ABSTRACT
The SHROB rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single recessive trait, a mutation resulting in truncation of all forms of the leptin receptor, designated fak. The mutation is on the same allele as the Zucker fatty trait (fa), but the latter results only in an amino acid substitution. SHROB have exaggerated circadian rhythms and abnormalities in hypothalamic function leading to hypersecretion of corticosterone. SHROB have fasting insulin levels 20 fold greater than heterozygous or wild type SHR (lean) siblings. The SHROB are glucose intolerant compared to lean siblings, but retain fasting euglycemia even on a high sucrose diet. The absence of fasting hyperglycemia suggests that polygenic interactions with additional modifier genes are required for Type 2 diabetes in obese rat models. Insulin resistance in SHROB is due mainly to diminished expressions of insulin receptor and IRS-1 proteins with subsequent effects on downstream postreceptor insulin action. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Dietary manipulations and pharmacological interventions, including treatments of hypertension, diabetes and hyperlipidemia, and modify the expressions of the various phenotypic components of metabolic syndrome X. The SHROB serves as a useful model to understand the interactions of the various metabolic abnormalities that make up Syndrome X including obesity, hypertenison and hyperinulinemia. Increased activity of the sympathetic nervous system may be a common factor leading by separate pathways to hypertension and to insulin resistance.
