Review Article

Vitamin and Mineral Deficiencies Which May Predisposeto Glucose Intolerance of Pregnancy

Lois Jovanovic-Peterson, MD, FACN, and Charles M. Peterson, MD

Sansum Medical Research Foundation, Santa Barbara. California

Key words: gestational diabetes, glucose intolerance, pregnancy, chromium, magnesium, potassium, pyridoxine

There is an increased requirement for nutrients in normal pregnancy, not only due to increased demand, butalso increased loss. There is also an increased insulin-resistant state during pregnancy mediated by the placentalanti-insulin hormones estrogen, progesterone, human somatomammotropin; the pituitary hormone prolactin; andthe adrenal hormone, cortisol. If the maternal pancreas cannot increase production of insulin to sustainnormoglycemia despite these anti-insulin hormones, gestational diabetes occurs. Gestational diabetes is associ-ated with excessive nutrient losses due to glycosuria. Specific nutrient deficiencies of chromium, magnesium,potassium and pyridoxine may potentiate the tendency towards hyperglycemia in gestational diabetic womenbecause each of these four deficiencies causes impairment of pancreatic insulin production. This reviewdescribes the pathophysiology of the hyperglycemia and the nutrient loss in gestational diabetes and furtherpostulates the mechanism whereby vitamin/mineral supplementation may be useful to prevent or amelioratepregnancy-related glucose intolerance.

Key teaching points:

• Normal pregnancy is associated with an increase in vitamin/mineral demand.• The vitamin/mineral demand is increased in gestational diabetic women due to the increased urinary losses due to glycosuria.• Specific nutrient deficiencies of chromium, magnesium, potassium and pyridoxine may potentiate the tendency towards hyper-glycemia in gestational diabetic women.

• Vitamin/mineral supplementation may be useful to prevent or ameliorate pregnancy-related glucose intolerance.

INTRODUCTION

The requirements for several nutrients are increased duringpregnancy [1]. Specific nutrients are necessary to maintainglucose homeostasis such as chromium, magnesium, potassiumand pyridoxine [2-5]. Pregnancy is a state of insulin-resistance[6]. If the woman's pancreas cannot increase insulin productionto compensate for the increasing insulin need throughout preg-nancy [7], gestational diabetes occurs [8]. Gestational diabetesincreases both maternal and fetal morbidity [9], and thus pre-vention of this common medical disease of pregnancy is par-amount. If the incidence or severity of glucose intolerance ofpregnancy can be prevented by nutrient supplementation, mor-bidities associated with this disease (pregnancy loss, fetal mac-rosomia, hypoglycemia, hyperinsulinemia and hypocalcemia)can be minimized. This review will summarize the pathophys-

iology of gestational diabetes and detail those vitamins andminerals that may play a role in the etiology or increase theseverity of the metabolic derangements associated with thisdisease.

PATHOPHYSIOLOGY OFGESTATIONAL DIABETES

With (and perhaps antecedent to) implantation of the tro-phoblast, the production of pregnancy related hormones begins(Table 1). These hormones immediately alter the metabolism ofnutrients to shift the priority of metabolic products towards thegrowing fetus. A buffering mechanism must be initiated earlyin pregnancy to prevent the mother from suffering deleterioushypoglycemia between feedings as her reserves continue to

Address reprint requests to: Lois Jovanovic-Peterson, MD, FACN, Sansurn Medical Research Foundation, 2219 Bath Street, Santa Barbara, CA 93105.

Journal of the American College of Nutrition, Vol. IS, No.1, 14-20 (1996)Published by the American College of Nutrition

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Table 1. Sequential Rise and Potency of the DiabetogenicHormones of Pregnancy

*Optimal time to screen for gestational diabetes.'" Optimal time to re-screen for gestational diabetes in those women who screennegative at 26 weeks.

Estradiol 32 26* IProlactin 36 10 2Human ChorionicSomatomammotropin 45 26* 3

Cortisol 50 26* 5Progesterone 65 4

flow to her unborn child. Maternal glucose homeostasis issustained by a delicate interplay of maternal hormones de-signed to increase fat storage, decrease energy expenditureand delay glucose clearance. Thus it is not surprising thatpregnancy may initiate the presentation of diabetes. In addit-ion, fetal needs are met through the fetal control of nutrientsmediated via a variety of messages, chiefly by fetal hormones,Hormonal messages from the conceptus can affect meta-bolic processes, uteroplacental blood flow, and cellulardifferentiation.Immediately after ovulation, the corpus luteum makes in-

