Placental insufficiency-induced intrauterine growth restriction (IUGR) fetuses have chronic hypoxaemia and elevated plasma catecholamine concentrations. In this study, we determined whether adrenergic responsiveness becomes desensitized in the perirenal adipose tissue of IUGR fetuses and lambs by measuring adrenergic receptor (AR) mRNA and protein levels. We also tested the ability of adrenaline to mobilize non-esterified fatty acids (NEFAs) in young lambs. Perirenal adipose tissue was collected from IUGR and control fetuses at 133 days of gestational age (dGA) and lambs at 18 days of age (dA). β 2 -AR mRNA concentrations were 59% and 74% lower (P < 0.05) in IUGR fetuses and lambs compared to controls, respectively, which also resulted in lower protein levels (P < 0.05). No treatment differences were detected for α 1A -, α 1B -, α 1D -, α 2A -, α 2B -, α 2C -, β 1 -and β 3 -AR expression. mRNA concentrations were also determined for hormone sensitive lipase (HSL), perilipin (lipid droplet-associated protein), and two adipokines, leptin and adiponectin. Adiponectin and HSL were not different between treatments at either age. Compared to controls, perilipin and leptin mRNA concentrations were lower (P < 0.05) in IUGR fetuses but not in lambs. Because of the β 2 -AR results, we challenged a second cohort of lambs with exogenous adrenaline at 21 dA. The ability of adrenaline to mobilize NEFA was 55 ± 15% lower (P < 0.05) in IUGRs than controls. Collectively, our findings indicate that elevated catecholamine exposure in utero causes desensitization of adipose tissue by down-regulation of β 2 -AR, and this persists in lambs. This impairment in adrenergic stimulated lipolysis might partially explain early onset obesity in IUGR offspring.

Chen X, Green AS, Macko AR, Yates DT, Kelly AC, Limesand SW. Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep. Am J Physiol Endocrinol Metab 306: E58 -E64, 2014. First published November 19, 2013 doi:10.1152/ajpendo.00517.2013.-Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and ␤-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 ␤-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 Ͻ 0.05) plasma NE concentrations and exhibited hyperglycemia (P Ͻ 0.01) and hypoinsulinemia (P Ͻ 0.01) compared with controls. GSIS during the NE infusion was also reduced (P Ͻ 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P Ͻ 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 (␣1D, ␣2A, ␣2C, and ␤1), G protein subunit-␣i-2, and uncoupling protein 2 were lower (P Ͻ 0.05) compared with controls, but ␤-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. adrenergic receptor; ␤-cell; intrauterine growth restriction; uncoupling protein 2; catecholamines SMALL-FOR-GESTATIONAL AGE or intrauterine growth-restricted (IUGR) infants are at greater risk for developing metabolic diseases such as type 2 diabetes mellitus (29,40,54). Impaired insulin secretion is associated with a diabetic phenotype indicating that in utero complications can permanently compromise ␤-cell development and function (27,28). A fetal sheep model with placental insufficiency-induced intruterine growth restriction shares many similarities with human IUGR fetuses, such as asymmetric growth, hypoxemia, hypoglycemia, hypoinsulinemia, and hypercatecholaminemia [epinephrine and norepinephrine (NE)] (4, 16,18,22,23,32,41,47). Furthermore, glucose-stimulated insulin secretion (GSIS) and ␤-cell mass are lower in IUGR sheep fetuses, which also replicate features in human IUGR fetuses (34 -36, 41, 53). Several characteristics of the fetal IUGR environment, including hypoglycemia, hypoxemia, and hypercatecholaminemia, are proposed to ...

In pregnancies complicated by placental insufficiency (PI), fetal hypoglycemia and hypoxemia progressively worsen during the third trimester, which increases circulating norepinephrine (NE). Pharmacological adrenergic blockade (ADR-block) at 0.9 gestation revealed that NE inhibits insulin secretion and enhanced β-cell responsiveness in fetuses with PI-induced intrauterine growth restriction (IUGR). NE concentrations in PI fetuses at 0.7 gestation were 3-fold greater compared to age-matched controls but the levels were similar to near-term controls. Therefore, our objective was to determine whether elevations in plasma NE concentrations inhibit insulin secretion and produce compensatory β-cell responsiveness in PI fetuses at 0.7 gestation. Fetal insulin was measured under basal, glucose-stimulated (GSIS), and glucose potentiated arginine-stimulated (GPAIS) conditions in the absence and presence of an ADR-block. Placental weights were 38% lower (P<0.05) in PI fetus than in controls, but fetal weights were not different. PI fetuses had lower (P<0.05) basal blood oxygen content, plasma glucose, IGF-1, and insulin concentrations and greater plasma NE concentrations (891±211 vs. 292±65 pg/ml; P<0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34±0.03 vs. 1.08±0.06 ng/ml; P<0.05). ADR-block increased GSIS in PI fetuses (1.19±0.11 ng/ml; P<0.05) but decreased GSIS in controls (0.86±0.02 ng/ml; P<0.05). Similarly, GPAIS was 44% lower (P<0.05) in PI fetuses than in controls, and ADR-block increased (P<0.05) GPAIS in PI fetuses but not in controls. Insulin content per islet was not different between treatments. We conclude that elevations in fetal plasma NE suppress insulin concentrations and that compensatory β-cells stimulus-secretion responsiveness is present before IUGR.

