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Elevated plasma norepinephrine inhibits insulin secretion, but adrenergic blockade reveals enhanced β-cell responsiveness in an ovine model of placental insufficiency at 0.7 of gestation

  • A. R. Macko (a1), D. T. Yates (a1), X. Chen (a1), A. S. Green (a1), A. C. Kelly (a1), L. D. Brown (a2) and S. W. Limesand (a1)...


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 threefold greater compared with 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 insulin secretion (GSIS) and glucose-potentiated arginine-stimulated insulin secretion (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, insulin-like growth factor-1 and insulin concentrations and greater plasma NE concentrations (891 ± 211 v. 292 ± 65 pg/ml; P < 0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34 ± 0.03 v. 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-cell stimulus-secretion responsiveness is present before IUGR.


Corresponding author

*Address for correspondence: S. W. Limesand, Department of Animal Sciences, University of Arizona, 1650 E Limberlost Dr., Tucson AZ 85719, USA. (Email


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1.Hendrix, N, Berghella, V. Non-placental causes of intrauterine growth restriction. Semin Perinatol. 2008; 32, 161165.
2.Reinehr, T, Kleber, M, Toschke, AM. Small for gestational age status is associated with metabolic syndrome in overweight children. Eur J Endocrinol. 2009; 160, 579584.
3.Reinehr, T, Kleber, M, Toschke, AM. Former small for gestational age (SGA) status is associated to changes of insulin resistance in obese children during weight loss. Pediatr Diabetes. 2010; 11, 431437.
4.Gatford, KL, Simmons, RA, De Blasio, MJ, Robinson, JS, Owens, JA. Review: placental programming of postnatal diabetes and impaired insulin action after IUGR. Placenta. 2010; 31, S60S65.
5.Barker, DJ, Hales, CN, Fall, CH, et al.Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993; 36, 6267.
6.Regnault, TR, Galan, HL, Parker, TA, Anthony, RV. Placental development in normal and compromised pregnancies. Placenta. 2002; 23(Suppl. A), S119S129.
7.Regnault, TR, Orbus, RJ, de Vrijer, B, et al.Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR). Placenta. 2002; 23, 132144.
8.Limesand, SW, Regnault, TR, Hay, WW Jr. Characterization of glucose transporter 8 (GLUT8) in the ovine placenta of normal and growth restricted fetuses. Placenta. 2004; 25, 7077. Vrijer, B, Regnault, TR, Wilkening, RB, Meschia, G, Battaglia, FC. Placental uptake and transport of ACP, a neutral nonmetabolizable amino acid, in an ovine model of fetal growth restriction. Am J Physiol Endocrinol Metab. 2004; 287, E1114E1124.
10.Leos, RA, Anderson, MJ, Chen, X, et al.Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction. Am J Physiol Endocrinol Metab. 2010; 298, E770E778.
11.Limesand, SW, Hay, WW Jr. Adaptation of ovine fetal pancreatic insulin secretion to chronic hypoglycaemia and euglycaemic correction. J Physiol. 2003; 547, 95105.
12.Jackson, BT, Piasecki, GJ, Cohn, HE, Cohen, WR. Control of fetal insulin secretion. Am J Physiol Regul Integr Comp Physiol. 2000; 279, R2179R2188.
13.Harwell, CM, Padbury, JF, Anand, RS, et al.Fetal catecholamine responses to maternal hypoglycemia. Am J Physiol. 1990; 259, R1126R1130., VB, Davidsen, ML, Wilkening, RB, Anthony, RV, Regnault, TR. Altered placental and fetal expression of IGFs and IGF-binding proteins associated with intrauterine growth restriction in fetal sheep during early and mid-pregnancy. Pediatr Res. 2006; 60, 507512.
15.Galan, HL, Hussey, MJ, Barbera, A, et al.Relationship of fetal growth to duration of heat stress in an ovine model of placental insufficiency. Am J Obstet Gynecol. 1999; 180, 12781282.
16.Fowden, AL. The role of insulin in fetal growth. Early Hum Dev. 1992; 29, 177181.
17.Limesand, SW, Rozance, PJ, Smith, D, Hay, WW Jr. Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction. Am J Physiol Endocrinol Metab. 2007; 293, E1716E1725.
18.Sperling, MA, Christensen, RA, Ganguli, S, Anand, R. Adrenergic modulation of pancreatic hormone secretion in utero: studies in fetal sheep. Pediatr Res. 1980; 14, 203208.
19.Rychkov, GY, Adams, MB, McMillen, IC, Roberts, ML. Oxygen-sensing mechanisms are present in the chromaffin cells of the sheep adrenal medulla before birth. J Physiol. 1998; 509, 887893.
20.Yates, DT, Macko, AR, Chen, X, et al.Hypoxemia-induced catecholamine secretion from adrenal chromaffin cells inhibits glucose-stimulated hyperinsulinemia in fetal sheep. J Physiol. 2012; 590, 54395447.
21.Bassett, JM. Metabolic effects of catecholamines in sheep. Aust J Biol Sci. 1970; 23, 903914.
22.Bassett, JM, Hanson, C. Catecholamines inhibit growth in fetal sheep in the absence of hypoxemia. Am J Physiol. 1998; 274, R1536R1545.
23.Sperling, MA, Ganguli, S, Leslie, N, Landt, K. Fetal-perinatal catecholamine secretion: role in perinatal glucose homeostasis. Am J Physiol. 1984; 247, E69E74.
