SHROB rat model of metabolic syndrome reveals unexpected benefits and off-target effects for multiple agents

SHROB rats are a substrain of spontaneously hypertensive rat (SHR) with a naturally occurring knockout of the leptin receptor. SHROB exhibit multiple abnormalities characteristic of human metabolic syndrome. We hypothesized that antidiabetic and antihypertensive agents may have a spectrum of therapeutic activity on components of metabolic syndrome.

Antidiabetic agents: All agents tested normalized glucose tolerance. PPAR-gamma agents also corrected hypertriglyceridemia, and ameliorated steatohepatitis and hypertension, while increasing subcutaneous fat. Glyburide did not affect body fat but worsened left ventricular hypertrophy. Sitagliptin normalized elevated glucagon levels and reduced visceral fat, without affecting overall adiposity.

Antihypertensive agents: All agents tested normalized blood pressure. Hydralazine and alpha-methyldopa worsened glucose tolerance and insulin resistance, whereas both were improved by another sympathoinhibitor, moxonidine. Captopril worsened glucose tolerance but lowered triglycerides, LDL cholesterol and proteinuria. Allylmercaptocaptoril, with an allyl moiety from garlic, improved glucose tolerance. Relative to captopril, it induced greater reductions in blood pressure and proteinuria. Both agents reduced fatty acid turnover in isolated abdominal adipocytes. Another garlic compound, diallyl sulfide, was effective in lowering blood glucose during an oxidative stress challenge.
Thus, preclinical drug trials in the SHROB model parallel those in humans, and suggest unexpected benefits of new agents, and possible risks of older agents.

The SHROB model may identify useful agents for treating metabolic syndrome.

The authors have received grant support from Merck and Bioline.