Low birth weight is an important risk factor for impaired glucose tolerance and diabetes later in life. One hypothesis is that fetal β-cells inherit a persistent defect as a developmental response to fetal malnutrition, a primary cause of intrauterine growth restriction (IUGR). Our understanding of fetal programming events in the human endocrine pancreas is limited, but several animal models of IUGR extend our knowledge of developmental programming in β-cells. Pathological outcomes such as β-cell dysfunction, impaired glucose tolerance, and diabetes are often observed in adult offspring from these animal models, similar to the associations of low birth weight and metabolic diseases in humans. However, the identified mechanisms underlying β-cell dysfunction across models and species are varied, likely resulting from the different methodologies used to induce experimental IUGR, as well as intraspecies differences in pancreas development. In this review, we first present the evidence for human β-cell dysfunction being associated with low birth weight or IUGR. We then evaluate relevant animal models of IUGR, focusing on the strengths of each, in order to define critical periods and types of nutrient deficiencies that can lead to impaired β-cell function. These findings frame our current knowledge of β-cell developmental programming and highlight future research directions to clarify the mechanisms of β-cell dysfunction for human IUGR.

Key points• Hypoxaemia was previously shown to lower fetal plasma insulin at euglycaemia and hyperglycaemia. Lowering insulin redistributes nutrients and spares glucose and oxygen.• Hypoxaemia also stimulates adrenal medullary secretion of adrenaline and noradrenaline, but the impact of adrenal catecholamines versus local noradrenaline secretion by sympathetic neurons has not been evaluated on insulin concentrations.• To determine the impact of adrenal medullary catecholamines on plasma insulin, we surgically demedullated the adrenal glands in fetal sheep and challenged them with acute hypoxaemia.• We found that fetal adrenal chromaffin cells were the source for hypoxia-induced increases in plasma adrenaline and noradrenaline.• Adrenal medullary catecholamines were essential for suppression of glucose-stimulated hyperinsulinaemia but not for reduced basal insulin concentrations. They also contributed to fetal hyperlactacaemia and hypocarbia independently of their effects on insulin.• This study demonstrates that fetal hypoxaemia reduces basal and glucose-stimulated insulin concentrations, but by different mechanisms. Glucose-stimulated hyperinsulinaemia is reduced by elevated plasma catecholamines secreted from the adrenal medulla, which helps to spare glucose and oxygen resources.Abstract Hypoxaemia elicits adrenergic suppression of fetal glucose-stimulated hyperinsulinaemia. We postulate that this effect is mediated by catecholamines, exclusively, from fetal adrenal chromaffin cells. To investigate this hypothesis, square-wave hyperglycaemic clamp studies were performed under normoxaemic (26 ± 0.9 mmHg) and hypoxaemic (14 ± 0.3 mmHg) steady-state conditions in near-term fetal sheep that had undergone either surgical sham or bilateral adrenal demedullation (AD), values mentioned are ± SEM. Under normoxaemic conditions plasma noradrenaline concentrations were lower in AD fetuses than in sham-operated fetuses (457 ± 122 versus 1073 ± 103 pg ml −1 , P < 0.05). Plasma insulin concentrations were not different at euglycaemia between shams (0.46 ± 0.07 ng ml −1 ) and AD fetuses (0.44 ± 0.04 ng ml −1 ) and increased (P < 0.05) with hyperglycaemia in both groups although to a lesser extent in AD fetuses (0.94 ± 0.19 ng ml −1 ) compared to shams (1.31 ± 0.15 ng ml −1 ; P < 0.05). Hypoxaemia increased plasma adrenaline (26-fold) and noradrenaline (5-fold) in shams but elicited no change in AD fetuses. Under hypoxaemic conditions, euglycaemic plasma insulin concentrations were reduced (P < 0.05) in both sham and AD fetuses to 0.30 ± 0.05 ng ml −1 and 0.27 ± 0.01 ng ml −1 respectively, and the insulin response to hyperglycaemia was abolished in shams but not affected in AD fetuses (0.33 ± 0.06 versus 0.73 ± 0.02 ng ml −1 , P < 0.05). Hypoxaemia also induced hyperlactacaemia and hypocarbia to a greater extent in shams than in AD fetuses, indicating that catecholamines potentiate reductions in oxidative metabolism independently of insulin. These findings demonstrate that the fetal adrenal chromaffin cells are the source for ...