Original Article
Relationship between insulin resistance and tissue blood flow in preeclampsia Nick Anim-Nyame a,b, John Gamble c, Suren R. Sooranna b, Mark R. Johnson b, and Philip J. Steer b
Objective: Preeclampsia is characterized by generalized endothelial dysfunction and impaired maternal tissue perfusion, and insulin resistance is a prominent feature of this disease. The aim of this study was to test the hypothesis that insulin resistance in preeclampsia is related to the reduced resting tissue blood flow. Methods: We used venous occlusion plethysmography to compare the resting calf muscle blood flow (measured as QaU) in 20 nulliparous women with preeclampsia and 20 normal pregnant controls matched for maternal age, gestational age, parity and BMI during the third trimester. Fasting blood samples were obtained to measure the plasma concentrations of insulin and glucose, and to calculate the fasting insulin resistance index (FIRI), a measure of insulin resistance in both groups of women. Results: Calf blood flow was significantly reduced in the preeclampsia group (1.93 0.86 QaU), compared with normal pregnant controls (3.94 1.1 QaU, P < 0.001). Fasting insulin concentrations and Insulin Resistance Index were significantly higher in preeclampsia compared with normal pregnancy (P < 0.001 for both variables). There were significant inverse correlations between resting calf blood flow and fasting insulin concentrations (r ¼ 0.57, P ¼ 0.008) and FIRI (r ¼ 0.59, P ¼ 0.006) in preeclampsia, but not in normal pregnancy. Conclusion: These findings support our hypothesis and raise the possibility that reduced tissue blood flow may a play a role in the increased insulin resistance seen in preeclampsia. Keywords: hypertension, insulin resistance, microcirculation, preeclampsia Abbreviations: BP, blood pressure; FIRI, fasting insulin resistance index; HOMA, homeostatic model assessment of insulin resistance; QaU, units of blood flow (ml/min per 100 g tissue)
Indeed, profound changes in the maternal metabolism occur in pregnancies complicated by the disease and these changes are similar to those observed in the insulin resistance syndrome [8,9], a cluster of metabolic risk factors for cardiovascular disease [10]. Muscle is the main peripheral site of insulin action [11] and insulin is delivered to the muscle cells from the circulation via both passive diffusion and transcapillary transport mechanisms involving endothelial cell surface binding [12]. The delivery process seems to be a rate-limiting factor for insulin action [13]. Although insulin uptake, per se, is not blood flow limited, peripheral blood flow does correlate with glucose uptake [14,15]. Thus, changes in microvascular function, including tissue blood flow, may affect insulin delivery and insulin resistance [16]. Indeed, Baron et al. [17] demonstrated attenuation of blood flow responses to insulin as an underlying mechanism for reduced skeletal muscle glucose uptake. However, these findings were not confirmed by other studies [18]. The clinical presentation of preeclampsia is suggestive of impaired tissue perfusion. We have shown that resting calf blood flow is reduced in pregnancies complicated by the disease [19] and precedes the clinical onset [20]. Furthermore, there is evidence that insulin resistance of preeclampsia is related to microvascular reactivity 23 years after preeclampsia [21]. In this study, we have investigated the hypothesis that the reduced tissue blood flow in preeclampsia may contribute to the insulin resistance in pregnancies complicated by the disease.
METHODS Participants We used a strain gauge plethysmography technique to measure the resting calf blood flow in the 20 women admitted with preeclampsia and 20 normal pregnant
Journal of Hypertension 2015, 33:1057–1063
INTRODUCTION
P
reeclampsia is a multisystem disorder of pregnancy, characterized by hypertension and generalized endothelial cell dysfunction [1]. Insulin resistance is a feature of the disease [2–5], which may persist even after the pregnancy [4]. The cause of insulin resistance in preeclampsia remains unclear, although it has been attributed to dyslipidaemia and endothelial dysfunction [6,7].
