Study of ligament ossification and abnormal glucose tolerance in the Zucker fatty rat

Abstract

Introduction Spinal ligament Ossification has been described in obese patients with an associated mild abnormal glucose tolerance. An epidemiological study of patients with Ossification of the posterior longitudinal ligament (OPLL) has shown a high rate of complications related to abnormal glucose tolerance. Although there were no signifi cant correlations between the severity of the ligament Ossification and fasting blood glucose values, or with hemoglobin A1c (an indicator of the severity of diabetes), signifi cant correlations were found with both fasting insulin levels and increased insulin secretory responsiveness. It was also reported that the severity of OPLL was mild in the non-insulin-dependent diabetes (NIDDM) group, and a high incidence of severe ossifi - cation was observed in those with borderline-type diabetes, which is manifested by mildly abnormal glucose tolerance [1]. The Zucker fatty rat (ZFR) is an animal model of obesity identifi ed by Zucker and colleagues as a natural spontaneous mutation among the 13M strain of hybrid rats (13C albino strain rats ?M strain black rats). These rats inherit obesity through a simple recessive gene (fa), and homozygous recessive animals are infertile because of incomplete gonadal development. A 25% rate of expression is observed when they are crossed with heterozygous rats [2]. Homozygous recessive rats (fa/fa) are considered ZFRs, whereas heterozygous rats (Fa/fa) and homozygous dominant rats (Fa/Fa) rats are called Zucker lean rats. It is easy to distinguish them because the ZFRs begin to exhibit obesity around 4 weeks after birth. The phenotype of ZFRs includes abnormal glucose tolerance, obesity secondary to overeating and sympathetic nervous system hypofunction, infertility secondary to gonadal hypofunction, decreased growth hormone (GH) secretion, and severe reactive hyperleptinemia and hyperinsulinemia. They have an internal physical environment that resembles what in humans is referred to as "obese syndrome" and "early-stage type II (non-insulin-dependent) diabetes." We consider them extremely suitable as an experimental animal model to elucidate spinal ligament Ossification, obesity, and insulin sensitivity. In addition to observing a tendency toward Ossification, which is the prodromal stage of ligament Ossification histologically in the anterior longitudinal ligament, the posterior longitudinal ligament, and the ligamentum fl avum, it is now clear that ectopic Ossification sites are observed in the periarticular ligaments, including the Achilles tendon in ZFRs, and we have been using these rats for research on spinal ligament Ossification in our department since 1984 [3]. Endocrinologically, ZFRs exhibit mild abnormal glucose tolerance in addition to the characteristics already described. A decrease in insulin secretion begins to be seen at around 12 months of age, pathologically resembling the so-called borderline to mildly abnormal glucose tolerance in humans. In recent years we have conducted histological studies on spinal ligaments, which are the sites of ectopic Ossification in ZFRs, and at the site of insertion of the Achilles tendon, where calcifi cation is observed in almost all animals. We have also examined experimental animals that have secondary hyperleptinemia and abnormal glucose tolerance due to leptin resistance, a characteristic of these rats. We prepared monosodium glutamate (MSG)-treated rats with non-treated Wistar rats and Zucker lean rats (NFRs). Both the ZFRs and MSG-treated rats displayed hyperleptinemia and were the same in terms of initially manifesting hyperinsulinemia associated with leptin resistance in the arcuate nucleus of the hypothalamus. We also carried out histopathological and immunohistochemical studies focusing on the contribution of the insulin/insulin-like growth factor 1 (IGF-I) signal pathway and compared their spinal ligament sites. © Springer 2006.