**4. Effect of gestational diabetes mellitus on fatty acid supply**

Gestational diabetes mellitus (GDM) affecting 2-10% of pregnant women in the United States (National Diabetes Statistics, 2011) is associated with insulin resistance during pregnancy. Its prevalence is rising worldwide. Analysing the GDM screening results between 1994-2002 in Colorado state (Dabelea et al., 2005), the prevalence of GDM was increasing from 1994-1996 to 2000-2002 in all ethnic groups: Hispanic (2.8% to 5.1%), African American (2.5% to 4.6%), Asian (6.3% to 8.6%) and non-Hispanic white (1.9% to 3.4%). Women with GDM are at risk to develop type 2 diabetes mellitus either immediately after delivery (5-10%) or later, in 10-20 years (35-60%).

The risk factors of developing GDM during pregnancy are higher pre-pregnancy BMI, smoking, increasing maternal age and GDM during previous pregnancy. Western diet contains high fat intake with high n-6/n-3 fatty acid ratio, refined sugar, fried and snack foods with high *trans* fatty acid content; all these factors may play an important role in developing impaired glucose tolerance and, hence, GDM. Maternal high fat diet during pregnancy decreased EPA and DHA values in liver in newborn pups as well as in suckling pups born from both diabetic and control mothers (Ghebremeskel et al., 1999). In the Project Viva (Radesky et al., 2008), pregnant women with maternal age above 40 years (OR: 11.3), pre-pregnancy BMI above 30 kg/m2 (OR: 3.44), GDM during prior pregnancy (OR: 58.3) and Hispanic ethnicity (OR: 3.19) had increased risk of developing GDM. However, dietary pattern during early pregnancy had no association with developing GDM.

#### **4.1 Fatty acid supply during pregnancy in women with gestational diabetes mellitus: Maternal effects**

As type 2 diabetes mellitus and obesity disturbs fatty acid supply, GDM may also have an effect on fatty acid metabolism in pregnant women. While only two studies were found investigating the effect of T1DM on maternal blood fatty acid composition, GDM was investigated in a number of studies. We found nine studies investigating the fatty acid supply during pregnancy in women with GDM and five studies investigating the fatty acid supply of newborns from mothers with GDM (Table 5).

In an early study (Chen CH et al., 1965), no difference was seen in LA values of mothers with GDM and controls at delivery. When in 2000 the diet and blood samples of pregnant women with GDM during the third trimester were analysed (Wijendran et al., 2000) women with GDM had significantly higher AA, EPA and DHA intakes than controls. Maternal erythrocyte PL contained more DHA, while other fatty acids didn't differ. The authors also determined the effect of fatty acid supply on plasma PL in these women at the 27-30th, 33- 35th and 36-39th weeks of pregnancy (Wijendran et al., 1999). Although there were no significant differences in the LA and AA values between the two groups, values of DHGLA and C22:5n-6 were significantly lower at each investigated time points. In contrast, among the n-3 fatty acids, ALA and DPA were significantly lower, while DHA was significantly higher in women with GDM than in healthy controls. Wijendran et al. provided three possible explanations for the lower ALA and higher DHA values: 1. either increased desaturation and elongation of ALA to DHA may be responsible for these alterations, or 2. increased selective oxidation of ALA or 3. enhanced release of DHA into plasma PL. Both in controls and mothers with GDM, the n-3 and n-6 LCPUFAs decreased as the result of the physiologic adaptation in pregnant women to the increased fetal n-3 and n-6 LCPUFA requirement during the third trimester. The authors also investigated the correlations

Gestational diabetes mellitus (GDM) affecting 2-10% of pregnant women in the United States (National Diabetes Statistics, 2011) is associated with insulin resistance during pregnancy. Its prevalence is rising worldwide. Analysing the GDM screening results between 1994-2002 in Colorado state (Dabelea et al., 2005), the prevalence of GDM was increasing from 1994-1996 to 2000-2002 in all ethnic groups: Hispanic (2.8% to 5.1%), African American (2.5% to 4.6%), Asian (6.3% to 8.6%) and non-Hispanic white (1.9% to 3.4%). Women with GDM are at risk to develop type 2 diabetes mellitus either immediately after

