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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

Published online by Cambridge University Press:  10 April 2013

A. R. Macko ,
D. T. Yates ,
X. Chen ,
A. S. Green ,
A. C. Kelly ,
L. D. Brown  and
S. W. Limesand
A. R. Macko
Affiliation:
Department of Animal Sciences, The University of Arizona, Tucson, AZ, USA
D. T. Yates
Affiliation:
Department of Animal Sciences, The University of Arizona, Tucson, AZ, USA
X. Chen
Affiliation:
Department of Animal Sciences, The University of Arizona, Tucson, AZ, USA
A. S. Green
Affiliation:
Department of Animal Sciences, The University of Arizona, Tucson, AZ, USA
A. C. Kelly
Affiliation:
Department of Animal Sciences, The University of Arizona, Tucson, AZ, USA
L. D. Brown
Affiliation:
Department of Pediatrics, Perinatal Research Center, University of Colorado School of Medicine, Aurora, CO, USA
S. W. Limesand*
Affiliation:
Department of Animal Sciences, The University of Arizona, Tucson, AZ, USA
*
*Address for correspondence: S. W. Limesand, Department of Animal Sciences, University of Arizona, 1650 E Limberlost Dr., Tucson AZ 85719, USA. (Email [email protected])
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Abstract

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.

Keywords

adrenergic receptorsfetusintrauterine growth restrictionpancreas
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 5 , October 2013 , pp. 402 - 410
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2013 

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References

1.Hendrix, N, Berghella, V. Non-placental causes of intrauterine growth restriction. Semin Perinatol. 2008; 32, 161–165.CrossRefGoogle ScholarPubMed
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, 579–584.Google Scholar
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, 431–437.CrossRefGoogle ScholarPubMed
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, S60–S65.Google Scholar
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, 62–67.Google Scholar
6.Regnault, TR, Galan, HL, Parker, TA, Anthony, RV. Placental development in normal and compromised pregnancies. Placenta. 2002; 23(Suppl. A), S119–S129.CrossRefGoogle ScholarPubMed
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, 132–144.Google Scholar
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, 70–77.CrossRefGoogle ScholarPubMed
9.de 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, E1114–E1124.CrossRefGoogle Scholar
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, E770–E778.CrossRefGoogle ScholarPubMed
11.Limesand, SW, Hay, WW Jr. Adaptation of ovine fetal pancreatic insulin secretion to chronic hypoglycaemia and euglycaemic correction. J Physiol. 2003; 547, 95–105.CrossRefGoogle ScholarPubMed
12.Jackson, BT, Piasecki, GJ, Cohn, HE, Cohen, WR. Control of fetal insulin secretion. Am J Physiol Regul Integr Comp Physiol. 2000; 279, R2179–R2188.CrossRefGoogle ScholarPubMed
13.Harwell, CM, Padbury, JF, Anand, RS, et al.Fetal catecholamine responses to maternal hypoglycemia. Am J Physiol. 1990; 259, R1126–R1130.Google ScholarPubMed
14.de, 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, 507–512.Google Scholar
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, 1278–1282.CrossRefGoogle Scholar
16.Fowden, AL. The role of insulin in fetal growth. Early Hum Dev. 1992; 29, 177–181.Google Scholar
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, E1716–E1725.Google Scholar
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, 203–208.CrossRefGoogle ScholarPubMed
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, 887–893.CrossRefGoogle ScholarPubMed
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, 5439–5447.CrossRefGoogle Scholar
21.Bassett, JM. Metabolic effects of catecholamines in sheep. Aust J Biol Sci. 1970; 23, 903–914.Google Scholar
22.Bassett, JM, Hanson, C. Catecholamines inhibit growth in fetal sheep in the absence of hypoxemia. Am J Physiol. 1998; 274, R1536–R1545.Google ScholarPubMed
23.Sperling, MA, Ganguli, S, Leslie, N, Landt, K. Fetal-perinatal catecholamine secretion: role in perinatal glucose homeostasis. Am J Physiol. 1984; 247, E69–E74.Google ScholarPubMed
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.Google Scholar
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, 3539–3549.CrossRefGoogle ScholarPubMed
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.Google Scholar
27.Green, AS, Rozance, PJ, Limesand, SW. Consequences of a compromised intrauterine environment on islet function. J Endocrinol. 2010; 205, 211–224.CrossRefGoogle ScholarPubMed
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, 1488–1497.CrossRefGoogle ScholarPubMed
29.Greenough, A, Nicolaides, KH, Lagercrantz, H. Human fetal sympathoadrenal responsiveness. Early Hum Dev. 1990; 23, 9–13.Google Scholar
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, 1067–1070.CrossRefGoogle ScholarPubMed
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, 441–447.CrossRefGoogle ScholarPubMed
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, 699–706.Google Scholar
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, E516–E523.Google Scholar
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, 433–442.CrossRefGoogle Scholar
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, R1297–R1305.CrossRefGoogle ScholarPubMed
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, 327–342.CrossRefGoogle ScholarPubMed
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, 433–442.CrossRefGoogle Scholar
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, E817–E823.Google Scholar
39.Cheung, CY. Fetal adrenal medulla catecholamine response to hypoxia-direct and neural components. Am J Physiol. 1990; 258, R1340–R1346.Google Scholar
40.Comline, RS, Silver, M. The development of the adrenal medulla of the foetal and new-born calf. J Physiol. 1966; 183, 305–340.Google Scholar
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, E530–E537.Google ScholarPubMed
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, 5439–5447.CrossRefGoogle Scholar
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, 274–276.Google Scholar
44.Robertson, RP. Estimation of beta-cell mass by metabolic tests: necessary, but how sufficient? Diabetes. 2007; 56, 2420–2424.CrossRefGoogle ScholarPubMed
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, 659–665.Google Scholar
46.Schmidt, C, Bladt, F, Goedecke, S, et al.Scatter factor/hepatocytes growth factor is essential for liver development. Nature. 1995; 373, 699–702.CrossRefGoogle ScholarPubMed
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, 3021–3030.CrossRefGoogle ScholarPubMed
48.Owens, JA, Falconer, J, Robinson, JS. Glucose metabolism in pregnant sheep when placental growth is restricted. Am J Physiol. 1989; 257, R350–R357.Google ScholarPubMed
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, 935–949.Google Scholar
50.Deibert, DC, DeFronzo, RA. Epinephrine-induced insulin resistance in man. J Clin Invest. 1980; 65, 717–721.CrossRefGoogle ScholarPubMed
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, E352–E364.CrossRefGoogle ScholarPubMed