Journal of Hypertension
a Department of Obstetrics and Gynaecology, Kingston Hospital, Kingston upon Thames, Surrey, bAcademic Department of Obstetrics and Gynaecology, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London and c School of Sports and Exercise Sciences, University of Birmingham, Birmingham, UK
Correspondence to Nick Anim-Nyame, Department of Obstetrics and Gynaecology, Kingston Hospital, Galsworthy Road, Kingston upon Thames, Surrey, KT2 7QB, UK. Tel: +44 208 934 2197; fax: +44 208 934 3318; e-mail: [email protected] Received 11 May 2014 Revised 17 November 2014 Accepted 17 November 2014 J Hypertens 33:1057–1063 ß 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000494
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1057
Anim-Nyame et al.
controls matched for maternal age, gestational age, parity and BMI. All of the women were recruited from the maternity unit of the Chelsea and Westminster Hospital, London. Women with preeclampsia were recruited from the antenatal wards and the normal pregnant controls from the antenatal clinic. All the women were nulliparous, nonsmokers and were not on any medication. None of the participants received intravenous infusion before or during the study. Women with a previous or present history of peripheral vascular disease, peripheral neuropathy or any other underlying medical disorders were excluded from the study. All study procedures complied with the declaration of Helsinki, informed consent was obtained from each participant and the study was approved by the Local Ethics Committee. Preeclampsia was diagnosed when patients developed both hypertension and proteinuria for the first time after 20 weeks gestation, and confirmed retrospectively when both hypertension and proteinuria reversed after the pregnancy. Hypertension was defined as an absolute blood pressure (BP) greater than or equal to 140 mmHg SBP or 90 mmHg DBP measured manually twice, at least 6 h apart. The first and fifth Korotkoff sounds were used to determine the systolic and diastolic components, respectively. Proteinuria was defined as more than 300 mg/l in a 24-h urine specimen [22]. The 24-h urine samples were collected into plastic jars containing phenyl mercuric acetate preservatives and protein was measured by colorimetric reactions using an autoanalyser [23]. All the women had normal 1-h 50 g glucose challenge test results between 26 and 28 weeks gestation (
Relationship between insulin resistance and tissue blood flow in preeclampsia Nick Anim-Nyame a,b, John Gamble c, Suren R. Sooranna b, Mark R. Johnson b, and Philip J. Steer b
Objective: Preeclampsia is characterized by generalized endothelial dysfunction and impaired maternal tissue perfusion, and insulin resistance is a prominent feature of this disease. The aim of this study was to test the hypothesis that insulin resistance in preeclampsia is related to the reduced resting tissue blood flow. Methods: We used venous occlusion plethysmography to compare the resting calf muscle blood flow (measured as QaU) in 20 nulliparous women with preeclampsia and 20 normal pregnant controls matched for maternal age, gestational age, parity and BMI during the third trimester. Fasting blood samples were obtained to measure the plasma concentrations of insulin and glucose, and to calculate the fasting insulin resistance index (FIRI), a measure of insulin resistance in both groups of women. Results: Calf blood flow was significantly reduced in the preeclampsia group (1.93 0.86 QaU), compared with normal pregnant controls (3.94 1.1 QaU, P < 0.001). Fasting insulin concentrations and Insulin Resistance Index were significantly higher in preeclampsia compared with normal pregnancy (P < 0.001 for both variables). There were significant inverse correlations between resting calf blood flow and fasting insulin concentrations (r ¼ 0.57, P ¼ 0.008) and FIRI (r ¼ 0.59, P ¼ 0.006) in preeclampsia, but not in normal pregnancy. Conclusion: These findings support our hypothesis and raise the possibility that reduced tissue blood flow may a play a role in the increased insulin resistance seen in preeclampsia. Keywords: hypertension, insulin resistance, microcirculation, preeclampsia Abbreviations: BP, blood pressure; FIRI, fasting insulin resistance index; HOMA, homeostatic model assessment of insulin resistance; QaU, units of blood flow (ml/min per 100 g tissue)