creasing amounts of 170H-progesterone. Lutenizing hormone(LH) from the pituitary is necessary to keep the corpus luteumfunctioning. Once conception and subsequent implantation oc-cur, human chorionic gonadotropin (hCG) simulates LH's roleto stimulate the corpus luteum's production of 170H-proges-terone until placental production of steroids is adequate. HCGis only needed for the ftrst 12 weeks of gestation as the corpusluteum is needed only during these early phases of placentalgrowth [10]. HCG itself does not have an effect on glucosehomeostasis. Other hormones that do promote glucose ho-meostasis are therefore urgently needed early in pregnancy.The adult ovary is capable of making steroids directly from

acetate, but this capability is not true of the placenta. Estrogenformation by the placenta is dependent on precursors whichreach it from both the fetal and maternal compartments. Toform estrogens, the placenta aromatizes androgens comingprimarily from the fetus. The fetal adrenal gland providesdihydroepiandrosterone (DHEA) which proceeds through a se-ries of hydroxylations and double bond formation or aromati-zation to estrogen and 17-beta estradiol. In addition, some ofthe fetal DHEA undergoes 16-alpha hydroxylation in the fetalliver andlor fetal adrenal gland to become 16 alpha hydroxy-dihydro-epiandrosterone (HDHEA) sulfate that is cleaved inthe placenta to 16-alpha OHHDHEA and aromatized to estriol[11]. The time course of the appearance of estrogens duringpregnancy is listed in Table 1. As can be seen, estrogens risewithin 35 days of conception.

Estrogens have weak anti-insulin properties. Table 1 alsoascribes relative diabetogenic properties to various hormones,In this table, estrogen has a relative potency of 1 on a scale of1 to 5. A major gluconeogenic property is derived from hor-monal stimulation of liver production of cortisol binding glob-ulin (CBG). As CBG is increased, the maternal adrenal glandsecretes more cortisol resulting in an increase in the level offree cortisol. Hypercortisolemia causes maternal insulin resis-tance, delayed glucose clearance, and thus more available glu-cose for fetal use. The appearance of cortisol appears timed tocontribute glucose to the rising demand for fetal fuels. The factthat cortisol markedly impairs glucose tolerance is an advan-tage at this point in pregnancy.In contrast to estrogen, progesterone production by the

placenta is independent of uteroplacental perfusion, fetal wellbeing or even the presence of a live fetus. Thus, progesteroneis not useful as a marker of impending abortion [12]. Themajority of placental progesterone is derived from readilyavailable cholesterol. The placenta does not make 17 OH-progesterone until the 32nd week when it starts to metabolizeprogesterone. Once the corpus luteum deteriorates, progester-one is the major fonn of the hormone. Progesterone has a directeffect on glucose metabolism [13]. When progesterone is ad-ministered to normal fasting women, the serum insulin concen-tration rises while glucose remains unchanged. In monkeys,progesterone increases both the early and total insulin secretoryresponses to glucose [14]. Blood progesterone concentrationdoes not peak until the 32nd week of gestation. Thus womenwho screen negative on a glucose screening test for gestationaldiabetes at 26 weeks may not pass the test at 32 weeks due tothe diabetogenic properties of increasing blood levels of pro-gesterone (a 4 on the scale of 1-5, see Table 1).Two other pregnancy related peptide hormones warrant

discussion. They are prolactin (hPRL) and human chorionicsomatomammotropin (hCS). Barberia and associates [15]showed that the initial rise in blood hPRL in pregnancy occurswithin a few days after the blood estradiol levels start toincrease above nonpregnant levels (30 to 33 days after the LHpeak), whereas the rise in hPRL levels above the nonpregnancyluteal phase levels occurs 32 to 36 days after the LH peak(Table 1). Estrogen seems to initiate the "turning on" of pro-lactin secretion. Without a rise in estrogen with a resultant risein prolactin levels, spontaneous abortion seems imminent [12].Prolactin is so named because it is necessary for lactation, apost partum event. What is a lactation promoting hormonedoing in the ftrst few days of pregnancy? Some researchers feelthat prolactin is "luteotropic" and works in concert with hCG tonourish the corpus luteum [16]. Others [l7] have suggested thatprolactin enhances cell-to-cell communication among the beta-cells in pancreatic islets. These investigators have shown aten-fold increase in beta cell coupling, independent of glucosestimulation. Thus, prolactin may be necessary early in preg-nancy to stimulate both maternal and fetal beta cell hypertro-

Relativediabetogenic potencyon a scale of I =weak to 5 = strong

Peakelevation(weeks)

Onset ofelevation(days)

