期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 306, 期 1, 页码 E58-E64出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00517.2013
关键词
adrenergic receptor; beta-cell; intrauterine growth restriction; uncoupling protein 2; catecholamines
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-084842]
- Southwest University, China [20710916]
- US Department of Agriculture-National Institute of Food and Agriculture Fellowship [2012-6701219855]
- [T32-HL-7249]
- [F32-DK-088514.]
Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and beta-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances beta-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater (P < 0.05) plasma NE concentrations and exhibited hyperglycemia (P < 0.01) and hypoinsulinemia (P < 0.01) compared with controls. GSIS during the NE infusion was also reduced (P < 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P < 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (alpha(1D), alpha(2A), alpha(2C), and beta(1)), G protein subunit-alpha (i-2), and uncoupling protein 2 were lower (P < 0.05) compared with controls, but beta-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets.
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