Inverse Agonist of Nuclear Receptor ERRγ Mediates Antidiabetic Effect Through Inhibition of Hepatic Gluconeogenesis
Autor: | Yong-Hoon Kim, Dongryeol Ryu, Seung Bum Park, Su Sung Kim, Chul-Ho Lee, Yo Na Kim, Gil Tae Gang, Inkyu Lee, Jin-Young Park, Cheol Soo Choi, Hueng Sik Choi, Minseob Koh, Taebo Sim, Seung Hoi Koo, Don Kyu Kim |
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Rok vydání: | 2013 |
Předmět: |
Male
medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism Blotting Western Biology Polymerase Chain Reaction Cell Line Rats Sprague-Dawley Mice Internal medicine Gene expression Internal Medicine medicine Animals Humans Hypoglycemic Agents Inverse agonist Receptor Original Research Metabolic disorder Gluconeogenesis nutritional and metabolic diseases Type 2 Diabetes Mellitus medicine.disease Rats Mice Inbred C57BL Tamoxifen Metabolism Endocrinology Liver Receptors Estrogen Nuclear receptor Hepatocytes medicine.drug |
Zdroj: | Diabetes |
ISSN: | 1939-327X 0012-1797 |
Popis: | Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder with diverse pathological manifestations and is often associated with abnormal regulation of hepatic glucose production. Many nuclear receptors known to control the hepatic gluconeogenic program are potential targets for the treatment of T2DM and its complications. Nevertheless, the therapeutic potential of the estrogen-related receptor γ (ERRγ) in T2DM remains unknown. In this study, we show that the nuclear receptor ERRγ is a major contributor to hyperglycemia under diabetic conditions by controlling hepatic glucose production. Hepatic ERRγ expression induced by fasting and diabetic conditions resulted in elevated levels of gluconeogenic gene expression and blood glucose in wild-type mice. Conversely, ablation of hepatic ERRγ gene expression reduced the expression of gluconeogenic genes and normalized blood glucose levels in mouse models of T2DM: db/db and diet-induced obesity (DIO) mice. In addition, a hyperinsulinemic-euglycemic clamp study and long-term studies of the antidiabetic effects of GSK5182, the ERRγ-specific inverse agonist, in db/db and DIO mice demonstrated that GSK5182 normalizes hyperglycemia mainly through inhibition of hepatic glucose production. Our findings suggest that the ability of GSK5182 to control hepatic glucose production can be used as a novel therapeutic approach for the treatment of T2DM. |
Databáze: | OpenAIRE |
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