Stimulation of Lactate Production in Human Granulosa Cells by Metformin and Potential Involvement of Adenosine 5′ Monophosphate-Activated Protein Kinase
| Autor: | Christopher D. Byrne, Susan Ingamells, Ananth Vijendren, Stephanie Coakley, Luckni Sellahewa, Rajiv Sreekumar, Iain T. Cameron, M. C. Richardson, Chantal D. Simonis |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adenosine monophosphate
medicine.medical_specialty Time Factors Endocrinology Diabetes and Metabolism Granulosa cell Clinical Biochemistry Context (language use) AMP-Activated Protein Kinases Models Biological Biochemistry chemistry.chemical_compound Endocrinology AMP-activated protein kinase Internal medicine Humans Hypoglycemic Agents Insulin Medicine Lactic Acid Protein kinase A Cells Cultured Granulosa Cells Dose-Response Relationship Drug biology business.industry Biochemistry (medical) Acetyl-CoA carboxylase AMPK Metformin Up-Regulation chemistry biology.protein Female Adiponectin business medicine.drug |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 94:670-677 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2008-2025 |
| Popis: | Context: Production of 3-carbon units (as lactate) by granulosa cells (GCs) is important in follicular and oocyte development and may be modulated by metformin. Objective: The aim of the study was to examine the action of metformin on GC lactate production and potential mediation via AMP-activated protein kinase (AMPK). Design: GCs were prepared from follicular aspirates. After exposure to metformin and other potential modulators of AMPK in culture, aspects of cellular function were examined. Setting: The study was conducted in a private fertility clinic/university academic center. Patients: Women undergoing routine in vitro fertilization participated in the study. Interventions: All agents were added in culture. Main Outcome Measures: Lactate output of GCs was measured. Cell extracts were prepared after culture, and phosphorylated forms of AMPK and acetyl CoA carboxylase (ACC) were assayed using Western analysis. Results: Metformin led to a rapid increase in lactate production by GCs [minimum effective dose, 250 μm; maximum dose studied, 1 mm (1.22-fold; P < 0.01)]. This dose range of metformin was similar to that required for stimulation of phospho-AMPK in GCs [minimum effective dose, 250 μm; maximum effect, 500 μm (2.01-fold; P < 0.001)]. Increasing phospho-ACC, as a representative downstream target regulated by AMPK, was apparent over a lower range (minimum effective dose, 31 μm; maximum effect, 250 μm; P < 0.001). A level of metformin (125 μm) insufficient for the stimulation of lactate output when used alone potentiated the effects of suboptimal doses of insulin on lactate production. Adiponectin (2.5 μg/ml) had a small but significant effect on lactate output. Conclusions: Metformin activates AMPK in GCs, stimulating lactate production and increasing phospho-ACC. Metformin also enhances the action of suboptimal insulin concentrations to stimulate lactate production. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|