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Maternal-fetal plasma glucose relationships in late monkey pregnancy
Maternal-fetal plasma glucose relationships in late monkey pregnancy RONALD A. CHEZ, M.D. DANIEL H. MINTZ, M.D. W. ANN REYNOLDS, PH.D. DONALD L. HUTCHINSON, M.D.t Bethesda, Maryland, Miami, Florida, and Chicago, Illinois
Maternal hyperglycemia was induced in six late gestation monkey pregnancies with intravenous glucose injection plus infusion. The maximum measured plasma glucose levels of the mother varied from 380 to 1,020 Gm. per cent. A significant linear relationship evolved beiween maietnal and feial plasma glucose peak coneenirations. A satu,ration litnit
to placental transfer of glucose across the placenta is not apparent from these data.
stance, a linear relationship between base-line maternal and fetal plasma glucose concentrations in human and monkey pregnancy has been observed. 7 " 10 Further, there is no apparent difference in placental transfer of glucose between the monkey and human being.U· 12 In our previous work we examined the linearity of the maternal-fetal glucose concentration gradient at maternal levels no greater than 270 mg. per cent; however, this may not be a high enough level to provide information on placental glucose transfer saturation. The study in this paper was designed to answer that question.
0 A K LEY AND C 0- W 0 R K E R S 1 have presented data obtained from normal and diabetic human pregnancies in which the maternal-fetal plasma glucose gradients did not remain linear when the level of glucose in maternal blood was substantially raised above physiologic values. This finding prompted the suggestion that there is a maximum maternal plasma concentration above which fetal plasma glucose is not further increased. Whether this was secondary to a saturation of placental transfer mechanisms or a fetal adaptive response of an undefined nature to protect against hyperglycemia was not established. The normal and streptozotocin-induced glucoseintolerant monkey ( Macaca mulatta) has been used to examine aspects of carbohydrate metabolism in pregnancy. 2 • 6 Data from this animal model equate to that obtained from human pregnancy. For in-
Methods Six accurately timed Rhesus monkey gestations (± one day) bred and maintained in the breeding colonies of the University of Pittsburgh and the University of Illinois were used. Two animals were normal and four received streptozotocin (SZ) prior to conception. Three of the latter had fasting hyperglycemia, glucosuria, and severe glucose intolerance (67, 85, 446). The other SZ animal had moderate glucose intolerance as demonstrated by a prolonged time for the disappearance of injected glucose and a normal fasting plasma glucose level. Experiments were performed under phencyclidine premedication and halothane anesthesia. As described in detail previously, 2 fetal blood samples were obtained sequentially from a T tube cannula in an interplacental vessel; maternal samples were obtained from a cannula in the vena cava.
From the Pregnancy Research Branch, National Institute of Child Health and Human Development, the Department of Medicine, University of Miami School of Medicine, and the Department of Anatomy, University of Illinois. Supported in part by grants from the Juvenile Diabetes Foundation and The National Foundation (CRBS 243). Received for publication May 7, 1974. Accepted June 5, 1974. Reprint requests: Dr. Ronald A. Chez, National Institutes Health Clinical Center, Room 13N234, Bethesda, Maryland 20014. tDied September 17,1973.
938
Maternal-fetal plasma glucose relationships 939
Volume 121 Number 7
Table I. Effect of intravenous glucose to the mother on maternal and fetal plasma glucose, insulin, and growth hormone concentrations
Animal
778, Normal
I
Amount
3.8 Gm. glucose
Site
Maternal
injected at 0
vena cava,
min., 380 mg./ min. glucose infused 0-30 min.
fetal vein
717, Nor- 5.8 Gm. glucose injected at 0 mal min., 500 mg./
57,
sz
2.5 Gm. glucose
injected at 0 min., 15 min., 290 mg./min. glucose infused 0-15 min., 580 mg./min. infused 15-30 min.
