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ORIGINAL RESEARCH |
From the Cattedra di Diabetologia, Dipartimento di Scienze Cliniche, Centro Interdipartimentale di Medicina Sociale, Università "La Sapienza," Roma, Italy.
Address reprint requests to: Professor F. Fallucca Viale del Policlinico, Diabetes Unit Department of Clinical Medical Sciences Il Clinica Medica Universita La Sapienza Roma, 00161 Italy E-mail: fallucca{at}tin.it
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Abstract |
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Methods: At baseline, AF was collected from 44 diabetic, 32 rhesus-isoimmunized, and 27 control pregnant women in late pregnancy. Fifty-two diabetic, six rhesus-isoimmunized, and nine control pregnant women had amniocentesis 2 hours after arginine infusion (30 g intravenous/30 minutes) at 33–36 weeks.
Results: Baseline AF glucose concentrations were significantly greater in diabetic women than the other conditions, and they related to the gestational age in the women with hemolytic disease of the newborn. Insulin and glucagon AF content of isoimmunized pregnancies overlapped controls, whereas insulin and insulin/glucagon molar ratios were significantly higher, and glucagon values lower, in diabetic pregnancies compared with isoimmunized and control pregnancies. In isoimmunized pregnancies, the AF concentrations of glucose, insulin, and glucagon were correlated with gestational age (less than 34, 34 weeks or more). The samples collected after arginine infusion, compared with those collected at baseline, showed significantly greater insulin and insulin/glucagon molar ratio values in diabetic (28 ± 5 versus 11 ± 1 µU/mL, P = .001; 29.4 ± 1.7 versus 12.0 ± 2.8, P = .001) and in Rh pregnant women (18 ± 6 versus 7.7 ± 0.7 µU/mL, P = .001; 30 ± 9 versus 3.4 ± 0.4 I/G, P = .001), whereas no significant difference was observed in the controls.
Conclusion: Basal islet hormone concentrations in AF are modified by maternal diabetes and further influenced by arginine administration. Arginine produces an AF response that is similar in pregnancies complicated by diabetes mellitus and rhesus-isoimmunization, despite different (hyperglycemia and euglycemia) maternal blood glucose levels.
Infants of diabetic mothers and those affected by rhesus hemolytic disease of the newborn have the same metabolic and clinical findings at birth: mild or severe hypoglycemia,1,2 hyperinsulinemia in cord blood,3,4 and anatomic changes of pancreatic islet (B-cell hyperplasia in erythroblastotic infants5 and hypertrophy associated with hyperplasia in infants of diabetic mothers6). Fetal metabolism is difficult to assess, so widespread use of amniocentesis has led to increased interest in the biochemical composition of amniotic fluid (AF). Measurements of AF insulin concentrations in diabetic pregnant women have been suggested as good indicators of fetal status because origin of AF insulin is supported by its inability to cross the placenta7 and its filtration in urine.8,9 Little information is available on glucagon secretion in fetal life, and we first measured glucagon concentrations in AF of normal pregnant women and those with pregnancies complicated by rhesus-isoimmunization10 and diabetes mellitus,11 suggesting fetal origin of pancreatic hormone.
It is well known that erythroblastosis fetalis, despite maternal euglycemia, appears to affect beta and alpha pancreatic cells in infants, with islet hyperplasia and normal beta-alpha cell ratio,12 functional evidence of hyperinsulinemia,13,14 and suppressibility of glucagon by glucose.15
We observed16 that fetal B-cell hyperfunction was precocious in diabetic pregnancy and that even a small increase of glucose in normal pregnant women might induce greater C-peptide concentrations in AF collected in early pregnancy. In a previous study,17 we observed that in diabetic pregnancy, fetal B-cell response could be amplified when amniocentesis was preceded by arginine tests in mothers. We suggested that arginine, unlike insulin, crossed the placenta, and for that reason, the amino-acid, in addition to hyperglycemia induced in fetuses by diabetic mothers, could have a synergistic effect on fetal endocrine pancreas, inducing a further increase of insulin secretion, responsible for greater insulin concentrations in AF. Our investigations of AF from pregnancies complicated by rhesus-isoimmunization and diabetes mellitus prompted us in recent years to measure insulin concentrations in AF collected after arginine infusion in rhesus-isoimmunized pregnant women. The results were compared with those from AF collected at baseline, other than with diabetic and control pregnancies.
