Increased beta-cell mass by islet transplantation and PLAG1 overexpression causes hyperinsulinemic normoglycemia and hepatic insulin resistance in mice.
OBJECTIVE
It is believed that an organism remains normoglycemic despite an increase in the beta-cell mass because of decreased insulin production by beta-cells on a per-cell basis. However, some transgenic mouse models with beta-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistance.


METHODS
Here, we investigated the effect of an increased beta-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in beta-cells, which leads to beta-cell expansion.


RESULTS
In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing. Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments.


CONCLUSIONS
In conclusion, we demonstrate that when excess beta-cells are grafted, insulin production on a per beta-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies.
Stamcel Instituut, Katholieke Universiteit Leuven, Leuven, Belgium. jeroen.declercq@med.kuleuven.be
Jeroen
J
Declercq
Anujith
A
Kumar
Janna A
JA
Van Diepen
Irene O C M
IO
Vroegrijk
Conny
C
Gysemans
Caterina
C
Di Pietro
Peter J
PJ
Voshol
Chantal
C
Mathieu
Nadine
N
Ectors
Wim J M
WJ
Van de Ven
Catherine M
CM
Verfaillie
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006946:Hyperinsulinism / Q000235:genetics*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000637:transplantation*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D007328:Insulin; C104382:PLAG1 protein, human; C491264:Plag1 protein, mouse; D005934:Glucagon