- Email: [email protected]
Resistance to insulin-mediated glucose uptake and hyperinsulinemia in women who had preeclampsia during pregnancy
BRIEF COMMUNICATION
AJH
1995; 8:768-771
Resistance to Insulin-Mediated Glucose Uptake and Hyperinsulinemia in Women Who Had Preeclampsia During Pregnancy Martin M.-T. Fuh, Chang-Sheng Yin, Dee Pei, Wayne H.-H. Sheu, Chii-Yuan Jeng, Y.-D. Ida Chen, and Gerald M. Reaven
Plasma glucose and insulin responses to a 75-g oral glucose load, and the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations after an infusion of somatostatin, insulin, and glucose, were determined 2 months after delivery in 26 women; 13 w h o had a normal pregnancy and 13 who developed preeclampsia. The plasma glucose response to oral glucose was not different in the two groups, but the plasma insulin response was significantly greater (P < .02) in those who had been preeclamptic. Although the mean (+-_SE) SSPI concentrations during the infusion study were sim-
p}
atients with high blood pressure, as a group, are resistant to insulin-mediated glucose uptake and hyperinsulinemic. 1~ On the basis of these observations and evidence that similar changes are seen in both genetic and dietaryinduced forms of rodent hypertension, s-7 it has been suggested that these abnormalities of insulin metab-
Received September 14, 1994. Accepted January 31, 1995. From the Division of Endocrinology and Metabolism (MM-TF, DP, WH-HS, C-YJ), Department of Obstetrics and Gynecology (C-SY), Tri-Services General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Medicine (Y-DIC, GMR), Stanford University School of Medicine and Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, Palo Alto, California. This research was supported by research grants from the National Science Council, Republic of China (NSC 79-0412-B016-56 and NSC 80-0412-B016-53); and the National Institutes of Health (HL-08506). Address correspondence and reprint requests to Martin M.-T. Fuh, Division of Endocrinology and Metabolism, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China, Taiwan.
© 1995 by the American Journal of Hypertension, Ltd.
ilar in the two groups (51 - 2 v 56 - 2 ~U/mL), the SSPG concentrations were significantly higher (P < .02) in those who developed preeclampsia (160 - 17 v 119 +-- 17 mg/dL). Thus, when studied 2 months after delivery, w o m e n who developed preeclampsia were relatively insulin resistant and hyperinsulinemic when compared to those who had an uncomplicated pregnancy. Am J Hypertens 1995;8:768-771 KEY WORDS: Insulin resistance, hyperinsulinemia, preeclampsia.
olism can lead to hypertension. In this context, the study of women who become hypertensive during pregnancy might provide additional insight into the causal relationship, if any, between insulin resistance, compensatory hyperinsulinemia, and blood pressure regulation. Indeed, there are published data that could be interpreted as providing evidence for a link between insulin resistance and preeclampsia. Specifically, there are reports of increased plasma glucose responses to intravenous glucose, s a decrease in the ability of insulin to lower blood glucose, 9 and higher plasma insulin responses to a glucose load among w o m e n with preeclampsia. 1°'11 More recently, evidence has been published that nonpreeclamptic hypertensive pregnant women are hyperinsulinemic when compared to normotensive control women 12 and that women who developed hypertension during pregnancy had higher plasma glucose responses to oral glucose than did those who remained normotensive.13 On the basis of this information, the current study was initiated, in which we quantified
0895-7061/95/$9.50 0895-7061 (95)00078-4
INSULIN RESISTANCEAND PREECLAMPSIA 769
AJH-JULY 1995-VOL. 8, NO. 7
the plasma glucose and insulin responses to oral glucose, as well as the ability of insulin to mediate glucose uptake 2 months after delivery in women who either had a normal pregnancy or had been preeclamptic. MATERIALS AND METHODS The study population consisted of 26 nulliparous women studied approximately 8 weeks after a normal delivery. Of this group, 13 had been diagnosed as having preeclampsia during pregnancy in accordance with the criteria of the American College of Obstetrics and Gynecology. 14 None of the subjects developing preeclampsia was hypertensive before becoming pregnant, and the blood pressure in the two groups was similar when they were first seen (112 + 4/71 + 3 v 113 -+ 3/70 -+ 2 mm Hg). Preeclampsia was defined by a rise in blood pressure above baseline values >140/90 mm Hg, or a rise in blood pressure of 30 mm Hg (systolic) or 15 mm Hg (diastolic), and with the development of proteinuria. Proteinuria was suspected if urine protein concentration was >100 mg/L in two random urine concentrations. Proteinuria was defined as a 24-h urine protein excretion >300 mg/day. An additional 13 women who delivered at approximately the same time as those with preeclampsia, but who had an uncomplicated pregnancy, volunteered to serve as the control population. All 26 subjects were of Chinese descent, living in Taipei, without a history of either hypertension or diabetes, and none of the participants smoked. The 26 subjects were studied on two occasions, approximately 8 weeks after delivery. None of the participants was nursing or taking oral contraceptives. Two tests were performed in each subject after an overnight fast. On one occasion, plasma glucose is and insulin 16 concentrations were measured before and 30, 60, 90, 120, and 180 rain after a 75-g oral glucose load. On another occasion, resistance to insulin-mediated glucose disposal was estimated by the insulin suppression test. 2'3 The statistical significances of differences between the baseline characteristics of the two groups were compared by Student's nonpaired t test, whereas two-way analysis of variance was used to compare the plasma glucose and insulin responses to oral glucose. Because of the great variability in the steadystate plasma glucose (SSPG) responses of the two groups, this variable was compared by X2 using 140 mg/dL as the cut-off point. RESULTS
Characteristics of the two groups 2 months after delivery are listed in Table 1. This information shows that the two groups were similar in terms of age and degree of obesity as estimated by body mass index.
TABLE 1. BASELINE CHARACTERISTICS OF THE TWO GROUPS (MEAN _+ SEM) Variable
Age (years) BMI (kg/m2) SystolicBP (mm Hg) Diastolic BP (mm Hg)
Normal
Preeclamptic
28 ± 1 22.5 ± 0.7 108 ± 4 72 ~ 4
29 ± I 23.5 ± 0.79 125 ± 3 85 ± 3
P
NS NS <.01 <.05
BMI, body mass index; BP, blood pressure.
On the other hand, both systolic (P < .01) and diastolic (P < .05) pressures were higher in those who had been preeclamptic during pregnancy. Indeed, three of 13 subjects who had preeclampsia would be classified as having mild diastolic hypertension (ie, blood pressure >90 to <95 mm Hg). Plasma glucose and insulin concentrations after a 75-g oral glucose challenge in the groups are shown in Figure 1. The results demonstrate that the plasma glucose responses were essentially identical in the two groups. In contrast, it is obvious from the results that the insulin response of the preeclamptic group was significantly greater than that of those who had a normal pregnancy (P < .02). The steady-state plasma insulin (SSPI) concentrations during the insulin suppression test were similar in the women who had either a normal pregnancy (51 + 2 ~U/mL) or had been preeclamptic (56 --- 2 p,U/ mL). However, the mean (-+SE) SSPG values were higher in those with preeclampsia (160 -+ 17 mg/dL) as compared to 119 + 17 mg/dL in the control group, and this difference was statistically significant by X2 (P < .02). DISCUSSION The data presented have shown that women who had preeclampsia during pregnancy were resistant to insulin-mediated glucose uptake and were hyperin160
200
INSULIN
GLUCOSE
150
120
to0
8O
"o
o
...
0 50
Preeclamptic
•
Women • .o.-
;
'
Control
io
',io'
/
180
0//
0
I
I 60
I
1
120
l
t
180
Time (minutes)
FIGURE 1. Plasma glucose (left) and insulin (right) concentrations in response to a 75-g oral glucose challenge 2 months after delivery in subjects with either a normal (C)--O) or preeclamptic (O-Q) pregnancy.
770
FUH ET AL
sulinemic w h e n studied 2 m o n t h s after delivery when compared to a group of women who had gone through a normal pregnancy. As such, these observations offer direct support for the conclusions of earlier studies, in which evidence of an association between high blood pressure and insulin resistance in pregnancy was based on estimates of plasma glucose and/or insulin responses to a glucose challenge, s-12 On the other hand, the data presented appear to be in conflict with the recent results of Jacober et a1,17 who reported that insulin-stimulated glucose disposal was similar when studied postpartum in 10 preclamptic women and 7 women undergoing a normal pregnancy. The reason for this disparity in experimental results is not immediately clear, but there are several differences between the two studies that may be relevant. First, we studied Chinese women, as compared to the African-American women examined by Jacober et al. 17 Second, our study population consisted of 26 women, 13 who had been preeclamptic and 13 who had had a normal pregnancy, as compared to the 17 subjects examined by Jacober et a117 (10 with a history of preeclampsia and 7 with a normal pregnancy). The relatively small size of the experimental population studied by Jacober et a117 may explain w h y two previous reports from the same group, based on measurements in five preeclamptic women in each study, 11"18 concluded that insulin resistance was present in these subjects. However, it should be noted that the conclusion from the studies of Madsen et al 1° and Bottoms et a118 that insulin resistance was present in preeclamptic women was based on demonstration of relative hyperinsulinemia, not direct measurements of insulin-mediated glucose disposal. In that context, it is of interest to note that in the current study we found evidence of both hyperinsulinemia (Figure 1) and insulin resistance. Finally, although we found that the women who had been preeclamptic were relatively insulin resistant when studied 2 months after delivery when compared to women who had undergone a normal delivery, the mean SSPG was only increased by -33%, and not all preeclamptic women were insulin resistant. Thus, we speculate that the most likely explanation for the difference between our results and those of Jacober et a117 is the finding that preeclamptic women are not homogenous with regard to insulin action, and that the more subjects studied, the more likely is the ability to discern the defect in insulin action. Although the experimental data are straightforward, they are subject to multiple possible interpretations. For example, it could be argued that the preeclamptic women had higher blood pressures 2 months after delivery, and hypertension per se was responsible for the insulin resistance and hyperinsulinemia. However, this alternative seems unlikely in
AJH-JULY 1995-VOL. 8, NO. 7
that these changes in insulin metabolism do not develop in patients with secondary forms of hypertension, 19'2° or in rats made hypertensive by renal artery stenosis. 21"22Furthermore, normotensive first degree relatives of patients with high blood pressure are relatively insulin resistant and hyperinsulinemic w h e n compared to a matched group of individuals without a family history of high blood pressure. 23'24 Alternatively, it could be argued that w o m e n who are prone to develop essential hypertension have certain characteristics that place them at greater risk to become preeclamptic. Although the women who developed preeclampsia did not have essential hypertension w h e n they became pregnant, their blood pressures 2 months after pregnancy were significantly higher than in those who had a normal pregnancy. These data suggest that these individuals may be at greater risk to develop hypertension. Because insulin resistance and hyperinsulinemia occur in both patients with essential hypertension, 1~ as well as their first degree relatives, 23'24 it seems reasonable to conclude that women at risk to develop hypertension are more likely to develop preeclampsia and be relatively resistant to insulin-mediated glucose disposal and hyperinsulinemia. If the women who develop preeclampsia are likely to be insulin resistant and hyperinsulinemic, the possibility that the two are causally related must be considered. Although this is a complex question, it might be approached initially in a relatively simple fashion. Specifically, if plasma insulin concentrations were routinely measured w h e n pregnant w o m e n were evaluated for gestational diabetes, it would be relatively simple to see if hyperinsulinemia, presumably secondary to insulin resistance, was present in those who developed preeclampsia. Even if this is the case, it does not necessarily mean that abnormal insulin metabolism is the cause of preeclampsia. On the other hand, it would certainly provide useful information as to who was at risk to develop this complication. REFERENCES
1. Ferrannini E, Buzzigoli G, Bonadonna R, et al: Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-357. 2. Shen D-C, Shieh S-M, Fuh M-T, et al: Resistance to insulin-stimulated-glucose uptake in patients with hypertension. J Clin Endocrinol Metab 1988;66:580-583. 3. SwislockiALM, Hoffman BB, Reaven GM: Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens 1989;2: 419-423. 4. Pollare T, Lithell H, Berne C: Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 1990;39:167-174. 5. Hwang I-S, Ho H, Hoffman BB, Reaven GM: Fructose-
INSULIN RESISTANCE A N D PREECLAMPSIA
AJH-JULY 1995-VOL. 8, NO. 7
6.
7.
induced insulin resistance and hypertension in rats. Hypertension 1987;10:512-516. Reaven CM, Chang H: Relationship between blood pressure, insulin concentration, and insulin action in SHR and WKY rats. Am J Hypertens 1991;4:34-38. Reaven GM, Twersky J, Chang H: Abnormalities of carbohydrate and lipid metabolism in Dahl rats. Hypertension 1991;18:630-635.
8.
Burt RL: Peripheral utilization of glucose in pregnancy. II: Preeclampsia. Obstet Gynecol 1955;6:51-54.
9.
Burt RL: Peripheral utilization of glucose in pregnancy. IV: Reactivity to insulin in pre-eclampsia. Obstet Gynecol 1957;9:310-316. Madsen SN, Hindberg I, Molsted-Pedersen L: Insulin response to oral glucose in patients with preeclampsia. Dan Med Bull 1973;20:13-15.
10.
11.
12.
Sowers JR, Standley PR, Jacober S, et al: Postpartum abnormalities of carbohydrate and cellular calcium metabolism in pregnancy induced hypertension. Am J Hypertens 1993;6:302-307. Bauman WA, Maimen M, Langer O: An association between hyperinsulinemia and hypertension during the third trimester of pregnancy. Am J Obstet Gynecol 1988;159:446M50.
13.
Solomon CG, Graves SW, Greene MF, Seely EW: Glucose intolerance as a predictor of hypertension in pregnancy. Hypertension 1994;23:717-721.
14.
American College of Obstetrics and Gynecology: Management of Preeclampsia. Technical Bulletin No. 91, February 1986.
15.
Kadish AH, Litle RL, Stenberg JC: A new and rapid method for the determination of glucose by rate of oxygen consumption. Clin Chem 1971;14:116-131.
771
16.
Hales CN, Randle PJ: Immunoassay of insulin with insulin antibody precipitate. Biochem J 1963;88:137146. 17. Jacober SJ, Morris DA, Sowers JR: Postpartum blood pressure and insulin sensitivity in African-American women with recent preeclampsia. Am J Hypertens 1994;7:933-936. 18. Bottoms SF, Niyogi TG, Standley PR, et al: Insulin resistance with the development of preeclampsia in urban black women (abstract). Am J Hypertens 1992; 5:74A. 19. Marigliano A, Tedde R, Sechi LA, et al: Insulinemia and blood pressure relationships in patients with primary and secondary hypertension, and with or without glucose metabolism impairment. Am J Hypertens 1990;3:521-526. 20.
21.
22.
23.
24.
Shamiss A, Carroll J, Rosenthal T: Insulin resistance in secondary hypertension. Am J Hypertens 1992;5:2628. Buchanan TA, Sipos GF, Gadalah S, et al: Glucose tolerance and insulin action in rats with renovascular hypertension. Hypertension 1991;18:341-347. Reaven GM, Ho H: Renal vascular hypertension does not lead to hyperinsulinemia in Sprague-Dawley rats. Am J Hypertens 1992;5:314--317. Ferrari P, Weidmann P, Shaw S, et al: Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent. Am J Med 1991; 91:589-596. Facchini F, Chen Y-DI, Clinkingbeard C, et al: Insulin resistance, hyperinsulinemia, and dyslipidemia in nonobese individuals with a family history of hypertension. Am J Hypertens 1992;5:694-699.
AJH
1995; 8:768-771
Resistance to Insulin-Mediated Glucose Uptake and Hyperinsulinemia in Women Who Had Preeclampsia During Pregnancy Martin M.-T. Fuh, Chang-Sheng Yin, Dee Pei, Wayne H.-H. Sheu, Chii-Yuan Jeng, Y.-D. Ida Chen, and Gerald M. Reaven
Plasma glucose and insulin responses to a 75-g oral glucose load, and the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations after an infusion of somatostatin, insulin, and glucose, were determined 2 months after delivery in 26 women; 13 w h o had a normal pregnancy and 13 who developed preeclampsia. The plasma glucose response to oral glucose was not different in the two groups, but the plasma insulin response was significantly greater (P < .02) in those who had been preeclamptic. Although the mean (+-_SE) SSPI concentrations during the infusion study were sim-
p}
atients with high blood pressure, as a group, are resistant to insulin-mediated glucose uptake and hyperinsulinemic. 1~ On the basis of these observations and evidence that similar changes are seen in both genetic and dietaryinduced forms of rodent hypertension, s-7 it has been suggested that these abnormalities of insulin metab-
Received September 14, 1994. Accepted January 31, 1995. From the Division of Endocrinology and Metabolism (MM-TF, DP, WH-HS, C-YJ), Department of Obstetrics and Gynecology (C-SY), Tri-Services General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Medicine (Y-DIC, GMR), Stanford University School of Medicine and Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, Palo Alto, California. This research was supported by research grants from the National Science Council, Republic of China (NSC 79-0412-B016-56 and NSC 80-0412-B016-53); and the National Institutes of Health (HL-08506). Address correspondence and reprint requests to Martin M.-T. Fuh, Division of Endocrinology and Metabolism, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China, Taiwan.
© 1995 by the American Journal of Hypertension, Ltd.
ilar in the two groups (51 - 2 v 56 - 2 ~U/mL), the SSPG concentrations were significantly higher (P < .02) in those who developed preeclampsia (160 - 17 v 119 +-- 17 mg/dL). Thus, when studied 2 months after delivery, w o m e n who developed preeclampsia were relatively insulin resistant and hyperinsulinemic when compared to those who had an uncomplicated pregnancy. Am J Hypertens 1995;8:768-771 KEY WORDS: Insulin resistance, hyperinsulinemia, preeclampsia.
olism can lead to hypertension. In this context, the study of women who become hypertensive during pregnancy might provide additional insight into the causal relationship, if any, between insulin resistance, compensatory hyperinsulinemia, and blood pressure regulation. Indeed, there are published data that could be interpreted as providing evidence for a link between insulin resistance and preeclampsia. Specifically, there are reports of increased plasma glucose responses to intravenous glucose, s a decrease in the ability of insulin to lower blood glucose, 9 and higher plasma insulin responses to a glucose load among w o m e n with preeclampsia. 1°'11 More recently, evidence has been published that nonpreeclamptic hypertensive pregnant women are hyperinsulinemic when compared to normotensive control women 12 and that women who developed hypertension during pregnancy had higher plasma glucose responses to oral glucose than did those who remained normotensive.13 On the basis of this information, the current study was initiated, in which we quantified
0895-7061/95/$9.50 0895-7061 (95)00078-4
INSULIN RESISTANCEAND PREECLAMPSIA 769
AJH-JULY 1995-VOL. 8, NO. 7
the plasma glucose and insulin responses to oral glucose, as well as the ability of insulin to mediate glucose uptake 2 months after delivery in women who either had a normal pregnancy or had been preeclamptic. MATERIALS AND METHODS The study population consisted of 26 nulliparous women studied approximately 8 weeks after a normal delivery. Of this group, 13 had been diagnosed as having preeclampsia during pregnancy in accordance with the criteria of the American College of Obstetrics and Gynecology. 14 None of the subjects developing preeclampsia was hypertensive before becoming pregnant, and the blood pressure in the two groups was similar when they were first seen (112 + 4/71 + 3 v 113 -+ 3/70 -+ 2 mm Hg). Preeclampsia was defined by a rise in blood pressure above baseline values >140/90 mm Hg, or a rise in blood pressure of 30 mm Hg (systolic) or 15 mm Hg (diastolic), and with the development of proteinuria. Proteinuria was suspected if urine protein concentration was >100 mg/L in two random urine concentrations. Proteinuria was defined as a 24-h urine protein excretion >300 mg/day. An additional 13 women who delivered at approximately the same time as those with preeclampsia, but who had an uncomplicated pregnancy, volunteered to serve as the control population. All 26 subjects were of Chinese descent, living in Taipei, without a history of either hypertension or diabetes, and none of the participants smoked. The 26 subjects were studied on two occasions, approximately 8 weeks after delivery. None of the participants was nursing or taking oral contraceptives. Two tests were performed in each subject after an overnight fast. On one occasion, plasma glucose is and insulin 16 concentrations were measured before and 30, 60, 90, 120, and 180 rain after a 75-g oral glucose load. On another occasion, resistance to insulin-mediated glucose disposal was estimated by the insulin suppression test. 2'3 The statistical significances of differences between the baseline characteristics of the two groups were compared by Student's nonpaired t test, whereas two-way analysis of variance was used to compare the plasma glucose and insulin responses to oral glucose. Because of the great variability in the steadystate plasma glucose (SSPG) responses of the two groups, this variable was compared by X2 using 140 mg/dL as the cut-off point. RESULTS
Characteristics of the two groups 2 months after delivery are listed in Table 1. This information shows that the two groups were similar in terms of age and degree of obesity as estimated by body mass index.
TABLE 1. BASELINE CHARACTERISTICS OF THE TWO GROUPS (MEAN _+ SEM) Variable
Age (years) BMI (kg/m2) SystolicBP (mm Hg) Diastolic BP (mm Hg)
Normal
Preeclamptic
28 ± 1 22.5 ± 0.7 108 ± 4 72 ~ 4
29 ± I 23.5 ± 0.79 125 ± 3 85 ± 3
P
NS NS <.01 <.05
BMI, body mass index; BP, blood pressure.
On the other hand, both systolic (P < .01) and diastolic (P < .05) pressures were higher in those who had been preeclamptic during pregnancy. Indeed, three of 13 subjects who had preeclampsia would be classified as having mild diastolic hypertension (ie, blood pressure >90 to <95 mm Hg). Plasma glucose and insulin concentrations after a 75-g oral glucose challenge in the groups are shown in Figure 1. The results demonstrate that the plasma glucose responses were essentially identical in the two groups. In contrast, it is obvious from the results that the insulin response of the preeclamptic group was significantly greater than that of those who had a normal pregnancy (P < .02). The steady-state plasma insulin (SSPI) concentrations during the insulin suppression test were similar in the women who had either a normal pregnancy (51 + 2 ~U/mL) or had been preeclamptic (56 --- 2 p,U/ mL). However, the mean (-+SE) SSPG values were higher in those with preeclampsia (160 -+ 17 mg/dL) as compared to 119 + 17 mg/dL in the control group, and this difference was statistically significant by X2 (P < .02). DISCUSSION The data presented have shown that women who had preeclampsia during pregnancy were resistant to insulin-mediated glucose uptake and were hyperin160
200
INSULIN
GLUCOSE
150
120
to0
8O
"o
o
...
0 50
Preeclamptic
•
Women • .o.-
;
'
Control
io
',io'
/
180
0//
0
I
I 60
I
1
120
l
t
180
Time (minutes)
FIGURE 1. Plasma glucose (left) and insulin (right) concentrations in response to a 75-g oral glucose challenge 2 months after delivery in subjects with either a normal (C)--O) or preeclamptic (O-Q) pregnancy.
770
FUH ET AL
sulinemic w h e n studied 2 m o n t h s after delivery when compared to a group of women who had gone through a normal pregnancy. As such, these observations offer direct support for the conclusions of earlier studies, in which evidence of an association between high blood pressure and insulin resistance in pregnancy was based on estimates of plasma glucose and/or insulin responses to a glucose challenge, s-12 On the other hand, the data presented appear to be in conflict with the recent results of Jacober et a1,17 who reported that insulin-stimulated glucose disposal was similar when studied postpartum in 10 preclamptic women and 7 women undergoing a normal pregnancy. The reason for this disparity in experimental results is not immediately clear, but there are several differences between the two studies that may be relevant. First, we studied Chinese women, as compared to the African-American women examined by Jacober et al. 17 Second, our study population consisted of 26 women, 13 who had been preeclamptic and 13 who had had a normal pregnancy, as compared to the 17 subjects examined by Jacober et a117 (10 with a history of preeclampsia and 7 with a normal pregnancy). The relatively small size of the experimental population studied by Jacober et a117 may explain w h y two previous reports from the same group, based on measurements in five preeclamptic women in each study, 11"18 concluded that insulin resistance was present in these subjects. However, it should be noted that the conclusion from the studies of Madsen et al 1° and Bottoms et a118 that insulin resistance was present in preeclamptic women was based on demonstration of relative hyperinsulinemia, not direct measurements of insulin-mediated glucose disposal. In that context, it is of interest to note that in the current study we found evidence of both hyperinsulinemia (Figure 1) and insulin resistance. Finally, although we found that the women who had been preeclamptic were relatively insulin resistant when studied 2 months after delivery when compared to women who had undergone a normal delivery, the mean SSPG was only increased by -33%, and not all preeclamptic women were insulin resistant. Thus, we speculate that the most likely explanation for the difference between our results and those of Jacober et a117 is the finding that preeclamptic women are not homogenous with regard to insulin action, and that the more subjects studied, the more likely is the ability to discern the defect in insulin action. Although the experimental data are straightforward, they are subject to multiple possible interpretations. For example, it could be argued that the preeclamptic women had higher blood pressures 2 months after delivery, and hypertension per se was responsible for the insulin resistance and hyperinsulinemia. However, this alternative seems unlikely in
AJH-JULY 1995-VOL. 8, NO. 7
that these changes in insulin metabolism do not develop in patients with secondary forms of hypertension, 19'2° or in rats made hypertensive by renal artery stenosis. 21"22Furthermore, normotensive first degree relatives of patients with high blood pressure are relatively insulin resistant and hyperinsulinemic w h e n compared to a matched group of individuals without a family history of high blood pressure. 23'24 Alternatively, it could be argued that w o m e n who are prone to develop essential hypertension have certain characteristics that place them at greater risk to become preeclamptic. Although the women who developed preeclampsia did not have essential hypertension w h e n they became pregnant, their blood pressures 2 months after pregnancy were significantly higher than in those who had a normal pregnancy. These data suggest that these individuals may be at greater risk to develop hypertension. Because insulin resistance and hyperinsulinemia occur in both patients with essential hypertension, 1~ as well as their first degree relatives, 23'24 it seems reasonable to conclude that women at risk to develop hypertension are more likely to develop preeclampsia and be relatively resistant to insulin-mediated glucose disposal and hyperinsulinemia. If the women who develop preeclampsia are likely to be insulin resistant and hyperinsulinemic, the possibility that the two are causally related must be considered. Although this is a complex question, it might be approached initially in a relatively simple fashion. Specifically, if plasma insulin concentrations were routinely measured w h e n pregnant w o m e n were evaluated for gestational diabetes, it would be relatively simple to see if hyperinsulinemia, presumably secondary to insulin resistance, was present in those who developed preeclampsia. Even if this is the case, it does not necessarily mean that abnormal insulin metabolism is the cause of preeclampsia. On the other hand, it would certainly provide useful information as to who was at risk to develop this complication. REFERENCES
1. Ferrannini E, Buzzigoli G, Bonadonna R, et al: Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-357. 2. Shen D-C, Shieh S-M, Fuh M-T, et al: Resistance to insulin-stimulated-glucose uptake in patients with hypertension. J Clin Endocrinol Metab 1988;66:580-583. 3. SwislockiALM, Hoffman BB, Reaven GM: Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens 1989;2: 419-423. 4. Pollare T, Lithell H, Berne C: Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism 1990;39:167-174. 5. Hwang I-S, Ho H, Hoffman BB, Reaven GM: Fructose-
INSULIN RESISTANCE A N D PREECLAMPSIA
AJH-JULY 1995-VOL. 8, NO. 7
6.
7.
induced insulin resistance and hypertension in rats. Hypertension 1987;10:512-516. Reaven CM, Chang H: Relationship between blood pressure, insulin concentration, and insulin action in SHR and WKY rats. Am J Hypertens 1991;4:34-38. Reaven GM, Twersky J, Chang H: Abnormalities of carbohydrate and lipid metabolism in Dahl rats. Hypertension 1991;18:630-635.
8.
Burt RL: Peripheral utilization of glucose in pregnancy. II: Preeclampsia. Obstet Gynecol 1955;6:51-54.
9.
Burt RL: Peripheral utilization of glucose in pregnancy. IV: Reactivity to insulin in pre-eclampsia. Obstet Gynecol 1957;9:310-316. Madsen SN, Hindberg I, Molsted-Pedersen L: Insulin response to oral glucose in patients with preeclampsia. Dan Med Bull 1973;20:13-15.
10.
11.
12.
Sowers JR, Standley PR, Jacober S, et al: Postpartum abnormalities of carbohydrate and cellular calcium metabolism in pregnancy induced hypertension. Am J Hypertens 1993;6:302-307. Bauman WA, Maimen M, Langer O: An association between hyperinsulinemia and hypertension during the third trimester of pregnancy. Am J Obstet Gynecol 1988;159:446M50.
13.
Solomon CG, Graves SW, Greene MF, Seely EW: Glucose intolerance as a predictor of hypertension in pregnancy. Hypertension 1994;23:717-721.
14.
American College of Obstetrics and Gynecology: Management of Preeclampsia. Technical Bulletin No. 91, February 1986.
15.
Kadish AH, Litle RL, Stenberg JC: A new and rapid method for the determination of glucose by rate of oxygen consumption. Clin Chem 1971;14:116-131.
771
16.
Hales CN, Randle PJ: Immunoassay of insulin with insulin antibody precipitate. Biochem J 1963;88:137146. 17. Jacober SJ, Morris DA, Sowers JR: Postpartum blood pressure and insulin sensitivity in African-American women with recent preeclampsia. Am J Hypertens 1994;7:933-936. 18. Bottoms SF, Niyogi TG, Standley PR, et al: Insulin resistance with the development of preeclampsia in urban black women (abstract). Am J Hypertens 1992; 5:74A. 19. Marigliano A, Tedde R, Sechi LA, et al: Insulinemia and blood pressure relationships in patients with primary and secondary hypertension, and with or without glucose metabolism impairment. Am J Hypertens 1990;3:521-526. 20.
21.
22.
23.
24.
Shamiss A, Carroll J, Rosenthal T: Insulin resistance in secondary hypertension. Am J Hypertens 1992;5:2628. Buchanan TA, Sipos GF, Gadalah S, et al: Glucose tolerance and insulin action in rats with renovascular hypertension. Hypertension 1991;18:341-347. Reaven GM, Ho H: Renal vascular hypertension does not lead to hyperinsulinemia in Sprague-Dawley rats. Am J Hypertens 1992;5:314--317. Ferrari P, Weidmann P, Shaw S, et al: Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent. Am J Med 1991; 91:589-596. Facchini F, Chen Y-DI, Clinkingbeard C, et al: Insulin resistance, hyperinsulinemia, and dyslipidemia in nonobese individuals with a family history of hypertension. Am J Hypertens 1992;5:694-699.