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Materials and Methods |
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. In recent years, we also measured islet hormones in AF collected 2 hours after arginine tolerance tests (30 g arginine monochloride intravenous/30 minutes), in nine control, 52 diabetic (20 gestational, 13 non–insulin-dependent, 19 insulin-dependent), and six rhesus-isoimmunized women (four at 33 and two at 36 weeks’ gestation). The investigation was explained to all participants, and each woman gave informed consent. The mean ± standard error cord hemoglobin values in erythroblastotic infants was 12.4 ± 0.6, with a range of 6.5–18.5 g/dL; six subjects had values less than 10 g/dL. Arginine was used because it is a physiologic substrate that crosses the placenta and does not modify blood glucose levels in mothers or fetuses. Crossing the placenta, arginine might influence the fetal secretion of alpha and beta cells. If that reaction occurs, fetal hormonal response in AF can be measured, enabling a derangement of insulin or glucagon secretion to be identified. Location of the placenta by ultrasound preceded amniocenteses, which were done early in the morning after overnight fasts. Blood-stained samples were discarded. Each AF sample from a rhesus-isoimmunized pregnant woman was submitted to direct spectrophotometry for determination of optical density difference at 450 nm, according to Liley.18
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Results |
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). In women with hemolytic disease of the newborn, glucose concentrations in AF collected before 34 weeks’ gestation were significantly higher than those collected later (Table 2). Insulin concentrations and insulin/glucagon molar ratios were significantly higher in women with diabetes mellitus than in women with hemolytic disease of the newborn and controls (Table 2), and there were no significant differences among women with hemolytic disease of the newborn according to the time of amniocenteses (Table 2). Glucagon concentrations were significantly lower in women with diabetes mellitus than in women with hemolytic disease of the newborn and controls (Table 2). Among women with hemolytic disease of the newborn, glucagon concentrations were significantly greater when AF was collected later in pregnancy (after 34 weeks) (Table 2).
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). There where no significant differences in glucagon concentrations among groups.
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) or limited to samples of AF collected after 34 weeks’ gestation (8.2 ± 1 versus 18 ± 6 µU/mL, 3.3 ± 0.5 versus 30 ± 9 molar ratio), whereas there were no differences in control pregnancies. |
Discussion |
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When we split women with rhesus hemolytic disease of the newborn according to time of AF sampling (before and after 34 weeks’ gestation), we found no difference in glucose concentrations between women with hemolytic disease of the newborn and control pregnancies in AF collected at the same time (34 weeks’ gestation or more). The more recent investigation of AF collected after arginine infusion in rhesus-isoimmunized pregnant women showed that despite maternal euglycemia, arginine might have a synergistic effect on fetal B-cell secretion, shown by greater insulin concentration and higher insulin/glucagon molar ratios, similar to those found in diabetic pregnant women in the same conditions. It is likely that the impaired endocrine pancreas of the erythroblastotic infant might be disclosed, in AF, by a synergistic effect of arginine, although in normoglycemia. Our results cannot explain the cause of fetal islet hyperplasia of erythroblastotic infants. Intrauterine anoxia, a result of reduced hemoglobin concentration, might be a mechanism. Our results suggest that in erythroblastotic infants, evaluated by hormone concentration in AF, neonatal hypoglycemia might be related to induced hyperinsulinemia and to greater glucagon secretion inhibition by insulin. That suggestion confirms our previous report,21 in which we found lower glucagon plasma levels in cord blood of infants with rhesus hemolytic disease.
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Footnotes |
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Received February 25, 1999. Received in revised form August 16, 1999. Accepted August 27, 1999.
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References |
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2. Pildes RS. Infants of diabetic mothers. N Engl J Med 1973;289: 902–4.
