Kinetics of glucose metabolism in mothers with intrauterine growth retardation

NUTRITION RESEARCH, Vol. 8, pp. 137-144, 1988 0271-5317/88 $3.00 + .00 Printed in the USA. Copyright (c) 1988 Pergamon Journals Ltd. All rights reserved.

KINETICS OF GLUCOSE METABOLISM IN MOTHERS WITH INTRAUTERINE GROWTH RETARDATION 1 Leela Raman, M.D. and Kamala Krishnaswamy, M.D. National Institute of Nutrition Indian Council of Medical Research Jamai Osmania PO, Hyderabad 500 007 India

ABSTRACT Data on oral and I.V. glucose t o l e r a n c e tests in normal pregnant women and pregnancy induced hypertensives (PIH) were subjected to kinetic analysis to obtain plasma zero c o n c e n t r a t i o n (CPO), area under the curve (AUC), half life (t 1/2) and metabolic c l e a r a n c e rat es (MCR). Since no d i f f e r e n c e s were observed either in the glucose t o l er an ce (both oral and I.V.) or in the various kinetic p a r a m e t e r s . b et ween the normal women and PIH's, the analysis of data was done in relation to the birth weight of the infant in b o t h these groups. Accordingly, women were divided into 4 groups. I. Normotensive normal birth weight (NBW), 2. normotensive IUGR, 3. hypertensive NBW, and 4. hypertensive IUGR. It was observed that fasting blood glucose was low in IUGR in N, NBW as well as PIHNBWs. AUC was low with shorter t 1/2 and faster MCR in IUGR as compared to normals both in normotensives and PIHs indicating a rapid elimination of glucose from the plasma with both oral and intravenous GTTs. A mechanism by the maternal tissue to take up higher amount of glucose for maintaining a high c o n c e n t r a t i o n gradient across the placenta in IUGR is being suggested. KEY WORDS: Oral glucose t o l e r a n ce tests, Metabolic c l e a r a n c e rate and intrauterine growth retardation, Area under the curve, Pregnancy induced hypertension and K i n t e t i c data analysis, Half life.

INTRODUCTION Earlier observations have shown that both oral and I.V. glucose tolerance are impaired in normal pregnancies and pre-eclampsia (1-4). It has been observed that women from poor social class and with s e v e r e pregnancy induced hypertension (PIH), had a significantly low fasting blood glucose as compared to well nourished women (5,6) and oral glucose t o l e r a n c e showed a poor peak response in IUGR pregnancies (7,8). However none of these studies clearly indicate as to whether the bioprocesses such as absorption or metabolism of glucose are a l t e r e d in these women. In o r d e r to c h a r a c t e r i s e the kinetic p a r a m e t e r s it is essential that the studies are carried out in a s y s t e m a t i c manner using both oral and I.V.G.T.T. The present study has been an a t t e m p t in this direction to c h a r a c t e r i s e the kinetic p a r a m e t e r s which would provide meaningful data for interpretation of metabolism and disposition of glucose in normal and abnormal pregnancies. 1To whom correspondence should be addressed. 137

