A potential role for skeletal muscle caveolin-1 as an insulin sensitivity modulator in ageing-dependent non-obese type 2 diabetes: studies in a new mouse model.
OBJECTIVE
Type 2 diabetes mellitus is a common age-dependent disease. We discovered that male offspring of non-diabetic C57BL/6 and DBA/2 mice, called JYD mice, develop type 2 diabetes when they grow old. JYD mice show characteristics of insulin resistance, hyperglycaemia and hyperinsulinaemia in old age without obesity. We postulated that the mechanism of age-dependent type 2 diabetes in this model relates to caveolin-1 status in skeletal muscle, which appears to regulate insulin sensitivity in the mice.


METHODS
We compared insulin sensitivity in aged C57BL/6 and JYD mice using glucose and insulin tolerance tests and (18)F-fluorodeoxyglucose positron emission tomography. We also determined insulin signalling molecules and caveolin proteins using western blotting, and altered caveolin-1 levels in skeletal muscle of C57BL/6 and JYD mice using viral vector systems, to examine the effect of this on insulin sensitivity.


RESULTS
In 30-week-old C57BL/6 and JYD mice, the basal levels of IRS-1, Akt and peroxisome proliferator-activated receptor-gamma decreased, as did insulin-stimulated phosphorylation of Akt and insulin receptor beta. However, caveolin-1 was only increased about twofold in 30-week-old JYD mice as compared with 3-week-old mice, whereas an eightfold increase was seen in C57BL/6 mice. Downregulation of caveolin-1 production in C57BL/6 mice caused severe impairment of glucose and insulin tolerance. Upregulation of caveolin-1 in aged diabetic JYD mice significantly improved insulin sensitivity with a concomitant increase of glucose uptake in the skeletal muscle.


CONCLUSIONS
The level of skeletal muscle caveolin-1 is correlated with the progression of age-dependent type 2 diabetes in JYD mice.
Oh
Y S
YS
Department of Biochemistry and Molecular Biology, Aging and Apoptosis Research Center, Seoul National University College of Medicine, 28 Yungon Dong, Chongno Ku, Seoul 110-799, South Korea.
Khil
L-Y
LY
Cho
K A
KA
Ryu
S J
SJ
Ha
M K
MK
Cheon
G J
GJ
Lee
T S
TS
Yoon
J-W
JW
Jun
H-S
HS
Park
S C
SC
D000375:Aging / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D051242:Caveolin 1 / Q000502:physiology*; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018482:Muscle, Skeletal / Q000503:physiopathology*; D049268:Positron-Emission Tomography
D001786:Blood Glucose; D051242:Caveolin 1; D007328:Insulin; D019788:Fluorodeoxyglucose F18