Decreased insulin production and increased insulin sensitivity in the Klotho mutant mouse, a novel animal model for human aging

We have recently identified a novel gene, klotho (kl), which may suppress s everal aging phenotypes. A defect of kl gene expression in the mouse result s in a syndrome resembling human aging, such as arteriosclerosis, skin atro phy, osteoporosis, and pulmonary emphysema. To determine whether mouse homo zygotes for the kl mutation (kl/kl) show abnormal glucose metabolism, an or al glucose tolerance test (OGTT) was performed at 6 to 8 weeks of age. Bloo d glucose levels during the OGTT were significantly lower in kl/kl mice ver sus wild-type mice. The insulin content of the pancreas was significantly l ower in kl/kl mice compared with wild-type mice. Decreased insulin producti on was also supported by Northern blot analysis showing lower levels of ins ulin mRNA in kl/kl mice. To examine how lower blood glucose levels may exis t in kl/kl mice despite decreased insulin production, insulin tolerance tes ts (ITTs) were performed. The glucose decline following insulin injection w as more severe in kl/kl mice versus wild-type mice, suggesting that insulin sensitivity was higher in kl/kl mice versus wild-type mice. In kl/kl mice, an augmented expression of GLUT4 in skeletal muscle was demonstrated by bo th Northern blot analysis and Western blot analysis. Thus, we conclude that insulin production is decreased and insulin sensitivity is increased in th e klotho mouse, a novel animal model for human aging. Copyright (C) 2000 by W.B. Saunders Company.