ArticleDiabetes2012
Metformin inhibits growth hormone-mediated hepatic PDK4 gene expression through induction of orphan nuclear receptor small heterodimer partner.
Article in Diabetes, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction.Aging cell · 2026Article
- Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway.Experimental & molecular medicine · 2023Article
- Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients.Endocrine connections · 2022Article
- Review
- Nrf2-SHP Cascade-Mediated STAT3 Inactivation Contributes to AMPK-Driven Protection Against Endotoxic Inflammation.Frontiers in immunology · 2020Article
- Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases.British journal of cancer · 2019Article
- The Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism.Cell metabolism · 2019Article
- Targeting hepatic pyruvate dehydrogenase kinases restores insulin signaling and mitigates ChREBP-mediated lipogenesis in diet-induced obese mice.Molecular metabolism · 2018Article
- Diurnal Variation in PDK4 Expression Is Associated With Plasma Free Fatty Acid Availability in People.The Journal of clinical endocrinology and metabolism · 2018Article
- Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2.Cell metabolism · 2014Article
- The role of pyruvate dehydrogenase kinase in diabetes and obesity.Diabetes & metabolism journal · 2014Review
- Regulation of pyruvate metabolism in metabolic-related diseases.Reviews in endocrine & metabolic disorders · 2014Review
- The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility.Nutrition & metabolism · 2014Article
- Article
- Energy metabolism in the liver.Comprehensive Physiology · 2014Review
- Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes.PloS one · 2013Article
- Transcriptional regulation of pyruvate dehydrogenase kinase.Diabetes & metabolism journal · 2012Article
Corrections and comments
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Authors and funding
12 authors at 8 institutions in 2 countries.
Funding
Abstract
Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP-dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.