title: Age-Dependent Onset of Insulin Resistance in Insulin-Resistant Mice.
abstract: We have previously isolated spontaneous insulin-resistant mice (ddY-H) and non-insulin-resistant mice (ddY-L) from ddY mice. In the present study, age-dependent onset of insulin resistance in obese ddY-H mice was investigated by comparing with lean ddY-L mice. In ddY-H mice fed a standard diet, an increase in elevation of glucose-stimulated plasma insulin level, glucose intolerance in an intraperitoneal glucose tolerance test, and a reduction of hypoglycemic action of insulin were found at 9 weeks of age, but not at 6 weeks of age. When ddY-H mice were administered nateglinide, a greater elevation of plasma insulin level and a less decrease of serum glucose level were observed at 9 weeks of age. These changes developed progressively with age. These findings suggest that insulin resistance is induced at 9 weeks of age. The age-related change in insulin resistance was correlated with reductions in mRNA expression and protein content of the insulin receptor (InsR), and insulin receptor substrate (IRS)-1 and IRS-2 in the epididymal adipose tissue. On the other hand, in the liver, mRNA expression of InsR and IRS-1 did not change at any age, although that of the IRS-2 was reduced. Thus, in ddY-H mice, insulin resistance and glucose-stimulated hyper-secretion of insulin are induced at 9 weeks of age and are reciprocally affected, resulting in progression to a more severe state at an older age. Insulin resistance may be attributed, at least in part, to the decreases in the mRNA expressions and proteins of InsR, IRS-1 and IRS-2 in adipose tissue.
authors.affiliation: Department of Clinical Pharmaceutics & Pharmacy Practice, Graduate School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Naohito
authors.initials: N
authors.lastname: Ide
authors.forename: Kasumi
authors.initials: K
authors.lastname: Arisawa
authors.forename: Kanami
authors.initials: K
authors.lastname: Ogura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kagawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Maeda
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D007328:Insulin / Q000097:blood*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D008815:Mice, Inbred Strains; D000077715:Nateglinide; D009765:Obesity / Q000097:blood / Q000150:complications*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; D000077715:Nateglinide; D010649:Phenylalanine; D011972:Receptor, Insulin; D005947:Glucose