Abstract |
Liver-specific thyroid hormone receptor-β (TRβ)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRβ agonists (GC-1 and KB-2115) in high-fat-fed male Sprague-Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRβ- and liver-specific thyromimetic, also prevented hepatic steatosis but did not induce fasting hyperglycemia, increase basal EGP rate, or diminish hepatic insulin sensitivity. Surprisingly, insulin-stimulated peripheral glucose disposal was diminished because of a decrease in insulin-stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB-2115 treatment was associated with a decrease in GLUT4 protein content. Thus, although both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRβ agonists must consider the potential adverse effects on insulin sensitivity.
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Authors | Daniel F Vatner, Dirk Weismann, Sara A Beddow, Naoki Kumashiro, Derek M Erion, Xiao-Hui Liao, Gary J Grover, Paul Webb, Kevin J Phillips, Roy E Weiss, Jonathan S Bogan, John Baxter, Gerald I Shulman, Varman T Samuel |
Journal | American journal of physiology. Endocrinology and metabolism
(Am J Physiol Endocrinol Metab)
Vol. 305
Issue 1
Pg. E89-100
(Jul 01 2013)
ISSN: 1522-1555 [Electronic] United States |
PMID | 23651850
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- 3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid
- Acetates
- Anilides
- Dietary Fats
- GC 1 compound
- Glucose Transporter Type 4
- Phenols
- Slc2a4 protein, rat
- Thyroid Hormone Receptors beta
- Triglycerides
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Topics |
- Acetates
(pharmacology)
- Anilides
(pharmacology)
- Animals
- Dietary Fats
(pharmacology)
- Fatty Liver
(drug therapy, metabolism, prevention & control)
- Gene Expression
(drug effects)
- Gluconeogenesis
(drug effects, physiology)
- Glucose Transporter Type 4
(metabolism)
- Hyperglycemia
(chemically induced, metabolism)
- Hyperinsulinism
(chemically induced, metabolism)
- Insulin Resistance
(physiology)
- Male
- Muscle, Skeletal
(drug effects, metabolism)
- Non-alcoholic Fatty Liver Disease
- Phenols
(pharmacology)
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
(drug effects, physiology)
- Thyroid Hormone Receptors beta
(agonists, metabolism)
- Triglycerides
(metabolism)
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