Hormone

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phy. In Table I, prolactin has a diabetogenic potency of 2 onthe scale of 1-5.Human chorionic somatomammotropin (hCS) is a protein

hormone with immunologic epitopes and biologic propertiessimilar to pituitary growth hormone (hGH). The original name,human placental lactogen, was so named because of its lacto-genic properties in animals; however, such properties in womenhave not been confirmed. Josimovich et al [18] found that hCShas luteotropic properties that would explain the rise of thishormone so early in pregnancy. Similar to prolactin, hCS hasan effect on glucose metabolism. HCS rates a potency of 3 inthe diabetogenic property scale.HCS does have growth hormone-like effects on tibial epi-

physial growth, body weight gain, and sulfate uptake by costalcartilage in the hypophysectomized rat, although the effectivedose required is 100 to 200 times that of growth hormone[19,20]. Binding studies in rodents suggest a potential role forthe hormone in fetal pancreatic development and maturation[21,22].The effects of hCS on fat and carbohydrate metabolism are

similar to those following treatment with growth hormone.There is inhibition of peripheral glucose uptake and stimulationof insulin release [23]. A comparable maximal increase inplasma free fatty acids occurs following administration of hCSor hGH in hypopituitorism. In addition, infusion of hCS into anhypophysectomized, diabetic man caused the blood glucose torise four-fold above baseline [24].

In summary, the hormonal changes early in pregnancy canbe viewed as a serial rise in hormones intended to maintain aconstant glucose supply to the fetus. As fetal metabolic require-ments increase, the gluconeogenic properties and concentrationof hormones rise. The order of hormonal presentation in preg-nancy is inverse to their relative gluconeogenic property. Thefirst hormone, human chorionic gonadotropin, has no hyper-glycemic effect and cortisol, a relatively late appearing hor-mone, has the most potent hyperglycemic effect (Table 1). Thesole purpose of the sequential rise could be so ordered as toprovide glucose substrate to the fetus, rather than for any otherpurpose. If the maternal pancreas cannot keep up with theinsulin resistance produced by these hormones, then maternalblood glucose rises which results in gestational diabetes. Nu-trients which are important in the maintenance of pancreaticfunction may be depleted in pregnancy, thus potentiating theglucose intolerance. Specific nutrients which are needed topreserve pancreatic function and/or increase insulin sensitivityare chromium, magnesium, potassium, and pyridoxine.

CHROMIUM

Chromium is believed to play a physiologic role as a co-factor for insulin, facilitating the initial attachment of the hor-mone to its peripheral receptor [25]. However chromium has

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not been found in the receptor [26]. There have been numerousbut unconfirmed reports of chromium deficiency in humansprimarily in patients maintained on prolonged parenteral nutri-tion [27]. Glucose intolerance has been the most consistentlyobserved effect of very low chromium intake.Some reports of chromium concentrations in plasma and

tissue suggest that pregnancy may be associated with chro-mium depletion [28,29]. Because of lack of established labo-ratory indices of human chromium status, the extent to whichchromium is important in human nutrition during pregnancy iscontroversial.The absorption of chromium is facilitated by certain amino

acids, such as histidine, which chelates chromium in the smallintestine [30] to prevent the precipitation of chromium at thebasic pH of the intestine. Other factors that facilitate absorptionof chromium have recently been demonstrated such as nicotinicacid and ascorbic acid [31,32]. Starches facilitate the absorp-tion of chromium as opposed to more simple sugars [33].Chromium absorption can also be influenced by plasma pro-teins and albumin [34]. Zinc and iron decrease chromiumabsorption, probably by competing for chelation [35]. Admin-istration of pharmacological doses of iron impairs chromiumabsorption because chromium and iron also appear to share acommon gastrointestinal transport mechanism. Pregnantwomen who are supplemented with pharmacological doses ofiron for treatment of anemia may therefore have a resultantchromium deficiency.Identification of chromium as an essential element was

based on its role in restoration of glucose tolerance in rats [36].Then, numerous reports through the years have noted thatchromium depletion impairs glucose tolerance in experimentalanimals [37-40].

Chromium Deficiency as a Cause of Non InsulinDependent DiabetesIs supplemental chromium beneficial in improving glu-

cose intolerance in patients with non-insulin dependent di-abetes? Depending on the severity, chromium deficiency cancause an impairment of glucose tolerance, glucosuria, fastinghyperglycemia, and insulin resistance. A decrease in insulinbinding and number of insulin receptors has been reported inthe presence of inadequate amounts of chromium [41]. It issuggested that in the presence of insulin, chromium increasesthe rate of glucose uptake, increases oxidation of glucose toCO2 , and increases the incorporation of glucose into fat [42].The results of pertinent studies [42-46] using chromium inpatients with impaired glucose metabolism are equally dividedas to the utility of chromium to improve glucose tolerance.These five studies looked at glucose intolerant patients (totalnumber of patients studied in the five studies reviewed was 47)with severe malnutrition (ages 6 months to 3 years) as well asobese, non-insulin dependent diabetic patients. The daily doses

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of chromium varied from 150 ,.,.g to 1000 ,.,.g. In two of thestudies the glucose tolerance test was significantly improved,but in the other two, there was no significant improvement. Inthe fifth study [45], of the 10 patients studied, five improvedand five did not.Studies of this nature are difficult to evaluate, and future

investigations may be just as difficult. When glucose intoler-ance is the only criteria for admission to a research protocoldesigned to observe the efficacy of chromium therapy onglucose tolerance, not the efficacy of chromium therapy inchromium deficient glucose intolerant subjects, it is inevitablethat patients with adequate chromium nutrition will be includedand conflicting reports of the efficacy of chromium are boundto occur [42].Chromium is an essential micronutrient in man and a defi-

ciency state can cause abnormalities in carbohydrate metabo-lism. It is unclear, however, whether chromium depletion playsany part in the pathogenesis of diabetes mellitus in man andfurther clinical investigations are necessary.

Chromium and Pregnancy

The depletion of chromium during normal pregnancy wasdocumented in the report by Hambidge and Rogerson [47].They compared the concentration of chromium in the hair ofnulliparous versus parous women and found a significantlylower concentration in the parous group of women. They hy-pothesized that this depletion may potentiate the glucose intol-erance of pregnancy.Mahalko and Bennson [48] also studied the impact of parity

on maternal hair chromium concentration. They further ob-served that when women had repeat pregnancies within a4-year interval, the hair concentration of chromium was mark-edly reduced.Thus far there is only one report in the literature which

studied the hair chromium content of women with gestationaldiabetes compared with nondiabetic pregnant women [49]. Thewomenwith gestational diabetes did show a significantly lowerconcentration of hair chromium taken at the end of pregnancycompared to the level in the first trimester. The normal glucosetolerant pregnant women had no decrease in hair chromiumconcentration. Of note, age and parity did not influence the haircontent of chromium in either group. The authors concludedthat their data suggested that impaired utilization of chromiummay be a possible etiology for gestational diabetes.

In our own study, we randomized 24 gestational diabeticwomen into a group that received chromium supplementation(4 ,.,.glk.g per day chromium as chromium picolinate, the RDAfor pregnancy) and into a group that received placebo. Thefasting plasma glucose and insulin levels were significantlylower in the chromium supplemented group after 8 weeks oftherapy. In addition, these women's peak plasma glucose andinsulin responses to a 100 g oral glucose load were also

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significantly lower than the levels obtained in those womenwho were not supplemented. However, when women withsevere glucose intolerance were given 4 ,.,.glk.g per day chro-mium, their hyperglycemia was not sufficiently improved andinsulin therapy was still necessary to normalize their glycemia.Perhaps the RDA for chromium in pregnancy is not sufficientto have an impact on the chromium deficiency associated withsevere hyperglycemia of gestational diabetes, and further stud-ies using larger doses of chromium are warranted.

MAGNESIUM AND POTASSIUM

Magnesium is second only to potassium as the most abun-dant intra-cellular cation [50]. Magnesium is intimately in-volved in a number of important biochemical reactions espe-cially in glucose utilization. Magnesium deficiency impairs thesodiumlpotassium-ATP-ase pump resulting in intra-cellular p0-tassium depletion. Such depletion impairs pancreatic insulinsecretion. Since low levels of magnesium preclude the normal-ization of potassium, only when magnesium is given to patientswith refractory potassium depletion can normal potassium andthus normal pancreatic function be achieved [51].One of the first epidemiological studies to demonstrate

magnesium deficiency in non-insulin-dependent diabetic pa-tients was conducted by Mather et al [52]. They found signif-icantly lower levels of serum magnesium in the diabetic pa-tients than in a group of non-diabetic controls. They also foundthat the level of serum magnesium was inversely related to thedegree of hyperglycemia. The findings of reduced serum mag-nesium concentrations in diabetes have been confirmed byseveral other studies [53-55]. Also confirmatory are the reportsthat glycosylated hemoglobin levels are inversely correlatedwith magnesium in plasma, muscle and mononuclear cells [54].Magnesium deficiency may be promoted by increased uri-