Indeed, profound changes in the maternal metabolism occur in pregnancies complicated by the disease and these changes are similar to those observed in the insulin resistance syndrome [8,9], a cluster of metabolic risk factors for cardiovascular disease [10]. Muscle is the main peripheral site of insulin action [11] and insulin is delivered to the muscle cells from the circulation via both passive diffusion and transcapillary transport mechanisms involving endothelial cell surface binding [12]. The delivery process seems to be a rate-limiting factor for insulin action [13]. Although insulin uptake, per se, is not blood flow limited, peripheral blood flow does correlate with glucose uptake [14,15]. Thus, changes in microvascular function, including tissue blood flow, may affect insulin delivery and insulin resistance [16]. Indeed, Baron et al. [17] demonstrated attenuation of blood flow responses to insulin as an underlying mechanism for reduced skeletal muscle glucose uptake. However, these findings were not confirmed by other studies [18]. The clinical presentation of preeclampsia is suggestive of impaired tissue perfusion. We have shown that resting calf blood flow is reduced in pregnancies complicated by the disease [19] and precedes the clinical onset [20]. Furthermore, there is evidence that insulin resistance of preeclampsia is related to microvascular reactivity 23 years after preeclampsia [21]. In this study, we have investigated the hypothesis that the reduced tissue blood flow in preeclampsia may contribute to the insulin resistance in pregnancies complicated by the disease.
METHODS Participants We used a strain gauge plethysmography technique to measure the resting calf blood flow in the 20 women admitted with preeclampsia and 20 normal pregnant
Journal of Hypertension 2015, 33:1057–1063
INTRODUCTION
P
reeclampsia is a multisystem disorder of pregnancy, characterized by hypertension and generalized endothelial cell dysfunction [1]. Insulin resistance is a feature of the disease [2–5], which may persist even after the pregnancy [4]. The cause of insulin resistance in preeclampsia remains unclear, although it has been attributed to dyslipidaemia and endothelial dysfunction [6,7].
Journal of Hypertension
a Department of Obstetrics and Gynaecology, Kingston Hospital, Kingston upon Thames, Surrey, bAcademic Department of Obstetrics and Gynaecology, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London and c School of Sports and Exercise Sciences, University of Birmingham, Birmingham, UK
Correspondence to Nick Anim-Nyame, Department of Obstetrics and Gynaecology, Kingston Hospital, Galsworthy Road, Kingston upon Thames, Surrey, KT2 7QB, UK. Tel: +44 208 934 2197; fax: +44 208 934 3318; e-mail: [email protected] Received 11 May 2014 Revised 17 November 2014 Accepted 17 November 2014 J Hypertens 33:1057–1063 ß 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000494
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1057
Anim-Nyame et al.
controls matched for maternal age, gestational age, parity and BMI. All of the women were recruited from the maternity unit of the Chelsea and Westminster Hospital, London. Women with preeclampsia were recruited from the antenatal wards and the normal pregnant controls from the antenatal clinic. All the women were nulliparous, nonsmokers and were not on any medication. None of the participants received intravenous infusion before or during the study. Women with a previous or present history of peripheral vascular disease, peripheral neuropathy or any other underlying medical disorders were excluded from the study. All study procedures complied with the declaration of Helsinki, informed consent was obtained from each participant and the study was approved by the Local Ethics Committee. Preeclampsia was diagnosed when patients developed both hypertension and proteinuria for the first time after 20 weeks gestation, and confirmed retrospectively when both hypertension and proteinuria reversed after the pregnancy. Hypertension was defined as an absolute blood pressure (BP) greater than or equal to 140 mmHg SBP or 90 mmHg DBP measured manually twice, at least 6 h apart. The first and fifth Korotkoff sounds were used to determine the systolic and diastolic components, respectively. Proteinuria was defined as more than 300 mg/l in a 24-h urine specimen [22]. The 24-h urine samples were collected into plastic jars containing phenyl mercuric acetate preservatives and protein was measured by colorimetric reactions using an autoanalyser [23]. All the women had normal 1-h 50 g glucose challenge test results between 26 and 28 weeks gestation (
