Hyperinsulinemia in glucose-tolerant women with preeclampsia A controlled study

H perinsulinemia in Glucose-Tolerant omen With Preeckmpsia

WY

A Controlled Study EsptmnzaMartinez Abundis, Manuel and E/eFerramini

Gonml~z Ortiz,

Essential hypertension is associated with insulin psistance and hyperinsulinemia. To assess n hether hyperinsulinemia is also present in hypertensive disease induced by pregnancy, we studied the plasma glucose and insulin responses to 50 g srf oral glucose in 10 women with definite, severe preeclampsia but normal glucose tolerance, and compared them with the responses observed in a well-matched control group of healthy pregnant women. FasEng plasma glucose concentrations were similar in healthy and preeclamptic pregnant mothers (4.1 + 0.4 mmol/L u 4.5 2 0.4 mmol /L, respectively, P = NS). Similar plasma glucose levels were also observed after glucose ingestion (5.5 + 0.3 mmollL v 6.2 2 0.3 m~nol/L in healthy and preeclamptfr: women, respehvely P = NS). In Contras& fasting plasma

ypertensive disease of pregnancy is associated with a high maternofetal mortality in both underdeveloped” and developed countries.“’ The cause of pregnancy-in-

Receiver! April 20,1995. Accepted Novemk 3,1955. C:zr; iire Hospital de Giwcoobstetricia, Centro Medico National de Occidente, U&S, Guadalajara, Jalisco, Mexico (EMA, MGO!, and CNR Institute of Clinical Physiology, Universi!y of Piss, Pka, Itily lQG, EF). Dr. Quifiones Galvan is supported by a grant from the Inslituto Mexicans del !kguro Social ( IMSSl .

AddJEE~drcprir~~boDr.Alfredo~ Galvan, CNA. ltitutr of Clinical Physiology, Via P. Savi 8, Piss 54126, P&I, Italy.

Alfred0 Quifimres GaIvan,

insulin concentrations in the preeclamptic women were significantly higher than in normal pregnant mothers (175 + 29 pmol/L v 101 2 II pmol/L, P < .OS). Postload plasma insulin concentrations were nearly fourfold higher in the preeclamptic group as compared with the control grollp (1162 -C 70 pmol/T, v 366 2 39 pmol/L, P < .Ol). We conclude that preeclampsia is associated with marked hyperinsulinemia both ir. the fasting state and after oral glucose ingestion, sqgesting that insulin resistance may play a role ;n pregnancy-induced hypertension. Am J Hypertens 1996:9:610-614 KEY

WORDS:

PreeChnpSia,

resistance, hyperinsulinemia, hypertension.

hUhI,

indin

pregnancy,

duced high blood pressure remains, however, largely unknown. Hyperiasulinemia and insulin resistance have been found to be associated with essential hypertension independently of obesity.5 It has also been suggested that insulin resistance is present in high blood pressure associated with pregnancy.“-” However, this suggestion consists of preliminary results reported in abstract form’ or is based on studies in which the confounding effect of otxsity and familial antecedents or. insulin levels was not considered.‘-’ Therefore, the present study was undertaken to analyze the insulin response to oral glucose in a group of preeclam$ic women in comparison with wellmatched healthy pregnant women.