3. From GLA, Driscoll SG, Steinke J. Serum insulin in newborn infants with erythroblastosis foetalis. Paediatrics 1969;44:549–52.
4. Sosenko IR, Kitzmiller JL, Loo SW, Blix P, Rubenstein AH, Gabbay KH. The infant of diabetic mother. Correlation of increased cord C-peptide levels with macrosomia and hypoglycemia. N Engl J Med 1979;301:859–62.[Abstract]
5. Milner RDG, Dinsdale F, Wirdnan PK, Van Assche FA. Pancreatic endocrine cell fractions in erythroblastosis fetalis. Diabetes 1983; 32:312–5.
6. Van Assche FA, Aerts L. The maternal endocrine pancreas. In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy and the newborn. Berlin: Springer-Verlag, 1979:115–31.
7. Adam Paj, Teramo K, Rahia N, Gitlini D, Schwartz R. Human fetal insulin metabolism early in gestation: Response to acute elevation of the fetal glucose concentration and placental transfer of human insulin. Diabetes 1969;18:409–16.[Medline]
8. Rubenstein AH. The significance of immunoassayable insulin in urine. JAMA 1969;209:254–6.[Medline]
9. Shiff D, Lowy C. Hypoglycemia and excretion of insulin in urine in hemolytic disease of the newborn. Ped Res 1970;4:280–5.
10. Gerlini G, Fallucca F, Pachi A, Bresadola M, Ossicini C, Russo A, et al. Amniotic fluid insulin and glucagon in normal pregnancy and pregnancy complicated by rhesus isoimmunisation. Br J Obstet Gynaecol 1977;84:819–23.[Medline]
11. Fallucca F, Gargiulo P, Troili F, Zicari D, Pimpinella G, Sciullo E, et al. Gastroenteropancreatic hormones in amniotic fluid from normal and diabetic pregnant women. Acta Endocrinologica 1986;112: suppl. 277:37–43.
12. Van Assche FA, De Gasparo M, Renaer M, Geptz W. The endocrine pancreas in erythroblastosis fetalis. Biol Neonat 1970;15:176–9.
13. Barret CT, Oliver TK. Hypoglycemia and hyperinsulinism in infants with erythroblastosis foetalis. N Eng J Med 1968;278: 1260–2.
14. Raivio KO, Osterlund K. Hypoglycemia and hyperinsulinemia associated with erythroblastosis foetalis. Pediatrics 1969;43:217–25.
15. Massi Benedetti F, Marini A, Caccamo MI, Falorni A. Blood glucose tolerance, insulin and glucagon response during intravenous glucose tolerance test in newborn infants affected by erythroblastosis foetalis. Acta Pediatrica Scand 1975;64:113–8.
16. Fallucca F, Sciullo E, Napoli A, Cardellini G, Maldonato A. Amniotic fluid insulin and C-peptide levels in diabetic and non-diabetic women during early pregnancy. J Clin Endocrinol Metab 1996;81:137–9.[Abstract]
17. Fallucca F, Gargiulo P, Troili F, Zicari D, Pimpinella G, Maldonato A, et al. Amniotic fluid insulin, C-peptide concentrations and fetal morbidity in infants of diabetic mothers. Am J Obstet Gynecol 1985;153:534–40.[Medline]
18. Liley AW. Liquor amnii analysis in the management of the pregnancy complicated by rhesus sensitization. Am J Obstet Gynecol 1961;82:1359–70.[Medline]
19. Pedersen J. Weight and length at birth of infants of diabetic mother. Acta Endocrinol 1954;16:330–42.
20. Grasso S, Messina A, Saporito N, Reitano G. Insulin secretion in the premature infant: Response to glucose and amino-acids. Pediatr Res 1973;14:782–3.
21. Fallucca F, Gerlini G, Russo A, Sbraccia C. Glucagon, insulin and insulin/glucagon molar ratio at birth in normal infants and in infants with RH hemolytic disease of the newborn. Horm Metab Res 1977;9:518–9.[Medline]
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