0
CHO* INSt CHO INS SGHt
48 758 810 L5 18.3 2L3 36 262 319 0.5 0.7 0.7 13 15 13
857 40.0 357 0.8 17
371 226 144 Day gesta42.0 55.0 tion, mother 7.6 Kg., female fetus 352 338 0.7 0.9 0.41 Kg., placenta 0.15 Kg., 14 10 amniotic fluid not measured
58 354 293 0.9 18.5 18.3 42 82 174 0.5 0.5 0.7 14 12 14
379 17.5
131 168 Day gesta220 16.5 16.5 tion, mother 11.6 192 158 Kg., 1uale fetus 1.8 2.5 0.5 7 Kg., pla10 13 centa 0.16 Kg., amniotic fluid not measured
Maternal vena cava,
CHO INS
fetal vein
CHO
min. glucose infused 0-30 min.
Time (min.)
Plasma assay
L3
62 0.8
INS SGH
~vfaternal
CHO
zo
I
2o
vena cava, fetal vein
INS CHO INS SGH
112 102 593 930 2.6 2.8 2.6 2.8 94 256 409 5.5 3.5 6.3 11 14 17
3o
198
1.0
11
1
/"\1\F"\
1,u.:::u
2.8 535 7.6 14
26,SZ
:1.0 Gm. glucose injected at 0 min., 310 mg./ min. glucose infused 0-30 min.
Maternal vena cava, fetal artery
CHO INS CHO INS SGH
54 559 678 4.7 2.2 6.2 42 164 227 1.2 8.0 6.8 25 17 23
sz
3.0 Gm. glucose injected at 0 min., :!90 mg./ min. glucose infused 0-30 min.
Maternal vena cava, fetal artery
CHO INS CHO INS SGH
100 103 500 667 0.8 0.5 0.6 1.0 107 219 6.6 20.0 10 12
324 22.0 9
3.0 Gm. glucose injected at 0 min., 290 mg./ min. glucose infused 0-15 min.
Maternal vena cava, fetal artery
CHO INS CHO INS SGH
217
443
85,
I
45
I
60
I
Comments
605 488 117 Day gesta2.9 2.8 tion, mother 5.2 549 Kg., male fetus 535 9.5 10.4 0.29 Kg., pla14 13 centa 0.13 Kg., amniotic fluid 152 mi.
895 7.7 398 10.2 14
148 Day gesta503 652 7.8 tion, mother 6.1 10.1 Kg., male fetus 316 340 12.1 15.0 0.45 Kg., pla14 27 centa 0.15 Kg., amn1ot1c fluid 223 mi.
714
393 140 Day gesta0.6 tion, mother 5.9 348 343 Kg., female fetus 24.0 21.0 0.49 Kg., pla8 11 centa 0.17 Kg., amniotic fluid
1.0
452
1.0
not tneasured
446,SZ
583 802 214 1.2 1.3 1.2 1.2 171 394 6.3 9.8 16
15
1.2
362 5.9 15
400
379 145 Day gesta0.9 0.8 tion, mother 6.1 352 329 Kg., female fetus 5.1 4.3 0.41 Kg., pla22 24 centa 0.14 Kg., amniotic fluid not measured
*Plasma glucose (milligrams per 100 mi.). t Plasma insulin ( millimicrograms per milliliter). tPiasma growth hormone (millimicrograms per milliliter).
After obtaining base-line samples, 0.5 Gm. of glucose per kilogram of body weight was injected intravenously to the mother. An infusion cf 0.1 Gm. of glucose per kilogram of body weight per minute was then infused for 15 or 30 minutes. Plasma glucose levels were determined by a glucose oxidase method (Glucostat, Worthington Laboratories) ;
plasma insulin and growth hormone were determined by radioimmunoassay. 2 Results
Table I details some of the clinical characteristics of the animals as well as the sequential maternal and fetal concentrations of plasma glucose, insulin,
940 Chez et ol.
April!, 1975 Am.]. Obstet. Gynecol.