The risk factors of developing GDM during pregnancy are higher pre-pregnancy BMI, smoking, increasing maternal age and GDM during previous pregnancy. Western diet contains high fat intake with high n-6/n-3 fatty acid ratio, refined sugar, fried and snack foods with high *trans* fatty acid content; all these factors may play an important role in developing impaired glucose tolerance and, hence, GDM. Maternal high fat diet during pregnancy decreased EPA and DHA values in liver in newborn pups as well as in suckling pups born from both diabetic and control mothers (Ghebremeskel et al., 1999). In the Project Viva (Radesky et al., 2008), pregnant women with maternal age above 40 years (OR: 11.3), pre-pregnancy BMI above 30 kg/m2 (OR: 3.44), GDM during prior pregnancy (OR: 58.3) and Hispanic ethnicity (OR: 3.19) had increased risk of developing GDM. However, dietary

**4.1 Fatty acid supply during pregnancy in women with gestational diabetes mellitus:** 

As type 2 diabetes mellitus and obesity disturbs fatty acid supply, GDM may also have an effect on fatty acid metabolism in pregnant women. While only two studies were found investigating the effect of T1DM on maternal blood fatty acid composition, GDM was investigated in a number of studies. We found nine studies investigating the fatty acid supply during pregnancy in women with GDM and five studies investigating the fatty acid

In an early study (Chen CH et al., 1965), no difference was seen in LA values of mothers with GDM and controls at delivery. When in 2000 the diet and blood samples of pregnant women with GDM during the third trimester were analysed (Wijendran et al., 2000) women with GDM had significantly higher AA, EPA and DHA intakes than controls. Maternal erythrocyte PL contained more DHA, while other fatty acids didn't differ. The authors also determined the effect of fatty acid supply on plasma PL in these women at the 27-30th, 33- 35th and 36-39th weeks of pregnancy (Wijendran et al., 1999). Although there were no significant differences in the LA and AA values between the two groups, values of DHGLA and C22:5n-6 were significantly lower at each investigated time points. In contrast, among the n-3 fatty acids, ALA and DPA were significantly lower, while DHA was significantly higher in women with GDM than in healthy controls. Wijendran et al. provided three possible explanations for the lower ALA and higher DHA values: 1. either increased desaturation and elongation of ALA to DHA may be responsible for these alterations, or 2. increased selective oxidation of ALA or 3. enhanced release of DHA into plasma PL. Both in controls and mothers with GDM, the n-3 and n-6 LCPUFAs decreased as the result of the physiologic adaptation in pregnant women to the increased fetal n-3 and n-6 LCPUFA requirement during the third trimester. The authors also investigated the correlations

**4. Effect of gestational diabetes mellitus on fatty acid supply** 

pattern during early pregnancy had no association with developing GDM.

supply of newborns from mothers with GDM (Table 5).

delivery (5-10%) or later, in 10-20 years (35-60%).

**Maternal effects** 


\* a.) = umbilical vein; b.) = umbilical artery. Abbreviations: see Table 4.

Table 5. Change in essential fatty acid and long-chain polyunsaturated fatty acid values compared to controls in mothers with gestational diabetes mellitus and infants born from mothers with gestational diabetes mellitus (GDM)

between, on the one hand, maternal fatty acids and on the other hand, HbA1c and prepregnancy BMI. Though there was an inverse association between plasma HbA1c and

Fatty Acid Supply in Pregnant Women with Type 1 Diabetes Mellitus 449

significant differences in the fatty acid composition of plasma lipids between mothers with