nary excretion due to glucosuria [55], decreased intestinalabsorption of magnesium and indirectly by the effect of hor-mones to impair intestinal absorption of this mineral. Gesta-tional diabetic women are predisposed to magnesium defi-ciency mediated by glucosuria and impaired intestinalabsorption secondary to iron supplementation [56]. When ges-tational diabetic women sustain hyperglycemia, the placentaenlarges from the overstimulation of the fetal pancreas tosecrete insulin, a powerful growth hormone in utero. Theresultant large placenta secretes excess steroid hormones whichfurther decrease intestinal absorption of magnesium. Magne-sium deficiency parallels potassium deficiency because theyare both intracellular cations. A loss of extracellular magne-sium due to obligatory urinary losses from glucosuria willresult in an intracellular-to-extracellular flux of both cationswhich will elicit the kidney regulation of serum potassium toincrease urinary potassium loss to maintain the serum levelsnormal. Pancreatic intracellular potassium is important for in-

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sulin secretion. Obligatory urinary potassium losses may there-fore further impair maternal pancreatic insulin secretion.The majority of the literature on the utility of magnesium

supplementation in pregnancy has been in the field of preg-nancy induced hypertension (Pili) [57-60]. These studiesclearly show that magnesium deficient states predispose toelevation in blood pressure and are improved with calcium andmagnesium supplementation. Magnesium supplementation, indoses of 1-3 g of magnesium salts, are recommended as anadjunctive therapy for the prevention of Pili; these recommen-dations might also improve glucose intolerance in gestationaldiabetic women.

PYRIDOXINE

Pyridoxine or B6 inhibits prolactin secretion [61]. Prolactinhas mild diabetogenic characteristics (Table 1). Pyridoxinereserves are depleted in early pregnancy [62], perhaps to allowthe rising blood prolactin level to exert its role to facilitateglucose transport to the fetus unopposed by the inhibitoryproperty of pyridoxine. Supplementation with pyridoxine tooearly in pregnancy, perhaps before the 10th gestational week(Table I), may suppress this action of prolactin. Supplementa-tion with pyridoxine in the second and third trimester, at a timewhen prolactin has reached blood levels greater than 200 nglml[63], may improve glucose intolerance in women with gesta-tional diabetes. Spellacy et al [64] noted a pyridoxine defi-ciency associated with gestational diabetes. Despite the manyyears of use of pyridoxine to ameliorate nausea of early preg-nancy, there are no studies which specifically looked at the useof pyridoxine supplementation in early pregnancy and suppres-sion of pituitary secretion of prolactin. Therefore, at present therole of pyridoxine to improve glucose intolerance in gestationaldiabetes remains speculative.

CONCLUSIONS

Gestational diabetes is associated with maternal and fetalmorbidity. Although specific therapy to treat the gestationaldiabetic woman has been well accepted, prevention of or re-duction of the severity of glucose intolerance in pregnancy bynutrient supplementation might provide an easy and inexpen-sive means to decrease the problems related to maternal hyper-glycemia. Specific nutrients which have been reported to havean impact on glucose intolerance in pregnancy include chro-mium, magnesium, potassium and pyridoxine. Larger scalestudies of supplementation with these nutrients need to beperformed to document that the prevalence and severity ofgestational diabetes might be reduced with the interventions.

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ACKNOWLEDGMENTS

The authors wish to thank Nutrition 21 for supporting inpart the research on the utility of chromium picolinate ingestational diabetes.

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60. Conradt A, Weidinger H, Algayer H: On the role of magnesium infetal hypotrophy, pregnancy induced hypertension, and pre-eclampsia. Mayo Bull 6:68-76, 1984.

61. Leldem IE, Reynolds RD: Challenges and directions in search forclinical applications of vitamin B6 . In Leldem IE, Reynolds RD(eds): "Current Topics in Nutrition and Disease, Vol 19, Physio-logical Applications of B6." New York: Alan Liss, pp 437-454,1988.

62. Jovanovic L, Dawood Y, Landesman R, Saxena BB: The hormonal

profile in early threatened abortion. Am J Obstet Gynecol 130:274-278, 1978.

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64. Spellacy WN, Buhi WC, Birk SA: Vitamin B6 treatment of ges-tational diabetes mellitus: studies of blood glucose and plasmainsulin. Am J Obstet Gynecol 127:599--602, 1977.

Received January 1995; revision accepted June 1995.

20

International Group for the Prevention of Atherosclerosis in ChildhoodCARE OF CHILDREN WITH HIGH ALTHEROSCLEROTIC RISK

October 13-16, 1996 Budapest, HungaryFo, info,m8t1on: T"",•• Sz8mosi, MO, Pfldi8tric OepllrtmflTlt No 2. SlllnmtllwfJi. UnlvINsity Mfldiclll

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