TY - JOUR
T1 - Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and β cell glucokinase genes
T2 - Genetic reconstitution of diabetes as a polygenic disease
AU - Terauchi, Yasuo
AU - Iwamoto, Keiji
AU - Tamemoto, Hiroyuki
AU - Komeda, Kajuro
AU - Ishii, Chikara
AU - Kanazawa, Yasunori
AU - Asanuma, Nahoko
AU - Aizawa, Toru
AU - Akanuma, Yasuo
AU - Yasuda, Kazuki
AU - Kodama, Tatsuhiko
AU - Tobe, Kazuyuki
AU - Yazaki, Yoshio
AU - Kadowaki, Takashi
PY - 1997/3/1
Y1 - 1997/3/1
N2 - Non-insulin-dependent diabetes mellitus (NIDDM) is considered a polygenic disorder in which insulin resistance and insulin secretory defect are the major etiologic factors. Homozygous mice with insulin receptor substrate-1 (IRS-1) gene knockout showed normal glucose tolerance associated with insulin resistance and compensatory hyperinsulinemia. Heterozygous mice with β cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and β cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes. Blood glucose levels 120 min after intraperitoneal glucose load (1.5 mg/g body wt) were 108±24 (wild type), 95±26 (IRS-1 knockout), 159±68 (GK knockout), and 210±38 (double knockout) mg/dl (mean±SD) (double versus wild type, IRS-1, or GK; P < 0.01). The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the β cells as the IRS-1 knockout mice (fasting insulin levels: 0.38±0.30 [double knockout], 0.35±0.27 [IRS-1 knockout] versus 0.25±0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18±0.68%; P < 0.01 [double knockout], 1.20±0.93%; P < 0.05 [IRS-1 knockout] versus 0.54±0.26% [wild type]), but impaired insulin secretion to glucose (the ratio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 103). In conclusion, the genetic abnormalities, each of which is nondiabetogenic by itself, cause overt diabetes if they coexist. This report provides the first genetic reconstitution of NIDDM as a polygenic disorder in mice.
AB - Non-insulin-dependent diabetes mellitus (NIDDM) is considered a polygenic disorder in which insulin resistance and insulin secretory defect are the major etiologic factors. Homozygous mice with insulin receptor substrate-1 (IRS-1) gene knockout showed normal glucose tolerance associated with insulin resistance and compensatory hyperinsulinemia. Heterozygous mice with β cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and β cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes. Blood glucose levels 120 min after intraperitoneal glucose load (1.5 mg/g body wt) were 108±24 (wild type), 95±26 (IRS-1 knockout), 159±68 (GK knockout), and 210±38 (double knockout) mg/dl (mean±SD) (double versus wild type, IRS-1, or GK; P < 0.01). The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the β cells as the IRS-1 knockout mice (fasting insulin levels: 0.38±0.30 [double knockout], 0.35±0.27 [IRS-1 knockout] versus 0.25±0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18±0.68%; P < 0.01 [double knockout], 1.20±0.93%; P < 0.05 [IRS-1 knockout] versus 0.54±0.26% [wild type]), but impaired insulin secretion to glucose (the ratio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 103). In conclusion, the genetic abnormalities, each of which is nondiabetogenic by itself, cause overt diabetes if they coexist. This report provides the first genetic reconstitution of NIDDM as a polygenic disorder in mice.
KW - glucokinase
KW - insulin receptor substrate-1
KW - insulin resistance
KW - insulin secretory dysfunction
KW - non-insulin-dependent diabetes mellitus
UR - http://www.scopus.com/inward/record.url?scp=0030961962&partnerID=8YFLogxK
U2 - 10.1172/JCI119250
DO - 10.1172/JCI119250
M3 - 学術論文
C2 - 9062343
AN - SCOPUS:0030961962
SN - 0021-9738
VL - 99
SP - 861
EP - 866
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -