Diabetes Research and Clinical Practice,
10 (1990)
147-152 147
Elsevier DIABET
00430
Quantitative
analysis of serum q-acid glycoprotein levels in normal and diabetic pregnancy
Masashi Honda ‘, Yasue Omori I, Satomi Minei ‘, Toshiko Oshiyama I, Meimi Shimizu ‘, Mayumi Sanaka ‘, Tomoko Kohama ‘, Masao Nakabayashi2 and Yukimasa Hirata ’ ‘Diabetes Centre and ‘Maternal
and Perinatal Centre, Tokyo Women’s Medical College, Tokyo, Japan
(Received 22 February 1990) (Revision received 19 April 1990) (Accepted 25 April 1990)
Summary In an attempt to clarify the mechanism of lipid metabolism during pregnancy, q-acid glycoprotein (CC,-AG) was analyzed in normal and diabetic pregnant women. Seventy-two determinations of serum CX, -AG levels were performed in 18 diabetic pregnant women and 82 determinations in 82 normal pregnant women in all three trimesters and within 14 days postpartum. Serum CC,-AG levels in both normal and diabetic pregnant women decreased throughout pregnancy and rapidly increased postpartum. In all gestational stages, the serum a,-AG levels were lower in diabetic women than in normal women, but the differences were not significant. No significant correlation was obtained between serum cr,-AG and hemoglobin A, (HbA, ) in diabetic patients. On the contrary, the serum triglyceride levels increased during pregnancy and decreased postpartum in both groups of subjects. These findings suggest that serum cc,-AG plays an important role in the activation of lipoprotein lipase during pregnancy. Key words: q-Acid glycoprotein; Serum triglyceride; protein lipase activation
Introduction Plasma glycoproteins have been considered important in the clinical evaluation of many diseases. The q-acid glycoprotein (a,-AG) is one of the plasma proteins proposed by Bollet [l] as an acute phase reactant, and it increases in many ____-. Address for correspondence: Dr. Masashi Honda, Diabetes Centre, Tokyo Women’s Medical College, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162, Japan. 0168-8227/90/$03.50
0 1990 Elsevier Science Publishers
Normal pregnancy;
Diabetic
pregnancy;
Lipo-
conditions such as acute-inflammation, cancer and collagen disease [2-41. Recently, or,-AG has been identified as a new co-factor in the lipoprotein lipase reaction [5]. Although it is known that lipid metabolism changes during pregnancy, especially diabetic pregnancy, it is still uncertain whether the a,-AG levels in pregnancy complicated with diabetes are altered. Therefore, we have investigated and compared the serum n,-AG levels in all gestational stages of normal and diabetic pregnancy.
B.V. (Biomedical
Division)
148
Materials and Methods Seventy-two blood samples obtained from 18 diabetic pregnant women and 82 samples from 82 normal pregnant women during all three trimesters and within 14 days postpartum were examined. Eighteen non-pregnant diabetic women and 25 age-matched normal non-pregnant women served as controls. The average age (years ; m _+ SE) of the normal non-pregnant women was 27.1 + 1.3 and 31.2 of:0.4 in the normal pregnant women. The mean HbA, (% ; m 2 SE) was 7.9 2 0.9 and 7.6 f 0.1 in the normal non-pregnant and pregnant subjects, respectively. The clinical data of the diabetic subjects are shown in Table 1. The body mass index of all the subjects used in this study was less than 25 kg/m2 and none of them was taking oral contraceptive pills or estrogen compounds. The collection of blood samples from the diabetic pregnant women was started when they were treated in our clinic and was performed serially in all trimesters and within 14 days postpartum. No serial collection of blood samples was done in the normal pregnant women. The samples were immediately centrifuged, and the serum fraction was collected and stored at - 20°C until just before the assay. Serum cc,-AG
was assayed by the single radial immunodiffusion method (NOR-Partigen q-Acid Glycoprotein Kit: Hoechst, Japan). The measurements were done in accordance with the directions provided by the manufacturer. Statistical analysis ofthe results was performed using Student’s t-test.
Results The changes in serum a,-AG levels in all gestational stages of normal and diabetic pregnancy are shown in Fig. 1. There was no significant difference in the a,-AG levels between normal nonpregnant women and normal pregnant women during the 1st or 2nd trimester. In the 3rd trimester, the cr,-AG levels were significantly lower than in the non-pregnant women and the 1st trimester. However, the a,-AG levels were increased significantly within 14 days postpartum compared to the other gestational stages. No significant difference in the cr,-AG levels was found between the diabetic non-pregnant women and diabetic pregnant women during the 1st trimester. During the 2nd and 3rd trimesters, the c(,-AG values were significantly lower than those obtained in the non-pregnant and pregnant
TABLE 1 Clinical data of the diabetic subjects used in this study
Age (years) Type of diabetes NIDDM IDDM Duration of diabetes HbA, (%) Complication(s)
(years)
Non-pregnant (n = 18)
Pregnant (n = 18)
29.2 f 0.9
30.6 + 1.2
10 cases 8 cases 6.4 f 1.1 11.3 f 0.7 diabetic retinopathy
10 cases 8 cases 7.9 * 1.5 9.0 * 0.1 diabetic retinopathy (8 cases) gestational toxicosis (8 cases)
All the subjects were treated with insulin. The values are the means k SE. NIDDM, non-insulin-dependent diabetes mellitus. IDDM, insulin-dependent diabetes mellitus.
(8 cases)
149
L
NO”-
L
25. ) -
regnant
~ri.e.ster -
Normal
-
Diabetic
days)
(Z-14 I
normal and diabetic subjects. Fig. 1. Serum q-acid glycoprotein levels in non-pregnant (I]) and pregnant (WA) The values are the means f SE. The numbers in parentheses represent the number of subjects. Significant difference from non-pregnant at *P < 0.05 and ***P < 0.001; from pregnant 1st trimester at + + P < 0.01 and + + + P < 0.001; and from pregnant 3rd trimester at * # * P < 0.001 by the unpaired r-test (two-tailed).
subjects in the 1st trimester. Postpartum, the u!,-AG levels were signifkantly increased compared to the other stages of gestation. There was no significant difference in the a,-AG levels between normal and diabetic nonpregnant subjects. Similarly, no significant difference was found between normal and diabetic pregnant women, although the cq-AG levels tended to be lower in diabetic pregnancy than in normal pregnancy. The a,-AG levels (mg/dl; m + SE) of the eight diabetic subjects whose pregnancies were complicated by late gestational toxicosis were 34.2 + 1.6 in the 2nd trimester and 30.3 + 1.8 in the 3rd trimester. These values were significantly lower (P < 0.05) than those obtained in the diabetic pregnant subjects without toxicosis (39.1 k 1.5 in
the 2nd trimester and 38.9 k 2.4 in the 3rd trimester). The relation between the diabetic metabolic control and the serum cr,-AG levels were investigated. All the diabetic patients had been treated with insulin. In the case of the diabetic nonpregnant women, the HbA, level was 11.7 k 0.8% (m f. SE). In the diabetic pregnant women, HbA, values (m k SE) in the lst, 2nd and 3rd trimesters and postpartum were 9.7 f 0.3x, 8.7 + 0.3x, 9.1 + 0.3% and 8.3 + 0.3%, respectively. No significant correlation was obtained between serum a,-AG and HbA,. The serum triglyceride levels were not significantly different in normal and diabetic subjects in all gestational stages and postpartum. However,
150 TABLE 2 Serum triglyceride in normal and diabetic pregnant subjects during the three gestational stages of pregnancy and postpartum Pregnant subjects
1st trimester 2nd trimester 3rd trimester Post-partum (2-14 days)
Serum triglyceride
(mg/dl)
Normal
Diabetic
89.9 f 15.4 112.3 + 9.0* 178.8 f 12.4+
88.4 f 11.8 161.8 + 16.3* 200.6 f 16.0’
126.2 + 13.5+
123.6 k 12.4#
The values are the means & SE. Significant differences for each group of subjects at *P< 0.05; compared to 1st trimester; + P < 0.05; compared to 2nd trimester; and # P < 0.05; compared to 3rd trimester.
the serum triglyceride levels significantly increased throughout pregnancy, and then decreased rapidly postpartum in both groups of subjects (Table 2).
Discussion It is well known that a,-AG is an ‘acute-phase protein’ [ 11, the level of which increases in many conditions such as in pregnancy complicated with acute inflammation [ 61. According to the results of the present study, serum cr,-AG levels decrease during the course of pregnancy and rapidly increase postpartum. Our findings are in agreement with the previous reports that plasma a,-AG levels decreased at term or in the last trimester of pregnancy [7,8], but there have been no reports of a rapid increase postpartum. Chu et al. [6] reported that at postpartum, the plasma a,-AG levels were not statistically different from those during pregnancy. In their study, the samples of postpartum were collected at 4 to 10 weeks after delivery. However in our study, the blood samples were collected 2 to 14 days after delivery, indicating that the difference in the results may be due to time interval after birth when the samples were collected.
The factors modulating serum cr,-AG are obscure. There are many reports that placental steroid hormones modulate plasma proteins [9-141, and that estrogen and progesterone compounds suppress the production of c(,-AG, haptoglobin and albumin [ 9,10,12]. Also, it has been known that placental steroid hormones modulate lipid metabolism during pregnancy [ 151. These placental steroid hormones increase markedly throughout pregnancy and decrease post-partum. In the pregnant diabetics, blood placental hormone, especially estrogen and progesterone concentrations were higher than in the pregnant non-diabetic subjects [ 16-191. We have previously reported that the serum estrogen and progesterone were markedly increased during normal and diabetic pregnancy and in the 3rd trimester the hormone concentrations were significantly higher in the diabetic subjects than in the normal subjects [ 161. In the present results, the c(,-AG levels decreased throughout pregnancy and increased post-partum, especially in diabetic pregnancy. These findings suggest that the decrease in the glycoprotein level may be due to increased placental steroid hormone concentrations during pregnancy. Our study also showed that the LX,-AGlevels in the diabetic pregnant subjects complicated with gestational toxicosis were significantly lower than those of the diabetic pregnant subjects without toxicosis. These results suggest that gestational toxicosis may be another reason for the decrease of a,-AG levels in the late pregnancy period. The relation between c(,-AG and placental function is still unknown. However, low estrogen concentration during pregnancy is a common index of placental dysfunction, Therefore, it appears that an increase in cr,-AG levels during pregnancy may also indicate poor placental function, but this requires further investigations. Different opinions have been presented concerning the influence of diabetes on blood glycoprotein levels. McMillan [20] reported an elevation of acute-phase serum protein in diabetes. In contrast, Guzdek et al. [21] reported a decreased ratio of neutral sugars to proteins in the
151
seromucoid of patients with untreated juvenile diabetes. A deficiency of endogenous insulin is responsible for the diminished proportion and this was improved with insulin treatment, but does not completely bring it to normal value. All the diabetic subjects used in our study were treated with insulin. Our results showed no significant difference in the serum c(,-AG levels between the diabetic patients and normal controls but tended to be lower in the diabetics. In favor with the findings of Guzdek et al. [ 2 I], our results indicate that the treatment of the diabetic subjects with insulin may have improved their metabolic state and glycoprotein concentrations but not to the normal level. It is known that lipid metabolism changes during pregnancy with increases in triglyceride, cholesterol and free-fatty acid levels. The main change in diabetic pregnant women is in the triglyceride levels, but the mechanism remains obscure. Biphasic lipid metabolism in pregnancy was proposed by Knopp et al. [22], who suggested that triglycerides were synthesized and increased in early pregnancy. In late pregnancy triglycerides further increase as a result of the increase in synthesis and a decrease in excretion. In patients with nephrotic syndrome, the elevation of plasma triglycerides is a direct result of excessive loss of a,-AG from the plasma into urine [ 51. The a,-AG activates the lipoprotein lipase resulting in increased triglyceride clearance [ 5,231. In this study, it was found that or,-AG decreased following the processes of normal and diabetic pregnancy and rapidly increased after delivery. Plasma triglycerides, on the other hand, were increased during pregnancy and decreased after delivery. The results of the present investigation suggest that the increase in the serum triglyceride concentrations during pregnancy maybe due to decreased a,-AG levels in the plasma. In conclusion, we have demonstrated that serum a,-AG levels decrease in normal and diabetic women during pregnancy and increase postpartum. The change in serum a,-AG during preg-
nancy plays an important lipase activation.
role in the lipoprotein
Acknowledgements We would like to thank Dr. C. Lowy of Guy’s and St. Thomas’s Hospital, University of London for her valuable suggestions; Dr. T. Amemiya of Maternal and Perinatal Centre, Tokyo Women’s Medical College for experimental assistance; Ms. L. Pancho for her assistance in writing the manuscript; and Ms. B. Leven and Ms. M. Onishi for their assistance in correcting and typing the manuscript, respectively. References Bollet, A.J. (1959) Plasma glycoprotein, mucoproteins and mucopolysaccharides. Arch. Intern. Med. 104, 152-160. Easto, E.A., Hardwicke, J. and Whitehead, P.H. (1962) The estimation oftwo a,-glycoproteins (orosomucoid and another a,-acid glycoprotein) in health and disease. J. Clin. Pathol. 15, 585-590. Snyder, S. and Ashwell, G. (1971) Quantitation of specific serum glycoproteins in malignancy. Clin. Chim. Acta 34, 449-455. Wolf, G.T., Chretien, P.B., Elias, E.G., Makuch, R.W., Baskies, A.M., Spiegel, H.E. and Weiss, J.F. (1979) Serum glycoproteins in head and neck squamous carcinoma. Am. J. Surg. 138,489-500. Staprans, I. and Felts, J.M. (1977) The effect of a,-acid glycoprotein (orosomucoid) on triglyceride metabolism in the nephrotic syndrome. Biochem. Biophys. Res. Commun. 79, 1272-1278. Chu, C.Y.-T., Singla, V.P., Wang, H.-P., Sweet, B. and Lai L.T.-Y. (1981) Plasma a,-acid glycoprotein levels in pregnancy. Clin. Chim. Acta 112, 235-240. Song, C.S., Merkatz, I.R., Ritkind, A.B., Gillete, P.N. and Kappoas, A. (1970) The influence of pregnancy and oral contraceptive steroids on the concentration of plasma protein. Am. J. Obstet. Gynecol. 108, 227-231. Laurell, C.B. (1968) Orosomucoid and a,-antitrypsin in maternal and fetal sera at parturition. Stand. J. Clin. Lab. Invest. 21, 136-138. Barbosa, J., Seal, U.S. and Doe, R.P. (1971) Effects of anabolic steroids on haptoglobin, orosomucoid, plasminogen, fibrinogen, transferrin, ceruloplasmin, a,-antitrypsin, /3-glucuronidase and total serum proteins. J. Clin. Endocrinol. 33, 388-398.
152 10 Seal, U.S. and Doe, R.P. (1969) Metabolic effects of gonadal hormones and contraceptive steroids. In: Salhanick, H.A., Kipnis, D. and Vanderwiele, R. (eds.) Protein and Amino Acid Metabolism, pp. 277-318, Plenum Press, New York. 11 Borglin, N.E. and Nyman, M. (1961) Effect of estrogens on the haptoglobin level in the blood. Stand. J. Clin. Lab. Invest. 13, 107-l 15. 12 Laurell, C.B., Kullander, S. and Thorell, J. (1968) Effect of administration of a combined estrogen-progestin contraceptive on the level of individual plasma proteins. Stand. J. Clin. Lab. Invest. 21, 337-343. 13 Musa, B.U., Doe, R.P. and Seal, U.S. (1967) Serum protein alterations produced in women by synthesis estrogens. J. Clin. Endocrinol. Metab. 27, 1463-1469. 14 Laurell, C.-B. and Skanse, B. (1963) Estrogen and plasma orosomucoid. J. Clin. Endocrinol. Metab. 23, 214-215. 15 Kim, H.-J. and Kalkhoff, R.K. (1975) Sex steroid influence on triglyceride metabolism. J. Clin. Invest. 56, 888-896. 16 Honda, M., Omori, Y., Minei, S., Sanaka, M., Azuma, K., Akihisa, R. and Hirata, Y. (1984) Serum total estrogen, progesterone, human placental lactogen and human chorionic gonadotropin in diabetic pregnancy. Tokyo Joshi Ikadaigaku Zasshi 54, 595-602. (in Japanese; abstract in English).
17 Levitz, M. and Selinger, M. (1970) Plasma estriol levels in class D diabetes of pregnancy. Am. J. Obstet. Gynecol. 108, 82-90. 18 Booth, M. and El Graf, T.A.R. (1974) Plasma progesterone concentration during the third trimester of diabetic pregnancy. J. Obstet. Gynaecol. Br. Commonw. 8 1, 768-776. 19 Larinkari, J., Laatikainen, L., Lanta, T., Moronen, P., Pesonen, K. and Laatikainen, T. (1982). Metabolic control and serum hormone levels in relation to retinopathy in diabetic pregnancy. Diabetologia 22, 327-332. 20 McMillan, D.E. (1989). Increased levels of acute-phase serum proteins in diabetes. Metabolism 38, 1042-1046. 21 Guzdek, A., Ciba, T. and Sarnecka-Keller, M. (1976)The influence of insulin on the proportion of neutral sugars in seromucoid of diabetic patients. Clin. Chim. Acta 72, 401-404. 22 Knopp, R.H., Saudek, CD., Arky, R.A. and O’Sullivan, J.B. (1973) Two phases of adipose tissue metabolism in pregnancy: maternal adaptations for fetal growth. Endocrinology 92, 984-988. 23 Popenoe, E.A. (1955) Characterization of a glycoprotein in the urine of patients with proteinuria. J. Biol. Chem. 217. 61-66.
10 (1990)
147-152 147
Elsevier DIABET
00430
Quantitative
analysis of serum q-acid glycoprotein levels in normal and diabetic pregnancy
Masashi Honda ‘, Yasue Omori I, Satomi Minei ‘, Toshiko Oshiyama I, Meimi Shimizu ‘, Mayumi Sanaka ‘, Tomoko Kohama ‘, Masao Nakabayashi2 and Yukimasa Hirata ’ ‘Diabetes Centre and ‘Maternal
and Perinatal Centre, Tokyo Women’s Medical College, Tokyo, Japan
(Received 22 February 1990) (Revision received 19 April 1990) (Accepted 25 April 1990)
Summary In an attempt to clarify the mechanism of lipid metabolism during pregnancy, q-acid glycoprotein (CC,-AG) was analyzed in normal and diabetic pregnant women. Seventy-two determinations of serum CX, -AG levels were performed in 18 diabetic pregnant women and 82 determinations in 82 normal pregnant women in all three trimesters and within 14 days postpartum. Serum CC,-AG levels in both normal and diabetic pregnant women decreased throughout pregnancy and rapidly increased postpartum. In all gestational stages, the serum a,-AG levels were lower in diabetic women than in normal women, but the differences were not significant. No significant correlation was obtained between serum cr,-AG and hemoglobin A, (HbA, ) in diabetic patients. On the contrary, the serum triglyceride levels increased during pregnancy and decreased postpartum in both groups of subjects. These findings suggest that serum cc,-AG plays an important role in the activation of lipoprotein lipase during pregnancy. Key words: q-Acid glycoprotein; Serum triglyceride; protein lipase activation
Introduction Plasma glycoproteins have been considered important in the clinical evaluation of many diseases. The q-acid glycoprotein (a,-AG) is one of the plasma proteins proposed by Bollet [l] as an acute phase reactant, and it increases in many ____-. Address for correspondence: Dr. Masashi Honda, Diabetes Centre, Tokyo Women’s Medical College, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162, Japan. 0168-8227/90/$03.50
0 1990 Elsevier Science Publishers
Normal pregnancy;
Diabetic
pregnancy;
Lipo-
conditions such as acute-inflammation, cancer and collagen disease [2-41. Recently, or,-AG has been identified as a new co-factor in the lipoprotein lipase reaction [5]. Although it is known that lipid metabolism changes during pregnancy, especially diabetic pregnancy, it is still uncertain whether the a,-AG levels in pregnancy complicated with diabetes are altered. Therefore, we have investigated and compared the serum n,-AG levels in all gestational stages of normal and diabetic pregnancy.
B.V. (Biomedical
Division)
148
Materials and Methods Seventy-two blood samples obtained from 18 diabetic pregnant women and 82 samples from 82 normal pregnant women during all three trimesters and within 14 days postpartum were examined. Eighteen non-pregnant diabetic women and 25 age-matched normal non-pregnant women served as controls. The average age (years ; m _+ SE) of the normal non-pregnant women was 27.1 + 1.3 and 31.2 of:0.4 in the normal pregnant women. The mean HbA, (% ; m 2 SE) was 7.9 2 0.9 and 7.6 f 0.1 in the normal non-pregnant and pregnant subjects, respectively. The clinical data of the diabetic subjects are shown in Table 1. The body mass index of all the subjects used in this study was less than 25 kg/m2 and none of them was taking oral contraceptive pills or estrogen compounds. The collection of blood samples from the diabetic pregnant women was started when they were treated in our clinic and was performed serially in all trimesters and within 14 days postpartum. No serial collection of blood samples was done in the normal pregnant women. The samples were immediately centrifuged, and the serum fraction was collected and stored at - 20°C until just before the assay. Serum cc,-AG
was assayed by the single radial immunodiffusion method (NOR-Partigen q-Acid Glycoprotein Kit: Hoechst, Japan). The measurements were done in accordance with the directions provided by the manufacturer. Statistical analysis ofthe results was performed using Student’s t-test.
Results The changes in serum a,-AG levels in all gestational stages of normal and diabetic pregnancy are shown in Fig. 1. There was no significant difference in the a,-AG levels between normal nonpregnant women and normal pregnant women during the 1st or 2nd trimester. In the 3rd trimester, the cr,-AG levels were significantly lower than in the non-pregnant women and the 1st trimester. However, the a,-AG levels were increased significantly within 14 days postpartum compared to the other gestational stages. No significant difference in the cr,-AG levels was found between the diabetic non-pregnant women and diabetic pregnant women during the 1st trimester. During the 2nd and 3rd trimesters, the c(,-AG values were significantly lower than those obtained in the non-pregnant and pregnant
TABLE 1 Clinical data of the diabetic subjects used in this study
Age (years) Type of diabetes NIDDM IDDM Duration of diabetes HbA, (%) Complication(s)
(years)
Non-pregnant (n = 18)
Pregnant (n = 18)
29.2 f 0.9
30.6 + 1.2
10 cases 8 cases 6.4 f 1.1 11.3 f 0.7 diabetic retinopathy
10 cases 8 cases 7.9 * 1.5 9.0 * 0.1 diabetic retinopathy (8 cases) gestational toxicosis (8 cases)
All the subjects were treated with insulin. The values are the means k SE. NIDDM, non-insulin-dependent diabetes mellitus. IDDM, insulin-dependent diabetes mellitus.
(8 cases)
149
L
NO”-
L
25. ) -
regnant
~ri.e.ster -
Normal
-
Diabetic
days)
(Z-14 I
normal and diabetic subjects. Fig. 1. Serum q-acid glycoprotein levels in non-pregnant (I]) and pregnant (WA) The values are the means f SE. The numbers in parentheses represent the number of subjects. Significant difference from non-pregnant at *P < 0.05 and ***P < 0.001; from pregnant 1st trimester at + + P < 0.01 and + + + P < 0.001; and from pregnant 3rd trimester at * # * P < 0.001 by the unpaired r-test (two-tailed).
subjects in the 1st trimester. Postpartum, the u!,-AG levels were signifkantly increased compared to the other stages of gestation. There was no significant difference in the a,-AG levels between normal and diabetic nonpregnant subjects. Similarly, no significant difference was found between normal and diabetic pregnant women, although the cq-AG levels tended to be lower in diabetic pregnancy than in normal pregnancy. The a,-AG levels (mg/dl; m + SE) of the eight diabetic subjects whose pregnancies were complicated by late gestational toxicosis were 34.2 + 1.6 in the 2nd trimester and 30.3 + 1.8 in the 3rd trimester. These values were significantly lower (P < 0.05) than those obtained in the diabetic pregnant subjects without toxicosis (39.1 k 1.5 in
the 2nd trimester and 38.9 k 2.4 in the 3rd trimester). The relation between the diabetic metabolic control and the serum cr,-AG levels were investigated. All the diabetic patients had been treated with insulin. In the case of the diabetic nonpregnant women, the HbA, level was 11.7 k 0.8% (m f. SE). In the diabetic pregnant women, HbA, values (m k SE) in the lst, 2nd and 3rd trimesters and postpartum were 9.7 f 0.3x, 8.7 + 0.3x, 9.1 + 0.3% and 8.3 + 0.3%, respectively. No significant correlation was obtained between serum a,-AG and HbA,. The serum triglyceride levels were not significantly different in normal and diabetic subjects in all gestational stages and postpartum. However,
150 TABLE 2 Serum triglyceride in normal and diabetic pregnant subjects during the three gestational stages of pregnancy and postpartum Pregnant subjects
1st trimester 2nd trimester 3rd trimester Post-partum (2-14 days)
Serum triglyceride
(mg/dl)
Normal
Diabetic
89.9 f 15.4 112.3 + 9.0* 178.8 f 12.4+
88.4 f 11.8 161.8 + 16.3* 200.6 f 16.0’
126.2 + 13.5+
123.6 k 12.4#
The values are the means & SE. Significant differences for each group of subjects at *P< 0.05; compared to 1st trimester; + P < 0.05; compared to 2nd trimester; and # P < 0.05; compared to 3rd trimester.
the serum triglyceride levels significantly increased throughout pregnancy, and then decreased rapidly postpartum in both groups of subjects (Table 2).
Discussion It is well known that a,-AG is an ‘acute-phase protein’ [ 11, the level of which increases in many conditions such as in pregnancy complicated with acute inflammation [ 61. According to the results of the present study, serum cr,-AG levels decrease during the course of pregnancy and rapidly increase postpartum. Our findings are in agreement with the previous reports that plasma a,-AG levels decreased at term or in the last trimester of pregnancy [7,8], but there have been no reports of a rapid increase postpartum. Chu et al. [6] reported that at postpartum, the plasma a,-AG levels were not statistically different from those during pregnancy. In their study, the samples of postpartum were collected at 4 to 10 weeks after delivery. However in our study, the blood samples were collected 2 to 14 days after delivery, indicating that the difference in the results may be due to time interval after birth when the samples were collected.
The factors modulating serum cr,-AG are obscure. There are many reports that placental steroid hormones modulate plasma proteins [9-141, and that estrogen and progesterone compounds suppress the production of c(,-AG, haptoglobin and albumin [ 9,10,12]. Also, it has been known that placental steroid hormones modulate lipid metabolism during pregnancy [ 151. These placental steroid hormones increase markedly throughout pregnancy and decrease post-partum. In the pregnant diabetics, blood placental hormone, especially estrogen and progesterone concentrations were higher than in the pregnant non-diabetic subjects [ 16-191. We have previously reported that the serum estrogen and progesterone were markedly increased during normal and diabetic pregnancy and in the 3rd trimester the hormone concentrations were significantly higher in the diabetic subjects than in the normal subjects [ 161. In the present results, the c(,-AG levels decreased throughout pregnancy and increased post-partum, especially in diabetic pregnancy. These findings suggest that the decrease in the glycoprotein level may be due to increased placental steroid hormone concentrations during pregnancy. Our study also showed that the LX,-AGlevels in the diabetic pregnant subjects complicated with gestational toxicosis were significantly lower than those of the diabetic pregnant subjects without toxicosis. These results suggest that gestational toxicosis may be another reason for the decrease of a,-AG levels in the late pregnancy period. The relation between c(,-AG and placental function is still unknown. However, low estrogen concentration during pregnancy is a common index of placental dysfunction, Therefore, it appears that an increase in cr,-AG levels during pregnancy may also indicate poor placental function, but this requires further investigations. Different opinions have been presented concerning the influence of diabetes on blood glycoprotein levels. McMillan [20] reported an elevation of acute-phase serum protein in diabetes. In contrast, Guzdek et al. [21] reported a decreased ratio of neutral sugars to proteins in the
151
seromucoid of patients with untreated juvenile diabetes. A deficiency of endogenous insulin is responsible for the diminished proportion and this was improved with insulin treatment, but does not completely bring it to normal value. All the diabetic subjects used in our study were treated with insulin. Our results showed no significant difference in the serum c(,-AG levels between the diabetic patients and normal controls but tended to be lower in the diabetics. In favor with the findings of Guzdek et al. [ 2 I], our results indicate that the treatment of the diabetic subjects with insulin may have improved their metabolic state and glycoprotein concentrations but not to the normal level. It is known that lipid metabolism changes during pregnancy with increases in triglyceride, cholesterol and free-fatty acid levels. The main change in diabetic pregnant women is in the triglyceride levels, but the mechanism remains obscure. Biphasic lipid metabolism in pregnancy was proposed by Knopp et al. [22], who suggested that triglycerides were synthesized and increased in early pregnancy. In late pregnancy triglycerides further increase as a result of the increase in synthesis and a decrease in excretion. In patients with nephrotic syndrome, the elevation of plasma triglycerides is a direct result of excessive loss of a,-AG from the plasma into urine [ 51. The a,-AG activates the lipoprotein lipase resulting in increased triglyceride clearance [ 5,231. In this study, it was found that or,-AG decreased following the processes of normal and diabetic pregnancy and rapidly increased after delivery. Plasma triglycerides, on the other hand, were increased during pregnancy and decreased after delivery. The results of the present investigation suggest that the increase in the serum triglyceride concentrations during pregnancy maybe due to decreased a,-AG levels in the plasma. In conclusion, we have demonstrated that serum a,-AG levels decrease in normal and diabetic women during pregnancy and increase postpartum. The change in serum a,-AG during preg-
nancy plays an important lipase activation.
role in the lipoprotein
Acknowledgements We would like to thank Dr. C. Lowy of Guy’s and St. Thomas’s Hospital, University of London for her valuable suggestions; Dr. T. Amemiya of Maternal and Perinatal Centre, Tokyo Women’s Medical College for experimental assistance; Ms. L. Pancho for her assistance in writing the manuscript; and Ms. B. Leven and Ms. M. Onishi for their assistance in correcting and typing the manuscript, respectively. References Bollet, A.J. (1959) Plasma glycoprotein, mucoproteins and mucopolysaccharides. Arch. Intern. Med. 104, 152-160. Easto, E.A., Hardwicke, J. and Whitehead, P.H. (1962) The estimation oftwo a,-glycoproteins (orosomucoid and another a,-acid glycoprotein) in health and disease. J. Clin. Pathol. 15, 585-590. Snyder, S. and Ashwell, G. (1971) Quantitation of specific serum glycoproteins in malignancy. Clin. Chim. Acta 34, 449-455. Wolf, G.T., Chretien, P.B., Elias, E.G., Makuch, R.W., Baskies, A.M., Spiegel, H.E. and Weiss, J.F. (1979) Serum glycoproteins in head and neck squamous carcinoma. Am. J. Surg. 138,489-500. Staprans, I. and Felts, J.M. (1977) The effect of a,-acid glycoprotein (orosomucoid) on triglyceride metabolism in the nephrotic syndrome. Biochem. Biophys. Res. Commun. 79, 1272-1278. Chu, C.Y.-T., Singla, V.P., Wang, H.-P., Sweet, B. and Lai L.T.-Y. (1981) Plasma a,-acid glycoprotein levels in pregnancy. Clin. Chim. Acta 112, 235-240. Song, C.S., Merkatz, I.R., Ritkind, A.B., Gillete, P.N. and Kappoas, A. (1970) The influence of pregnancy and oral contraceptive steroids on the concentration of plasma protein. Am. J. Obstet. Gynecol. 108, 227-231. Laurell, C.B. (1968) Orosomucoid and a,-antitrypsin in maternal and fetal sera at parturition. Stand. J. Clin. Lab. Invest. 21, 136-138. Barbosa, J., Seal, U.S. and Doe, R.P. (1971) Effects of anabolic steroids on haptoglobin, orosomucoid, plasminogen, fibrinogen, transferrin, ceruloplasmin, a,-antitrypsin, /3-glucuronidase and total serum proteins. J. Clin. Endocrinol. 33, 388-398.
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