Circulating Adrenomedullin Is Elevated in Gestational Diabetes and Its Role in Impaired Insulin Production by β-Cells
| Autor: | Michael A. Belfort, Meena Balakrishnan, Chandra Yallampalli, Manu Banadakoppa, Madhu Chauhan, Yuanlin Dong |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Blood Glucose medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment Clinical Biochemistry 030209 endocrinology & metabolism Biochemistry Cell Line Wortmannin Adrenomedullin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Pregnancy Insulin-Secreting Cells Diabetes mellitus Internal medicine medicine Humans Insulin 030212 general & internal medicine Receptors Adrenomedullin Receptor Clinical Research Articles Homeodomain Proteins Glucose tolerance test medicine.diagnostic_test business.industry Biochemistry (medical) Glucose Tolerance Test medicine.disease Gestational diabetes Diabetes Gestational chemistry Trans-Activators PDX1 Female business |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 104:697-706 |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Context Defective pancreatic β-cell adaptation in pregnancy plays an important role in the pathophysiology of gestational diabetes mellitus (GDM), but the molecular basis remains unclear. Objectives of this study were to determine if circulating levels of adrenomedullin (ADM) in women with GDM are elevated and to assess the effects of ADM on insulin synthesis and secretion by human pancreatic β-cells. Design A stable gene product of ADM precursor, midregional pro-adrenomedullin (MR-proADM), was measured in plasma of pregnant women with normal glucose tolerance (NGT, n = 10) or GDM (n = 11). The β-Lox5 cell line, derived from human pancreatic β-cells, was transduced with homeodomain transcription factor pancreatic-duodenal homeobox (PDX) factor 1 (PDX1) encoding lentiviral vector and treated with different doses of ADM. mRNA for insulin, ADM, and its receptor components in β-Lox5 cells and insulin in media were measured. Results Plasma MR-proADM levels were significantly higher in GDM compared with patients with NGT. Pancreatic β-Lox5 cells express mRNA for insulin, ADM, and its receptor components. PDX1 transduction and cell-cell contact synergistically promote β-Lox5 cells insulin mRNA and secretion. Furthermore, ADM dose-dependently inhibited mRNA and secretion of insulin in β-Lox5 cell aggregates. These inhibitory effects were blocked by ADM antagonist ADM22-52, cAMP-dependent protein kinase A inhibitor KT5720, and Erk inhibitor PD98059, but not by PI-3K the inhibitor wortmannin. Conclusions Circulating ADM concentrations were elevated in pregnant women with GDM. ADM suppresses insulin synthesis and secretion by pancreatic β-cells in vitro. Thus, increased circulating ADM may contribute to the defective adaptation of β-cells in diabetic pregnancies, and blockade of ADM actions with its antagonists may improve β-cell functions. |
| Databáze: | OpenAIRE |
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