As part of a prospective cohort study, a nested case-control study was carried out by Chen X et al. (Chen X et al., 2010) to investigate the differences in fatty acid status of women with impaired glucose tolerance, GDM and controls. In contrast to earlier studies (Wijendran et al., 2000; Thomas et al., 2006), this population had higher saturated fatty acid intake, while dietary LA, DHA and PUFA intakes were significantly lower in the diabetic group than in controls. At study entry (16th week) women who developed impaired glucose tolerance later, had higher plasma EPA absolute values; however, the percentage of PUFAs didn't differ significantly among the three groups. During the third trimester, mothers with GDM had higher AA, DHA and PUFA absolute concentrations, while women with impaired glucose tolerance had higher LA, ALA, EPA and DHA absolute values. Similarly to study entry, PUFA percents didn't differ among the groups. These data showed that not only GDM disturbs fatty acid supply of pregnant women, but impaired glucose tolerance as well. The authors also investigated the effect of BMI and found significantly higher concentrations of saturated and monounsaturated fatty acids and PUFAs in women with impaired glucose tolerance and BMI higher than 25 kg/m2 at study entry than in normal weighted women with impaired glucose tolerance. During the third trimester, overweight and obese women with GDM had the highest fatty acid absolute concentration. These results indicate that the disturbance in the fatty acid metabolism is more pronounced when beyond the mild hyperglycaemia obesity is also present. Results of this study raised the possibility that reducing pregravid weight and modifying diet (increasing PUFAs and reducing saturated fatty acids) may reduce circulating free fatty acids, therefore decreasing insulin resistance and inflammation and lower future maternal

**4.2 Fatty acid supply in newborns of mothers with gestational diabetes mellitus: Fetal** 

Macrosomia and lipid abnormalities are common complications associated with maternal diabetes during pregnancy. Offspring of diabetic mothers are prone to develop obesity, type 2 diabetes mellitus and cardiovascular diseases during adulthood. In an animal study (Soulimane-Mokhtari et al., 2008), diabetic and control rats were fed a control diet or diet rich in EPA and DHA. During pregnancy of the diabetic rats, VLDL- and LDL-cholesterol were significantly decreased in the intervention group. Moreover, similar changes were seen in the macrosomic offspring: maternal fish oil diet significantly decreased VLDL- and LDLcholesterol. As n-3 LCPUFA supplementation during pregnancy restored tissue lipase activities to normal range and ameliorated long-term prognosis of macrosomia, n-3 fatty

Maternal diabetes during pregnancy (characterised by hyperglycaemia, hyperlipidaemia, hyperlipoproteinaemia and altered T-cell function) may result in metabolic programming of the offspring causing obesity, impaired glucose tolerance, hyperlipidaemia and hyperlipoproteinaemia during adulthood (Khan, 2007). In Chinese children of mothers with GDM, significantly higher systolic and diastolic blood pressures and lower HDL-cholesterol levels were seen than in controls at the age of 8 years. High umbilical cord insulin was an independent risk factor of both abnormal glucose tolerance and obesity; hence, in utero hyperinsulinaemia and hyperglycaemia may have long-term effects on developing type 2

acid supplementation may be beneficial for mothers with GDM.

GDM and controls at delivery in an Italian study (Ortega-Senovilla et al., 2009).

risk of type 2 diabetes mellitus.

**effects** 

plasma PL AA also in the controls, this association was more pronounced in women with GDM. Similarly, positive correlation was found between mean fasting plasma insulin and plasma PL AA values. These correlations may indicate impairment in the transport of AA to the fetus. Prepregnancy BMI was correlated inversely to maternal DHA and positively to maternal AA values in the diabetic group. These findings suggest that maternal alterations in plasma PL DHA values may be more pronounced in obese women with GDM.

An English research group (Thomas et al., 2006) investigated the diet of pregnant women with and without GDM during the third trimester, and reported several differences. Diabetic women ingested less fat than controls, and the ratios of fatty acids in the diet were also different: diabetic women had lower saturated, monounsaturated and *trans* fatty acid intake, but higher PUFA intake. Interestingly, the distribution of PUFAs was largely similar in the two groups, only one fatty acid differed between the two groups: mothers with GDM ingested more DHA. They also investigated the effect of ethnicity on dietary fatty acid intake. Afro-Caribbean mothers with GDM had lower total fat, saturated, monounsaturated, *trans* fatty acid and PUFA intake than Caucasian mothers. The diet of the Afro-Caribbean GDM group contained lower LA, AA, n-6 PUFA and ALA values, while higher EPA and DHA compared to Caucasian mothers with GDM.