IWPER~NSULINEMIA

199b-VOL. 9, NO. 6

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All patients were studied at 8 riM after an overnight !iO to 12 h) fast. A polyethylene 18-gauge catheter Screening for gestational diabetes dlring the third iii-NX, inserted into an antecubital vein for blood samrnester is a routine test in our outpatient clinic. During pling. Oral glucose tolerance was assessed by the in8 months, we identified 10 patients with severe pre- gestion of 50 g glucose load. Before the start of the eclampsia, diagnosed according to the following crite- study and again 60 min after gltlcuse ingestion, blood ria: 1) High blood pressure defined as systolic blood sampies were obtained for the measureT--,I? of pressure increases of 30 mm Hg or greater or diastolic plasma glucose (by the glucose oxidase method on blood pressure increases of 15 mm Hg or greater, a Beckman Glucose Analyzer [Bmkman Jnstruments above the average value during the first 20 week5 of Inc., Fullerton, CA]) and insulin (by m&oimmunoasgestation and; 2) Proteinuria. Severity of preeclamp say). Blood pressure was measured at baseiincl with sia was judged when at least two of the following the use of a standard mercury sphygrnomanometer. signs were present: 1) proteinuria of 2 g / 24 h or more; The protocol was reviewed and approved by the 2) Increased serum creatinine values (>1.2 mg/dL Institutional Review Board of the Centro Med& Naunless known to be elevated previously); 3) elevated cional de Occidente, Instituto Mexican0 de1 *gum hepatic enzymes; 4) headaches or other cerebral or Social at Guadalajara, Jalisco, Mexico. Purpose, navisual disturbaiicea; 5) efigastric pain; 6) retinal hem- ture, and risks involved in the study were explained orrhage, exudates, or papillede:zi;z: 7) platelet count to all the patients before obtaining their oral consent 26 kg/m’), ischcmic plasma glucose concentrations (4.1 2 0.4 mmol! L u heart disease, nephropathy, dyslipidemia, chronic hy- 4.5 + 0.4 mmol /L, control and preeclamptic mothers, pertension plus preeclnmpsia, gestational diabetes respec;iuely; P = NSj and glucose levels 1 h after mellitus or glucose intolerance, or drug treatment glucose ingestion (5.,5 + 0.3 mmol/ L ‘c 6.2 + 0.3 known to influence plasma insulin or glucose concen- mmol/ I,, P = NS) were similar in the two groups. In trations. contrast, fasting plasma insulin concentrations in the preeclamptic women were significantly higher than in normal pqna2t mothers (175 “_ 29 pmoi / I, ~101 f 11 pmol/ L, P < .05). Postload plasma insulin conTABLE 1. CLINICAL CHARACTERISTICS OF THE STUDY SUBJECTS centrations lvere nearly fourfold higher in the preeclamptic group as compared with the control group Normal (1162 -C 70 pmol/L Y 366 f 39 p;nol/Z, P < .01~. PregnancyiVeeclampsia P MATERTAL

Characteristics

Age (yr) I-‘rqestatior$ RMT (kgim’) Number of pregnancies Gestational age (weeks) Systolic blood pressure him Hg) Diastobc bled pr~%sure (mm Hg)

ANU METHODS

(n = 1Oi

In = 10)

Value

28 + 6

28 2 6

5s

24.8 f 1.1

25.3 .k 0.9

NS

3.0 2 0.5 32 2 4

2.3 + 0.7 3? f 2

114 23

153 -+ 4

74 2 7

NS NS
110 7 7 i .YH -- Vhn urc mcIln + SEAI. P 1dW~ refer fo fh rT~~wrisor!rfpwp mrmfs by Ihe mpuired 5rudent t h!. BMI, My

muss index.

DISCUSSION There is mention in the jitzrature of high insulin ievels in hypertensive and i o; preeclamptic it’~n‘z’f;.~-~ in their report, Bauman et al9 ?!;a iound hyperinsulinemia with normz! giucose tolerance in a group of qli women with high blood pressure as compregrJ:.. pared with normotensive pregnant wcmcn. Ikwever, the comparison was not controlled for oi3esity nor was it specified whether the hypertensive women had chronic essential hypertension, gestational hyvrtension, or preeclampsia.’ 9 Thus, the issue ol whetkcr Frc-