24.Yates, DT, Macko, AR, Nearing, M, et al.Developmental programming in response to intrauterine growth restriction impairs myoblast function and skeletal muscle metabolism. J Pregnancy. 2012; 2012:631038. doi: 10.1155/2012/631038.
25.Chen, X, Fahy, AL, Green, AS, et al.Beta2-adrenergic receptor desensitization in perirenal adipose tissue in fetuses and lambs with placental insufficiency-induced intrauterine growth restriction. J Physiol. 2010; 588, 35393549.
26.Yates, DT, Green, AS, Limesand, SW. Catecholamines mediate multiple fetal adaptations during placental insufficiency that contribute to intrauterine growth restriction: lessons from hyperthermic sheep. J Pregnancy. 2011; 2011:740408. doi: 10.1155/2011/740408.
27.Green, AS, Rozance, PJ, Limesand, SW. Consequences of a compromised intrauterine environment on islet function. J Endocrinol. 2010; 205, 211224.
28.Limesand, SW, Rozance, PJ, Zerbe, GO, Hutton, JC, Hay, WW Jr. Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction. Endocrinology. 2006; 147, 14881497.
29.Greenough, A, Nicolaides, KH, Lagercrantz, H. Human fetal sympathoadrenal responsiveness. Early Hum Dev. 1990; 23, 913.
30.Lagercrantz, H, Sjoquist, B, Bremme, K, Lunell, NO, Somell, C. Catecholamine metabolites in amniotic fluid as indicators of intrauterine stress. Am J Obstet Gynecol. 1980; 136, 10671070.
31.Okamura, K, Watanabe, T, Tanigawara, S, et al.Biochemical evaluation of fetus with hypoxia caused by severe preeclampsia using cordocentesis. J Perinat Med. 1990; 18, 441447.
32.Pardi, G, Cetin, I, Marconi, AM, et al.Venous drainage of the human uterus: respiratory gas studies in normal and fetal growth-retarded pregnancies. Am J Obstet Gynecol. 1992; 166, 699706.
33.Limesand, SW, Rozance, PJ, Macko, AR, et al.Reductions in insulin concentrations and beta-cell mass precede growth restriction in sheep fetuses with placental insufficiency. Am J Physiol Endocrinol Metab. 2013; 304, E516E523.
34.Regnault, TR, Orbus, RJ, Battaglia, FC, Wilkening, RB, Anthony, RV. Altered arterial concentrations of placental hormones during maximal placental growth in a model of placental insufficiency. J Endocrinol. 1999; 162, 433442.
35.Limesand, SW, Jensen, J, Hutton, JC, Hay, WW Jr. Diminished β-cell replication contributes to reduced β-cell mass in fetal sheep with intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol. 2005; 288, R1297R1305.
36.Green, AS, Chen, X, Macko, AR, et al.Chronic pulsatile hyperglycemia reduces insulin secretion and increases accumulation of reactive oxygen species in fetal sheep islets. J Endocrinol. 2012; 212, 327342.
37.Regnault, TR, Orbus, RJ, Battaglia, FC, Wilkening, RB, Anthony, RV. Altered arterial concentrations of placental hormones during maximal placental growth in a model of placental insufficiency. J Endocrinol. 1999; 162, 433442.
38.Green, AS, Macko, AR, Rozance, PJ, et al.Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus. Am J Physiol Endocrinol Metab. 2011; 300, E817E823.
39.Cheung, CY. Fetal adrenal medulla catecholamine response to hypoxia-direct and neural components. Am J Physiol. 1990; 258, R1340R1346.
40.Comline, RS, Silver, M. The development of the adrenal medulla of the foetal and new-born calf. J Physiol. 1966; 183, 305340.
41.Padbury, JF, Ludlow, JK, Ervin, MG, Jacobs, HC, Humme, JA. Thresholds for physiological effects of plasma catecholamines in fetal sheep. Am J Physiol. 1987; 252, E530E537.
42.Yates, DT, Macko, AR, Chen, X, et al.Hypoxemia-induced catecholamine secretion from adrenal chromaffin cells inhibits glucose-stimulated hyperinsulinemia in fetal sheep. J Physiol. 2012; 590, 54395447.
43.Kawai, K, Yokota, C, Ohashi, S, Watanabe, Y, Yamashita, K. Evidence that glucagon stimulates insulin secretion through its own receptor in rats. Diabetologia. 1995; 38, 274276.
44.Robertson, RP. Estimation of beta-cell mass by metabolic tests: necessary, but how sufficient? Diabetes. 2007; 56, 24202424.
45.Hermans, MP, Schmeer, W, Henquin, JC. The permissive effect of glucose, tolbutamide and high K+ on arginine stimulation of insulin release in isolated mouse islets. Diabetologia. 1987; 30, 659665.
46.Schmidt, C, Bladt, F, Goedecke, S, et al.Scatter factor/hepatocytes growth factor is essential for liver development. Nature. 1995; 373, 699702.
47.Thorn, SR, Regnault, TR, Brown, LD, et al.Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle. Endocrinology. 2009; 150, 30213030.
48.Owens, JA, Falconer, J, Robinson, JS. Glucose metabolism in pregnant sheep when placental growth is restricted. Am J Physiol. 1989; 257, R350R357.
49.Owens, JA, Gatford, KL, De Blasio, MJ, et al.Restriction of placental growth in sheep impairs insulin secretion but not sensitivity before birth. J Physiol. 2007; 584, 935949.
50.Deibert, DC, DeFronzo, RA. Epinephrine-induced insulin resistance in man. J Clin Invest. 1980; 65, 717721.
51.Brown, LD, Rozance, PJ, Thorn, SR, Friedman, JE, Hay, WW Jr. Acute supplementation of amino acids increases net protein accretion in IUGR fetal sheep. Am J Physiol Endocrinol Metab. 2012; 303, E352E364.
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