The same authors also compared the plasma fatty acid supply of these women at diagnosis (Thomas et al., 2004). Women with GDM had significantly higher LA values in the plasma TG fraction, higher AA values in the plasma CPG and STE fraction and higher DHA values in the plasma TG fraction than healthy controls, while ALA was significantly lower in plasma STE in women with GDM. These alterations may be explained by the high glucose concentration that led to the mobilisation of LA, ALA, AA and DHA from adipose tissue and liver. When comparing the fatty acid supply of both plasma and erythrocyte membrane lipids in these women at diagnosis (Min et al., 2004), in plasma CPG higher AA and lower ALA values were found in the mothers with GDM, while values of DHGLA, AA, C22:4n-6 as well as ALA, EPA, DPA and DHA was significantly lower in erythrocyte CPG lipids in the diabetic than in the control group. This discrepancy between plasma and erythrocyte membrane lipid composition may arise as an effect of GDM causing reduction of incorporation of these fatty acids into red blood cells and other tissues. As erythrocyte membrane lipid composition is very similar to that of the vascular endothelium, these alterations in erythrocyte membrane lipids may indicate that endothelium may be also affected in GDM.

In another study carried out in London, significantly lower ALA and higher AA in plasma CPG fraction was found in diabetic mothers than in healthy controls at delivery (Min et al., 2005b). However, AA was significantly lower in erythrocyte membrane PC fraction.

Min et al. carried out a pilot study in Korea, where the habitual diet contains higher n-3 fatty acid and lower total fat intake than the typical Western-type diet (Min et al., 2006). Women with GDM had lower ALA and higher DHA in plasma PC fractions at delivery, while values of AA was lower in erythrocyte PC and PE fractions in women with GDM than in controls. Comparing the AA and DHA values in GDM patients and controls living in Korea or in the UK, in both study groups lower AA and DHA values were found in erythrocyte PC lipids of the GDM groups than in the controls. However, Korean women (both diabetic and control) had higher DHA values than British women. This finding suggests that the reduction of erythrocyte membrane AA and DHA values in women with GDM might be attributed to effects of the disease itself regardless of ethnicity, obesity or diet. In contrast, there were no

plasma PL AA also in the controls, this association was more pronounced in women with GDM. Similarly, positive correlation was found between mean fasting plasma insulin and plasma PL AA values. These correlations may indicate impairment in the transport of AA to the fetus. Prepregnancy BMI was correlated inversely to maternal DHA and positively to maternal AA values in the diabetic group. These findings suggest that maternal alterations

An English research group (Thomas et al., 2006) investigated the diet of pregnant women with and without GDM during the third trimester, and reported several differences. Diabetic women ingested less fat than controls, and the ratios of fatty acids in the diet were also different: diabetic women had lower saturated, monounsaturated and *trans* fatty acid intake, but higher PUFA intake. Interestingly, the distribution of PUFAs was largely similar in the two groups, only one fatty acid differed between the two groups: mothers with GDM ingested more DHA. They also investigated the effect of ethnicity on dietary fatty acid intake. Afro-Caribbean mothers with GDM had lower total fat, saturated, monounsaturated, *trans* fatty acid and PUFA intake than Caucasian mothers. The diet of the Afro-Caribbean GDM group contained lower LA, AA, n-6 PUFA and ALA values, while higher EPA and