612

ABLJNDIS

ET AL

tor in preeclampsia. Prec~lamysia appears to be a disorder of vasospasm with increased rcactivit;! to vasopressors such as angiotensjn II, catecholamines, This vascular hyprresponand vasopressin.“-” siveness is present as early as the 16th week of pregnancy, and precedes the onset of hypcrtcnsion.” In addition, endothclia! cells of preeclamytic patients may abnormally release pressor substances, such as enduthelin-1 (ET-1 ), which cause long-Iasting vasoconstriction ” ;~nd stimulation of catucholamine release.” Norepincphrine and ET-I ievels have been found to be higher in preeclamptic women than in heal thy pregnant women or prqna nt 1%omen with chronic hypcrtension.‘i’-17 Sympathetic r)vernctivity may lead to insulin resistance, as has been suggcstcd by Ju!ius ct ;I] iti and others.‘” TINIS, a primary activation ol sympathetic outflow could account for both high blood pressure and insulin resistance in preeclamptic women. pco.01 Alternatively, some cl5dpncc suggests that insulin can stimulate the release of vasopressor substances in humans. Insulin stimulates ET-1 production from endothclial cell cultures”’ and, in rats, eve;r physiologic amounts of insulin are associated with increased ET-1 gene expression.” However, in healthy human volunteers, administration of insulin at physiologic doses does not increase serum ET-I levels,” but simiiar studies are not avaiiable in hyperten:iiT:e or preeclamptic paricnts. There is evidence that in viva insulin stimulates sympathetic nervous system activity.” It has been recently demonslratcd that insulin-resistant patients with essenBASAL tial hypertension have higher norepinephrine output in forearm tissues in response to insulin than normotensive insulin-sunsitive individuals.“’ If these cfftrts of insulin are preserved or amplified in preeclamptic womerl, hyperinsulinemia might play a primary role in the increa,sed vascular resistance and high cardiac output that are observed in preeclampsia. In the preeclamptic patients studied by ZemeI and eclampsia per se is assuciatcd with hyperinsulinemia cc’-workers, suppressed platelet Ca?‘-ATI’asc activity remained unresolved. In the current report, WC detn- predicted the development of preeclampsia, and coronstrate that women with clear-cut preeclampsia but related with reduced intracellular Ca” efflux in umnormal glucose tolerance have higher insulin levels in bilical cord smooth muscle cells at delivery.7,‘5 Thus, comparison wi:h matched healthy pregnant women. in preeclamftic women, insulin resistance / hyperinSeveral reports have indicated that hyperinsulinsulincmi; is associated with an increment in intracelemia is prescr.t in a substantial proportion of patients lular Ca’” at the smooth muscle level. In line with with essential hype;tensioc.‘,‘O In our study, normal this, we have recently found that platelets from hyperplasma glucose levels in the face of marked hypcrintensive insulin-resistant subjects exhibited a higher sulinemia strongly suggest that ; state of rcsist?Tce intracellular calcium concentration after in vivo expoto insulin action on glucose metabolism is also present sure to physiologic doses of insulin as compared with in preeclamptir rvpmt3. Several hypotheses can be Flatclcts 0btained from ntlrmotensive, insulin-sensiadvanced to explain the presence of hyperinsulintive subjects.;“ Thus, in analogy with essential hyperemia /insulin resistance in this condition. Hypcrinsutension. altered intracellular calcium handling might linemia might be a secondary event or a primary fnc- represent the link between insulin resistance! hypcr-

HYPERINSULWEMIA

insulinemia and i+$ bloti ;.?~ssure in tilt pathogenesis of preeclampsia. In preeclamfsia, an increase in cardiac output has been proposed as the primary hcrnodynamic event, which is associated with compensatory vasodilation to maintain normotensir>p in the early stages of prreclampsia.” Later, jw:i:+~al va5culdr resistance increases, leading to hyperten:.ion.’ ‘L’ Through its antinatriurctic action,*!’ hype1 inwr ;int:mia might favor the initial volrmw expansion that is obscrvc;d il! znrly pregnancy and Inter contributes to the increase in pcriF!‘.wal vascular resistance bv activating or facilitating the action of vasopressors during the last months of pregnancy, Hyperuricemia has been described as an early predictive finding in prwclamptic w~cI:c,~.“-~~ Some evidence suggests that hyperuricemia i:; preeclnmpsia is attributable to enhanced tubular reabsorption of uric acid .“*3’ Reccn tly, we have demonstrated that physiologic hyperinsuhnemia is associated with a net decrease (-30%) in fractional uric acid excretion in healthy humans.” Thus, hyycrinsutinemia might precede or aggravate the hyptruricemia of prccclampsia. ACKNOWLEDGMENTS

-2.

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Drs. Martinez Abundis and GonraI~‘zUrti~ arc pwtdoctoral students of the Curso de Mx5tria en C‘iencias Medicas, Uni-

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