
D000293:Adolescent; D000328:Adult; D000496:Alloxan; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D016381:Islets of Langerhans Transplantation / Q000473:pathology; D007668:Kidney; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D013154:Spleen; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
D007328:Insulin; D000496:Alloxan; D005947:Glucose