600
~ 500
•
Normal
"
Stz
r
~
pregnancy at 117 days' gestation) and not in the two normal control pregnancies. Fig. 1 correlates the peaks in maternal and fetal plasma glucose concentrations. A linear relationship evolved ( r 0.94, p < 0.01).
"
0 94
E"
~ 4001
"
3001 i200L·
Comment
~
100 0
300
I
400
500
600
700
800
900
1000
1100
MATERNAL PLASMA GLUCOSE ( mg %)
Fig. 1. Monkey maternal-fetal plasma glucose ratio.
and growth hormone volumes obtained during the experiments. The maximum measured plasma glucose levels of the mother obtained after glucose injection/infusion vary from 379 to 1,020 Gm. per cent. The extent of maternal plasma insulin response relates to the degree of induced glucose intolerance of the animals. The changes in fetal plasma glucose concentrations show a consistent pattern of a gradual increment to a peak and then a slow decline in the presence of more rapidly decreasing maternal glucose levels. The peak fetal plasma glucose range is 198 to 549 mg. per cent. In four instances, the maternal-fetal plasma glucose gradient is reversed at the end of the sampling time. Prompt increments in fetal plasma insulin concentrations are seen in the four SZ pregnancies (including particularly the
REFERENCES
I. Oakley, N. W., Beard, R. W., and Turner, R. C.: Br. Med. ]. l: 466, 1972. 2. Mintz, D. H., Chez, R. A., and Horger, E. 0., III: J. Clin. Invest. 48: 176, 1969. 3. Chez, R. A., Mintz, D. H., Horger, E. 0., III, and Hutchinson, D. L.: J. Clin. Invest. 49: 1517, 1970. 4. Chez, R. A., Mintz, D. H., and Hutchinson, D. L.: Metabolism 20: 805, 1971. 5. Mintz, D. H., Chez, R. A., and Hutchinson, D. L.: J. Clin. Invest. 51: 837, 1972. 6. Pitkin, R. M., and Reynolds, W. A.: Diabetes 19: 85, i970. 7. Wolf, H., Stubbe, P., and Sabata, V.: Pediatrics 45: 36, 1970.
The effects of exogenously induced maternal hyperglycemia upon fetal-newborn plasma glucose levels in the human being at term have been examined. 1 • 7 -n. 13 In these studies, maximum maternal values of 180 to 450 mg. per cent and associated fetal values of 170 to 300 mg. per cent were obtained; the correlation was linear in those studies in which it was examined. We have previously reported a significant correlation between monkey maternal and fetal plasma glucose levels at maternal concentrations of from 40 to 268 mg. per cent. 10 In this present study, maternal glucose values up to 1,020 Gm. per cent also result in a linear relationship with fetal plasma glucose levels. A saturation limit to placental transfer of glucose in either the normal or SZ pregnancy is not apparent. This contrasts with the human data and interpretations of Oakley and associates. 1 However, the conditions of their experiments differ from ours in species and length of gestation (term human being versus premature monkey) , the amount and rate of glucose infused, the peak maternal plasma glucose concentrations obtained, and the site of fetal sampling. Possibly, equitable data would be obtained in the human being and monkey under more similar experimental conditions.
8. Paterson, P., Phillips, L., and Wood, C.: AM. J. 0BSTET. GYNECOL. 102: 938, 1967. 9. Coltart, T. M., Beard, R. W., Turner, R. C., and Oakley, N. W.: Br. Med. J. 4: 17, 1969. 10. Chez, R. A., Mintz, D. H., and Hutchinson, D. L.: In Scow, R. 0., editor: Proceedings Fourth International Congress on Endocrinology, 1974, p. 1017. 11. Chinard, F. P., Danesino, V., Hartmann, W. L., Huggett, A., St. G., Paul, W., and Reynolds, S. R. M.: J. Physiol. 132: 289, 1956. 12. Battaglia, F. C., Helleghers, A. E., Heller, C. ]., and Behrman, R.: AM. J. 0BSTET. GYNECOL. 88: 32, 1964. 13. Cordaro, L., Jr., Grunt, ]. A., and Anderson, G. G.: AM. ]. 0BSTET. GYNECOL. 107: 560, 1970.
