Insulin resistance and increased pancreatic beta-cell proliferation in mice expressing a mutant insulin receptor (P1195L).
Several mutations of the tyrosine kinase domain of insulin receptor (IR) have been clinically reported to lead insulin resistance and insulin hypersecretion in humans. However, it has not been completely clarified how insulin resistance and pancreatic beta-cell function affect each other under the expression of mutant IR. We investigated the response of pancreatic beta-cells in mice carrying a mutation (P1195L) in the tyrosine kinase domain of IR beta-subunit. Homozygous (Ir(P1195L/P1195L)) mice showed severe ketoacidosis and died within 2 days after birth, and heterozygous (Ir(P1195L/wt)) mice showed normal levels of plasma glucose, but high levels of plasma insulin in the fasted state and after glucose loading, and a reduced response of plasma glucose lowering effect to exogenously administered insulin compared with wild type (Ir(wt/wt)) mice. There were no differences in the insulin receptor substrate (IRS)-2 expression and its phosphorylation levels in the liver between Ir(P1195L/wt) and Ir(wt/wt) mice, both before and after insulin injection. This result may indicate that IRS-2 signaling is not changed in Ir(P1195L/wt) mice. The beta-cell mass increased due to the increased numbers of beta-cells in Ir(P1195L/wt) mice. More proliferative beta-cells were observed in Ir(P1195L/wt) mice, but the number of apoptotic beta-cells was almost the same as that in Ir(wt/wt) mice, even after streptozotocin treatment. These data suggest that, in Ir(P1195L/wt) mice, normal levels of plasma glucose were maintained due to high levels of plasma insulin resulting from increased numbers of beta-cells, which in turn was due to increased beta-cell proliferation rather than decreased beta-cell apoptosis.
Ogino
J
J
Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Sakurai
K
K
Yoshiwara
K
K
Suzuki
Yoichi
Y
Ishizuka
N
N
Seki
N
N
Suzuki
Yoshifumi
Y
Koseki
H
H
Shirasawa
T
T
Hashimoto
N
N
Yagui
K
K
Saito
Y
Y
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D049109:Cell Proliferation; D005947:Glucose / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D011972:Receptor, Insulin; D005947:Glucose