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

• Published in: Metabolism, clinical and experimental Vol. 49; no. 9; pp. 1118 - 1123
• Main Authors: Utsugi, T., Ohno, T., Ohyama, Y., Uchiyama, T., Saito, Y., Matsumura, Y., Aizawa, H., Itoh, H., Kurabayashi, M., Kawazu, S., Tomono, S., Oka, Y., Suga, T., Kuro-o, M., Nabeshima, Y., Nagai, R.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2000; Elsevier
• Subjects: Adrenocorticotropic Hormone - blood; Aging - physiology; Animals; Biological and medical sciences; Blood Glucose - analysis; Development. Metamorphosis. Moult. Ageing; Fundamental and applied biological sciences. Psychology; Gene Expression; Glucose Tolerance Test; Glucose Transporter Type 4; Growth Hormone - blood; Humans; Hypoglycemia - metabolism; Insulin - blood; Insulin - pharmacology; Islets of Langerhans - anatomy & histology; Islets of Langerhans - metabolism; Mice; Mice, Mutant Strains; Models, Biological; Monosaccharide Transport Proteins - genetics; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Muscle, Skeletal - metabolism; RNA, Messenger - analysis; Thyrotropin - blood; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Animal model; Pancreatic hormone; Ageing; Rodentia; Glucose tolerance test; Insulin; Endocrine secretion; Protein hormone; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal; Physiology
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1053/meta.2000.8606

We have recently identified a novel gene, klotho (kl), which may suppress several aging phenotypes. A defect of kl gene expression in the mouse results in a syndrome resembling human aging, such as arteriosclerosis, skin atrophy, osteoporosis, and pulmonary emphysema. To determine whether mouse homozygotes for the kl mutation (kl/ kl) show abnormal glucose metabolism, an oral glucose tolerance test (OGTT) was performed at 6 to 8 weeks of age. Blood glucose levels during the OGTT were significantly lower in kl/ kl mice versus wild-type mice. The insulin content of the pancreas was significantly lower in kl/ kl mice compared with wild-type mice. Decreased insulin production was also supported by Northern blot analysis showing lower levels of insulin mRNA in kl/ kl mice. To examine how lower blood glucose levels may exist in kl/ kl mice despite decreased insulin production, insulin tolerance tests (ITTs) were performed. The glucose decline following insulin injection was 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 both Northern blot analysis and Western blot analysis. Thus, we conclude that insulin production is decreased and insulin sensitivity is increased in the klotho mouse, a novel animal model for human aging.