Maternal hyperglycemia was induced in six late gestation monkey pregnancies with intravenous glucose injection plus infusion. The maximum measured plasma glucose levels of the mother varied from 380 to 1,020 Gm. per cent. A significant linear relationship evolved beiween maietnal and feial plasma glucose peak coneenirations. A satu,ration litnit
to placental transfer of glucose across the placenta is not apparent from these data.
stance, a linear relationship between base-line maternal and fetal plasma glucose concentrations in human and monkey pregnancy has been observed. 7 " 10 Further, there is no apparent difference in placental transfer of glucose between the monkey and human being.U· 12 In our previous work we examined the linearity of the maternal-fetal glucose concentration gradient at maternal levels no greater than 270 mg. per cent; however, this may not be a high enough level to provide information on placental glucose transfer saturation. The study in this paper was designed to answer that question.
0 A K LEY AND C 0- W 0 R K E R S 1 have presented data obtained from normal and diabetic human pregnancies in which the maternal-fetal plasma glucose gradients did not remain linear when the level of glucose in maternal blood was substantially raised above physiologic values. This finding prompted the suggestion that there is a maximum maternal plasma concentration above which fetal plasma glucose is not further increased. Whether this was secondary to a saturation of placental transfer mechanisms or a fetal adaptive response of an undefined nature to protect against hyperglycemia was not established. The normal and streptozotocin-induced glucoseintolerant monkey ( Macaca mulatta) has been used to examine aspects of carbohydrate metabolism in pregnancy. 2 • 6 Data from this animal model equate to that obtained from human pregnancy. For in-
Methods Six accurately timed Rhesus monkey gestations (± one day) bred and maintained in the breeding colonies of the University of Pittsburgh and the University of Illinois were used. Two animals were normal and four received streptozotocin (SZ) prior to conception. Three of the latter had fasting hyperglycemia, glucosuria, and severe glucose intolerance (67, 85, 446). The other SZ animal had moderate glucose intolerance as demonstrated by a prolonged time for the disappearance of injected glucose and a normal fasting plasma glucose level. Experiments were performed under phencyclidine premedication and halothane anesthesia. As described in detail previously, 2 fetal blood samples were obtained sequentially from a T tube cannula in an interplacental vessel; maternal samples were obtained from a cannula in the vena cava.
From the Pregnancy Research Branch, National Institute of Child Health and Human Development, the Department of Medicine, University of Miami School of Medicine, and the Department of Anatomy, University of Illinois. Supported in part by grants from the Juvenile Diabetes Foundation and The National Foundation (CRBS 243). Received for publication May 7, 1974. Accepted June 5, 1974. Reprint requests: Dr. Ronald A. Chez, National Institutes Health Clinical Center, Room 13N234, Bethesda, Maryland 20014. tDied September 17,1973.
938
Maternal-fetal plasma glucose relationships 939
Volume 121 Number 7
Table I. Effect of intravenous glucose to the mother on maternal and fetal plasma glucose, insulin, and growth hormone concentrations
Animal
778, Normal
I
Amount
3.8 Gm. glucose
Site
Maternal
injected at 0
vena cava,
min., 380 mg./ min. glucose infused 0-30 min.
fetal vein
717, Nor- 5.8 Gm. glucose injected at 0 mal min., 500 mg./
57,
sz
2.5 Gm. glucose
injected at 0 min., 15 min., 290 mg./min. glucose infused 0-15 min., 580 mg./min. infused 15-30 min.
