Hydrochlorothiazide exacerbates metabolic syndrome in the SHROB rat model

Metabolic syndrome consists of hypertension, insulin resistance, dyslipidemia and fatty liver. Thiazides are the leading treatment for hypertension, but some clinical studies have suggested adverse metabolic effects. We sought for the first time to characterize the metabolic effects of thiazides in an animal model of metabolic syndrome. SHROB rats are obese, hypertensive and express every component of human metabolic syndrome. Adult female SHROB rats (N=6 per group) were fed a purified diet (AIN 93) replete with electrolytes and treated in their drinking water for 5 weeks with either vehicle (250 ppm saccharine and 100 ppm sodium benzoate) or hydrochlorothiazide (achieved dose of 44±2 mg/kg/d). Systolic blood pressure fell progressively from 184±5 to 142±2 mmHg with thiazide treatment while remaining unchanged in controls. Heart rate was not affected. Body weight, food intake, and water intake did not differ between groups, nor did fasting glucose or insulin. Oral glucose tolerance testing (6 g/kg by gavage after an 18h fast) showed increased plasma glucose levels in the thiazide group (at 60 min post load, 394±48 vs 214±51 mg/dL in controls, P<0.05 by t‐test). Insulin levels at the same time were half again higher in SHROB treated with thiazide (90±20 vs 61±14 ng/mL in controls, NS, but two‐way ANOVA shows a difference, P<0.05 by F‐test). Relative liver mass was increased in the thiazide group relative to controls (43±3 vs 35±3 g/kg body weight, P<0.05 by t‐test). Thus, thiazide was an effective antihypertensive therapy in the SHROB model of metabolic syndrome but worsened glucose tolerance and insulin resistance and enlarged the already fatty liver. The secretory response of the pancreas to glucose was apparently not impaired or even increased, suggesting that insulin signaling may be affected by thiazides. Research support for this study was given by Ophthalmology Education Worldwide