title: Antihyperglycemic mechanism of metformin occurs via the AMPK/LXRα/POMC pathway.
abstract: Metformin is a first-line drug for treating type 2 diabetes. Although metformin is known to phosphorylate AMP-activated protein kinase (AMPK), it is unclear how the glucose-lowering effect of metformin is related to AMPK activation. The aim of this study was to identify the urinary endogenous metabolites affected by metformin and to identify the novel underlying molecular mechanisms related to its anti-diabetic effect. Fourteen healthy male subjects were orally administered metformin (1000 mg) once. First morning urine samples were taken before and after administration to obtain metabolomic data. We then further investigated the anti-diabetic mechanism of metformin in vitro and in vivo. The fluctuation of the metabolite cortisol indicated that the neuroendocrine system was involved in the anti-diabetic effect of metformin. Actually we found that metformin induced AMPK/liver X receptor α (LXRα) phosphorylation, followed by pro-opiomelanocortin (POMC) suppression in rat pituitary cells. We confirmed this result by administering metformin in an animal study. Given that cortisol stimulates gluconeogenesis, we propose the anti-hyperglycemic effect of metformin is attributed to reduced POMC/adrenocorticotropic hormone (ACTH)/cortisol levels following AMPK/LXRα phosphorylation in the pituitaries.
authors: 1] Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea [2] Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Kumsun
authors: K
authors: Cho
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea.
authors: Jae Yong
authors: JY
authors: Chung
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Sung Kweon
authors: SK
authors: Cho
authors: 1] Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Hyun-Woo
authors: HW
authors: Shin
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors: In-Jin
authors: IJ
authors: Jang
authors: 1] Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [3] Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Jong-Wan
authors: JW
authors: Park
authors: 1] Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea [2] Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Kyung-Sang
authors: KS
authors: Yu
authors: 1] Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea [2] Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Joo-Youn
authors: JY
authors: Cho
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D000071518:Liver X Receptors; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D008954:Models, Biological; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D025341:Principal Component Analysis; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D006854:Hydrocortisone
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