0
CHO* INSt CHO INS SGHt
48 758 810 L5 18.3 2L3 36 262 319 0.5 0.7 0.7 13 15 13
857 40.0 357 0.8 17
371 226 144 Day gesta42.0 55.0 tion, mother 7.6 Kg., female fetus 352 338 0.7 0.9 0.41 Kg., placenta 0.15 Kg., 14 10 amniotic fluid not measured
58 354 293 0.9 18.5 18.3 42 82 174 0.5 0.5 0.7 14 12 14
379 17.5
131 168 Day gesta220 16.5 16.5 tion, mother 11.6 192 158 Kg., 1uale fetus 1.8 2.5 0.5 7 Kg., pla10 13 centa 0.16 Kg., amniotic fluid not measured
Maternal vena cava,
CHO INS
fetal vein
CHO
min. glucose infused 0-30 min.
Time (min.)
Plasma assay
L3
62 0.8
INS SGH
~vfaternal
CHO
zo
I
2o
vena cava, fetal vein
INS CHO INS SGH
112 102 593 930 2.6 2.8 2.6 2.8 94 256 409 5.5 3.5 6.3 11 14 17
3o
198
1.0
11
1
/"\1\F"\
1,u.:::u
2.8 535 7.6 14
26,SZ
:1.0 Gm. glucose injected at 0 min., 310 mg./ min. glucose infused 0-30 min.
Maternal vena cava, fetal artery
CHO INS CHO INS SGH
54 559 678 4.7 2.2 6.2 42 164 227 1.2 8.0 6.8 25 17 23
sz
3.0 Gm. glucose injected at 0 min., :!90 mg./ min. glucose infused 0-30 min.
Maternal vena cava, fetal artery
CHO INS CHO INS SGH
100 103 500 667 0.8 0.5 0.6 1.0 107 219 6.6 20.0 10 12
324 22.0 9
3.0 Gm. glucose injected at 0 min., 290 mg./ min. glucose infused 0-15 min.
Maternal vena cava, fetal artery
CHO INS CHO INS SGH
217
443
85,
I
45
I
60
I
Comments
605 488 117 Day gesta2.9 2.8 tion, mother 5.2 549 Kg., male fetus 535 9.5 10.4 0.29 Kg., pla14 13 centa 0.13 Kg., amniotic fluid 152 mi.
895 7.7 398 10.2 14
148 Day gesta503 652 7.8 tion, mother 6.1 10.1 Kg., male fetus 316 340 12.1 15.0 0.45 Kg., pla14 27 centa 0.15 Kg., amn1ot1c fluid 223 mi.
714
393 140 Day gesta0.6 tion, mother 5.9 348 343 Kg., female fetus 24.0 21.0 0.49 Kg., pla8 11 centa 0.17 Kg., amniotic fluid
1.0
452
1.0
not tneasured
446,SZ
583 802 214 1.2 1.3 1.2 1.2 171 394 6.3 9.8 16
15
1.2
362 5.9 15
400
379 145 Day gesta0.9 0.8 tion, mother 6.1 352 329 Kg., female fetus 5.1 4.3 0.41 Kg., pla22 24 centa 0.14 Kg., amniotic fluid not measured
*Plasma glucose (milligrams per 100 mi.). t Plasma insulin ( millimicrograms per milliliter). tPiasma growth hormone (millimicrograms per milliliter).
After obtaining base-line samples, 0.5 Gm. of glucose per kilogram of body weight was injected intravenously to the mother. An infusion cf 0.1 Gm. of glucose per kilogram of body weight per minute was then infused for 15 or 30 minutes. Plasma glucose levels were determined by a glucose oxidase method (Glucostat, Worthington Laboratories) ;
plasma insulin and growth hormone were determined by radioimmunoassay. 2 Results
Table I details some of the clinical characteristics of the animals as well as the sequential maternal and fetal concentrations of plasma glucose, insulin,
940 Chez et ol.
April!, 1975 Am.]. Obstet. Gynecol.
600
~ 500
•
Normal
"
Stz
r
~
pregnancy at 117 days' gestation) and not in the two normal control pregnancies. Fig. 1 correlates the peaks in maternal and fetal plasma glucose concentrations. A linear relationship evolved ( r 0.94, p < 0.01).
