Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

Abstract

Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-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 β-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 (α1D, α2A, α2C, and β1), G protein subunit-αi-2, and uncoupling protein 2 were lower (P < 0.05) compared with controls, but β-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.

Keywords: adrenergic receptor; catecholamines; intrauterine growth restriction; uncoupling protein 2; β-cell.

Fig. 1.

Daily biochemical values during treatment conditions. Plasma norepinephrine (NE) concentrations (A), plasma glucose concentrations (B), plasma insulin concentrations (C), and arterial blood partial pressure of oxygen (Po₂; D) are presented for control (n = 6) and NE fetuses (n = 6) relative to days of treatment. The samples collected on day 0 were prior to the chronic NE or vehicle infusions being initiated. Subsequent sampling was performed during the chronic infusions initiated on day 0 following the pretreatment studies and continued through day 7. Significant differences between control and NE-infused fetuses are indicated in results.

Fig. 2.

Insulin concentrations during pre- (pre) and posttreatment (post) glucose-stimulated insulin secretion (GSIS) studies. Mean plasma insulin concentrations during baseline and hyperglycemic steady-state periods for pre- and posttreatment GSIS studies are presented for control and NE-infused fetuses. **Significance, P < 0.01.

Fig. 3.

Insulin concentrations during pre- and posttreatment GPAIS studies. In the GPAIS studies, area under the curve calculations for plasma insulin concentration are presented for control and NE-infused fetuses during the pretreatment and posttreatment studies. **Significance, P < 0.01.

Fig. 4.

Expression levels in isolated pancreatic islets. The relative fold changes for adrenergic receptors (ARs), G protein subunit-α_i-2, and uncoupling protein 2 (UCP2) are presented for isolated pancreatic islets from chronic NE-infused fetuses and controls. Symbols indicate significance; *P < 0.05 and **P < 0.01.