138

L. RAMANand K. KRISHNASWAMY

It is well established that t 1/2 or elimination r a t e constant ~Kt is an index of both distribution and elimination of any compound given intravenously. In addition metabolic c l e a r a n c e rate can be calculated, as an a c c u r a t e index of the body handling of any substance. Since I.V. glucose t o l e r a n c e curves follow a first order kinetics, a detailed kinetic analysis o f glucose was done using the data on oral and I.Vo glucose to le r a n c e tests done earlier in normals and in women with PIH (5,6). Since low birth weight is a common problem in India and seen in 35-40% of the births especially in the poor under privileged women, an a t t e m p t was made to r e l a t e the changes in glucose metabolism to intrauterine growth r et ar d at i o n in normotensive and PIH women. METHODS AND MATERIALS The subjects s e l e c t e d for both oral and I.V. glucose t o l e r a n c e consisted of normals and mild and severe PIH b e t w e e n 34-38 weeks of gestation. Mild PIH was defined when blood pressure taken at two points of t i m e in a resting s t a t e was above 140/90 mm, Hg, with/without e d e m a or w i t h / w i t h o u t proteinuria (trace or +). S e v e r e PIH was defined as diastolic B.P. above 100 mm Hg with significant proteinuria (++/++§ All these women belonged to poor social class. Oral dietary surveys r e v e a l e d that the average cal o r i e intake was 1600 and proteins 40 gms (mainly from vegetable sources). Oral glucose t o l e r a n c e tests were pe r f o rm ed in 116 apparently normals, 11 mild PIHs and 51 s e v e r e PIHs with proteinuria, by administering 50 gms of glucose dissolved in 200 ml of water. I.G. glucose t o l e r a n c e tests were done in 53 normals, 12 mild PIHs and 23 s e v e r e PIHs by slowly injecting glucose over a period of 2 minutes (0.5 gm/kg body weight) a f t e r overnight fast. Women with o t h er pregnancy complications such as heart disease, gestational diabetes and congenital d ef o r m i t i es were excluded from the study. Blood samples were obtained at I/2 hour intervals upto 3 hours in oral and at 10 minutes intervals with I.V. glucose t o l er an ce tests (upto 60 minutes). Blood glucose was analysed by Nelson Somogyi technique with quality control of the assay method, using WHO r e f e r e n c e samples for plasma glucose. The d a t a on oral GTT was analysed for area under the curve using trapezoid rule (10). The apparent oral c l e a r a n c e (AOC) for oral GTT was calculated by the formula dose g i v e n / A U C 0 J ~ 6 ~ taking into consideration the ' F ' fraction (being not known). The s ta ti s ti c a l d i f f e r e n ces were calculated by students ' t ' test. I.V. glucose t o l e r a n c e t e s t data were analysed according to one compartmental open model and elimination constant K, t 1/2 and metabolic c l e a r a n c e r a t e were c a l c u l a t e d by the method of Gibaldi and Perrier (10). The following formulae were used: t 1/2

MCR =

-

0.693 , where in, K was obtained from log c o n c e n t r a t i o n vs K time plot Dose given AUC 0f 6 0

Individual t i m e plots of plasma concentrations were pooled in each group in order to arrive at the group regression and plasma disappearance r a t e of glucose. The regressions were t e s t e d for s t a t i s t i c a l d if f er en ces by the method of Snedecor and Cochran (11).

GLUCOSE METABOLISM IN INDIAN WOMEN

139

The birth weights of infants born to all these mothers at term were recorded. Birth weight below 1 SD for that gestational age was classified as intrauterine growth r et ard at i o n (IUGR), the growth curve of Ghosh et al used for r e f e r e n c e (12). F i f t y nine (34.9%) and 54 (53.4%) infants born to control and PIH mothers showed evidence of IUGR ( = 10.95 (P 0.001)). Since preliminary analysis of pooled d a t a on glucose t o l e r a n c e and kinetics did not show any d i f f e r e n c e b e t w e e n normal pregnancies and PIH, the data w e r e analysed in both these conditions in relation to the birth weights of the infants. Accordingly the subjects were divided into 4 groups: Group I (N)

Normotensives mothers giving birth to normal birth weight infants.

Group II (N)

Normotensives mothers with IUGR

Group III

PIH with normal birth weight infants

Group IV

PIH with IUGR

RESULTS Mean body weight and fat fold thickness at triceps of the normotensive women were 46.5 L 2.8 kg and 8.5 L 5.01 ram. Fi f t y per c e n t of the women (both normotensives and PIHs) were primigravidas. Mean body weight and fat fold thickness were higher (48.8 + 5.52 kgs and 10.9 + 3.82 mm) in women with PIH due to the presence of e d e m a _ The glucose t o l e r a n c e curves a f t e r oral G.T.T. in the d i f f e r e n t groups of women are shown in Fig. 1. The basal glucose levels during G.T.T. were consistently and significantly lower in women with IUGR as compared to women GLUCOSE TOLERANCE CURVE IN NORMAL AND PIH WOMEN

WITH OR WITHOUT IUGR

110 ~

100

~

....

LP-.-----..-e,

CONTROL

PIH CONTROL(IUGR) (IUGR)

P, 9O FIG. 1. Glucose tolerance curves in normal and PIH women with or without IUGR.

m

~

8O

r

70 60

7

\i"--.." lIP

TIME I N HOURS

140

L. RAMAN and K. KRISHNASWAMY

with normal weight infants in both normotensives and hypertensives. To confirm that the lower glucose response was a function of poor peak response independent of fasting blood glucose, the area under the curve (AUC) and apparent oral clearances (AOC) were calculated. It was observed that AUC was significantly reduced and AOC of glucose was significantly higher in women with IUGR pregnancies as compared to women with normal weight infants both in normotensives and hypertensives. TABLE 1 Groups

N

Fasting blood glucose mg/dl

AUC (mg/ml/mt)

AOC (ml/min)

Mean birth Weig.ht (kg)

I

74

65.4+12.04 a

149.7+25.26c

343§

de

2.95+0.344 a

II

42

55.6X15.55 ab

131.7+__24.40ac

384+_94.5de

2.28+_0.138ab

346+61.4 a

2.97+0.445 b

i

Ill

31

65.2+14.47 b

148.9+25~79 a

IV

31

51.5+13.92 ab

I12.3+27.68ac

467.5+97.0a8

2.20+0.223ab

Values are means + SD; Values bearing similar superscripts (vertically) are significantly different; abe = P ( 0 . 0 0 1 ;

c =P<0.01;

d =J)~0.02.

Intravenous glucose tolerance: The regression equation for the various groups and p e r c e n t a g e elimination (K) and plasma zero c o n c e n t r a t io n (CPO) are indicated in Table 2. The plasma TABLE 2 Kinetics of I.V. glucose t o l e r a n c e in pregnancy

Groups

N

Regression equation of I.V.G.T.T.

K%

t 1/2

CPO

Mean birth weight {kg)

I

36

Y=2.3667 - 0.009606x

2.21

31.33 ab

233 c

2.99+0.05 cb

II

17

Y=2.3049 - 0.010759x

2.48

27,97 a

202 cd

2.27+0.05 c

Ill

12

Y=2.4341 - O.OlOI~4x

2.35

29.52

272 de

2.63+0.17 be

IV

23

Y=2.2921 - 0.010339x

2.38

29.11 b

196 de

1.78+0.14 e

m

Values bearing the same superscripts v e r t i c a l l y are significantly different; a = P(0.01;

b = P~0.05;

c,d,e = P ( 0 . 0 0 1 .

GLUCOSE METABOLISM IN INDIAN WOMEN

141

disappearance of glucose was of first order kinetics. The p e r c e n t a g e of glucose eliminated, and t h e r e f o r e the halflife (tl/2) studied up to 60 minutes indicated that the disappearance r a t e of glucose was much faster in mothers in IUGR pregnancies in both normotensives and hypertensives. This was also r e f l e c t e d in faster MCR and lower AUC in IUGR (Fig. 2). VALUES

Fasting GlucoseBlood (rag/d|)

ARE

MEANS

• SD.

1

/60 AUCmg/mi/min. [] NORMAL [] PIHIUGR

~0

30

40

20

FIG. 2. Fasting blood glucose, AUC and metabolic clearance rate (MCR) with IV glucose load in normal and abnormal pregnancy

~00

".: 300 ~0000 -L 200"

i

:i

Ii i! i 123~'

201 234

m 2 3 4

DISCUSSION Studies on oral and intravenous glucose tolerance t est s have constantly pointed to an impairment in glucose t o l e r a n c e during normal pregnancy (1-3). This impairment has been a t t r i b u t e d to various factors such as insulin insensitivity, increased s ecr et i o n of HPL and corticosteroids, pyridoxine deficiency etc. resulting in impaired responses (12,13). It is also r e p o r t e d that women suffering from PIH have impaired glucose to le r a n c e and that such women develop diabetes at a later age (14). In India, both PIH of severe nature and eclampsia are more o f t en seen in the undernourished women where chronic malnutrition due to low energy intake is a common feat u r e in the poor social class (6,15). The s t a t e of glucose homeostasis in chronic undernutrition has remained a m a t t e r of speculation. The present study demonstrates ~hat both fasting blood glucose and i n cr em en t values a f t e r oral or I.V.G.T.T. are lower in women giving birth to IUGR infants. It may be presumed that low fasting glucose and increment values in IUGR could be r e f l e c t i o n of b e t t e r and f a s t e r utilisation of glucose. However since absolute and in c r e m e n t values are difficult to i n t er p r et in assessing the glucose kinetics, the data on both oral and I.V.G.T.T. were subjected to appropriate kinetic analysis.

142

L. RAMANand K. KRISHNASWAMY

Area under the curve is reflection of plasma concentration of a nutrient and with oral load would depend on both absorption from the gut as well as the clearance from the plasma. On the other hand, metabolic clearance rate is a function of elimination which can be judged by apparent oral clearance, or when substance is given intravenously, by accurate calculation. In the present study, the apparent oral clearance was s i g n i f i c a n t l y higher in IUGR indicating a rapid removal of glucose from the plasma. Area under the curve and it' 1/2 were significantly reduced in IUGR irrespective of the cause as compared to normals. Intravenous kinetics also indicated essentially a similar picture in IUGR, A question thus would arise as to why there is a rapid clearance of glucose in IUGR. Most of the IUGR pregnancies occur in undernourished mothers and the glucose homeostasis is geared towards adjustment to low energy intakes. Fetus depend mainly on maternal glucose for its energy needs. Thus in IUGR pregnant mothers, low fasting glucose would be resulting in poor placental perfusion of glucose. However since placental pool constitutes 20% of the total maternal pool, it is possible that when the glucose load is given, there may be more flooding of the placental bed with higher amount of glucose to create a high concentration gradient across the placenta and may be a adaptation mechanism for better placental perfusion. This in turn is reflected in faster MCR. However the faster clearance would also be for Supplying glucose to vital organs such as brain, kidney etc. of the mother for their energy needs in a semistarved state. Since the compensatory mechanism cannot be stretched too far due to chronic poor availability of substrates, fetal energy needs are compromised resulting in growth retardation (Flow diagram) Abell in 15000 oral GTTs observed a high incidence of IUGR with both hypoglycemic and hyperglycemic curves. FLOW DIAGRAM

Mother

i

Chronic energy deficit

$

Low/normal glucose ,jp ~ Placenta

V

Inadequate reserves

Faster MCR (A compensatory mechanism)

and/or

Poor, intervillOUSpoor trans'~ferCirculati~

.L Low glucose Probable low insulin production Fetus Poor s o growth

m

~

P o o deposition

Features of IUGR

r

carbohydrate reserves (Hypoglycemia)

GLUCOSE METABOLISM IN INDIAN WOMEN

143

Earlier observations indicated that peak response of both oral a n d I.V. glucose tolerance curves were significantly lower in both undernourished pregnant normal and PIH women as compared to wellnourished women indicating that undernutrition altered the glucose response (15,6). In this study the data analysis was in only the undernourished women and most of the PIHs belonged to poor class of population with similar dietary intakes. From the present study it is clear that undernourished women giving birth to IUGR have an altered response irrespective of the cause. PIH per s_e_edid not have any e f f e c t on glucose metabolism. The behaviour of glucose kinetics by the IUGR mothers in this study are somewhat similar to xenohiotic clearance which h a v e been documented in undernourished men and women (17). Further studies are needed to resolve the questions of the transfer of nutrients and xenobiotics across the placenta in conditions of IUGR. ACKNOWLEDGEMENT The authors thank the Director, Dr. B.S. Narasinga Rao, National Institute of Nutrition for his encouragement in carrying out this study. REFERENCES 1.

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Transport

mechanisms

Accepted for publication August 21, 1987

in the

fetus.

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