"
0 94
E"
~ 4001
"
3001 i200L·
Comment
~
100 0
300
I
400
500
600
700
800
900
1000
1100
MATERNAL PLASMA GLUCOSE ( mg %)
Fig. 1. Monkey maternal-fetal plasma glucose ratio.
and growth hormone volumes obtained during the experiments. The maximum measured plasma glucose levels of the mother obtained after glucose injection/infusion vary from 379 to 1,020 Gm. per cent. The extent of maternal plasma insulin response relates to the degree of induced glucose intolerance of the animals. The changes in fetal plasma glucose concentrations show a consistent pattern of a gradual increment to a peak and then a slow decline in the presence of more rapidly decreasing maternal glucose levels. The peak fetal plasma glucose range is 198 to 549 mg. per cent. In four instances, the maternal-fetal plasma glucose gradient is reversed at the end of the sampling time. Prompt increments in fetal plasma insulin concentrations are seen in the four SZ pregnancies (including particularly the
REFERENCES
I. Oakley, N. W., Beard, R. W., and Turner, R. C.: Br. Med. ]. l: 466, 1972. 2. Mintz, D. H., Chez, R. A., and Horger, E. 0., III: J. Clin. Invest. 48: 176, 1969. 3. Chez, R. A., Mintz, D. H., Horger, E. 0., III, and Hutchinson, D. L.: J. Clin. Invest. 49: 1517, 1970. 4. Chez, R. A., Mintz, D. H., and Hutchinson, D. L.: Metabolism 20: 805, 1971. 5. Mintz, D. H., Chez, R. A., and Hutchinson, D. L.: J. Clin. Invest. 51: 837, 1972. 6. Pitkin, R. M., and Reynolds, W. A.: Diabetes 19: 85, i970. 7. Wolf, H., Stubbe, P., and Sabata, V.: Pediatrics 45: 36, 1970.
The effects of exogenously induced maternal hyperglycemia upon fetal-newborn plasma glucose levels in the human being at term have been examined. 1 • 7 -n. 13 In these studies, maximum maternal values of 180 to 450 mg. per cent and associated fetal values of 170 to 300 mg. per cent were obtained; the correlation was linear in those studies in which it was examined. We have previously reported a significant correlation between monkey maternal and fetal plasma glucose levels at maternal concentrations of from 40 to 268 mg. per cent. 10 In this present study, maternal glucose values up to 1,020 Gm. per cent also result in a linear relationship with fetal plasma glucose levels. A saturation limit to placental transfer of glucose in either the normal or SZ pregnancy is not apparent. This contrasts with the human data and interpretations of Oakley and associates. 1 However, the conditions of their experiments differ from ours in species and length of gestation (term human being versus premature monkey) , the amount and rate of glucose infused, the peak maternal plasma glucose concentrations obtained, and the site of fetal sampling. Possibly, equitable data would be obtained in the human being and monkey under more similar experimental conditions.
8. Paterson, P., Phillips, L., and Wood, C.: AM. J. 0BSTET. GYNECOL. 102: 938, 1967. 9. Coltart, T. M., Beard, R. W., Turner, R. C., and Oakley, N. W.: Br. Med. J. 4: 17, 1969. 10. Chez, R. A., Mintz, D. H., and Hutchinson, D. L.: In Scow, R. 0., editor: Proceedings Fourth International Congress on Endocrinology, 1974, p. 1017. 11. Chinard, F. P., Danesino, V., Hartmann, W. L., Huggett, A., St. G., Paul, W., and Reynolds, S. R. M.: J. Physiol. 132: 289, 1956. 12. Battaglia, F. C., Helleghers, A. E., Heller, C. ]., and Behrman, R.: AM. J. 0BSTET. GYNECOL. 88: 32, 1964. 13. Cordaro, L., Jr., Grunt, ]. A., and Anderson, G. G.: AM. ]. 0BSTET. GYNECOL. 107: 560, 1970.