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Thyroid hormone receptor beta agonists corrected NAFLD, but promoted insulin resistance
PHILADELPHIA — Thyroid hormone receptor beta agonists, investigational agents for the treatment of dyslipidemia and nonalcoholic fatty liver disease, had a negative effect on insulin sensitivity, based on data presented here.
Due to the promise for reduced hepatic steatosis with thyroid hormone receptor beta agonists Daniel F. Vatner, MD, PhD, fellow of endocrinology at Yale-New Haven Hospital, and colleagues tested two agents with potential benefits in male rats: GC-1/sobetirome and KB-2115/eprotirome.
The GC-1 treatment resulted in a decrease in liver triglycerides at all doses tested. However, increased hepatic glucose production (3.8 mg/kg vs. 6 mg/kg, P<.02) caused fasting hyperglycemia (P<.01) and hyperinsulinemia (P<.01), researchers reported.
“In this era of calorie excess and cardiovascular morbidity, you can see where thyroid hormone therapy might be an attractive drug target. However, most of us are familiar with the many adverse side effects of thyroid hormone excess,” Vatner said during a late-breaking session at the American Diabetes Association’s 72nd Scientific Sessions.
The agent may have also had an adipose action despite the liver-specific properties, and researchers said it may have contributed to the increase in fasting glucose production. Although GC-1 reduced nonalcoholic fatty liver disease (NAFLD), treatment did not improve hepatic insulin sensitivity; it had no effect on whole-body insulin-mediated glucose uptake (P=.4).
After 10 days of using the more hepatic-specific compoound, KB2115 (0.1 mg daily), researchers observed a 60% reduction of NAFLD (P<.001). This substantial decrease occurred without a compelling change in glycerol turnover or fasting hyperglycemia, they said.
Researchers did find that there was a threefold increase in fasting plasma insulin concentration, and hepatic insulin sensitivity was not improved with KB2115 (P=.2).
According to data, PEPCK1 mRNA was not changed by KB2115 treatment, and suppressed with insulin use, and there was a twofold increase of PEPCK1 protein. Researchers concluded that the thyroid hormone receptor beta agonists could correct NAFLD.
“However, any potential pharmacologic application of these promising compounds must take into account or at least evaluate the potential to exacerbate insulin resistance, particularly when such agents would likely be used in diabetic patients,” Vatner said. – by Samantha Costa
For more information:
Vatner D. 151-LB. Presented at: the American Diabetes Association’s 72nd Scientific Sessions Meeting; June 8-12, 2012; Philadelphia.
Disclosure: Dr. Vatner reports no relevant financial disclosures.