The same authors also compared the plasma fatty acid supply of these women at diagnosis (Thomas et al., 2004). Women with GDM had significantly higher LA values in the plasma TG fraction, higher AA values in the plasma CPG and STE fraction and higher DHA values in the plasma TG fraction than healthy controls, while ALA was significantly lower in plasma STE in women with GDM. These alterations may be explained by the high glucose concentration that led to the mobilisation of LA, ALA, AA and DHA from adipose tissue and liver. When comparing the fatty acid supply of both plasma and erythrocyte membrane lipids in these women at diagnosis (Min et al., 2004), in plasma CPG higher AA and lower ALA values were found in the mothers with GDM, while values of DHGLA, AA, C22:4n-6 as well as ALA, EPA, DPA and DHA was significantly lower in erythrocyte CPG lipids in the diabetic than in the control group. This discrepancy between plasma and erythrocyte membrane lipid composition may arise as an effect of GDM causing reduction of incorporation of these fatty acids into red blood cells and other tissues. As erythrocyte membrane lipid composition is very similar to that of the vascular endothelium, these alterations in erythrocyte membrane lipids may indicate that

In another study carried out in London, significantly lower ALA and higher AA in plasma CPG fraction was found in diabetic mothers than in healthy controls at delivery (Min et al.,

Min et al. carried out a pilot study in Korea, where the habitual diet contains higher n-3 fatty acid and lower total fat intake than the typical Western-type diet (Min et al., 2006). Women with GDM had lower ALA and higher DHA in plasma PC fractions at delivery, while values of AA was lower in erythrocyte PC and PE fractions in women with GDM than in controls. Comparing the AA and DHA values in GDM patients and controls living in Korea or in the UK, in both study groups lower AA and DHA values were found in erythrocyte PC lipids of the GDM groups than in the controls. However, Korean women (both diabetic and control) had higher DHA values than British women. This finding suggests that the reduction of erythrocyte membrane AA and DHA values in women with GDM might be attributed to effects of the disease itself regardless of ethnicity, obesity or diet. In contrast, there were no

2005b). However, AA was significantly lower in erythrocyte membrane PC fraction.

in plasma PL DHA values may be more pronounced in obese women with GDM.

DHA compared to Caucasian mothers with GDM.

endothelium may be also affected in GDM.

significant differences in the fatty acid composition of plasma lipids between mothers with GDM and controls at delivery in an Italian study (Ortega-Senovilla et al., 2009).

As part of a prospective cohort study, a nested case-control study was carried out by Chen X et al. (Chen X et al., 2010) to investigate the differences in fatty acid status of women with impaired glucose tolerance, GDM and controls. In contrast to earlier studies (Wijendran et al., 2000; Thomas et al., 2006), this population had higher saturated fatty acid intake, while dietary LA, DHA and PUFA intakes were significantly lower in the diabetic group than in controls. At study entry (16th week) women who developed impaired glucose tolerance later, had higher plasma EPA absolute values; however, the percentage of PUFAs didn't differ significantly among the three groups. During the third trimester, mothers with GDM had higher AA, DHA and PUFA absolute concentrations, while women with impaired glucose tolerance had higher LA, ALA, EPA and DHA absolute values. Similarly to study entry, PUFA percents didn't differ among the groups. These data showed that not only GDM disturbs fatty acid supply of pregnant women, but impaired glucose tolerance as well. The authors also investigated the effect of BMI and found significantly higher concentrations of saturated and monounsaturated fatty acids and PUFAs in women with impaired glucose tolerance and BMI higher than 25 kg/m2 at study entry than in normal weighted women with impaired glucose tolerance. During the third trimester, overweight and obese women with GDM had the highest fatty acid absolute concentration. These results indicate that the disturbance in the fatty acid metabolism is more pronounced when beyond the mild hyperglycaemia obesity is also present. Results of this study raised the possibility that reducing pregravid weight and modifying diet (increasing PUFAs and reducing saturated fatty acids) may reduce circulating free fatty acids, therefore decreasing insulin resistance and inflammation and lower future maternal risk of type 2 diabetes mellitus.

#### **4.2 Fatty acid supply in newborns of mothers with gestational diabetes mellitus: Fetal effects**

Macrosomia and lipid abnormalities are common complications associated with maternal diabetes during pregnancy. Offspring of diabetic mothers are prone to develop obesity, type 2 diabetes mellitus and cardiovascular diseases during adulthood. In an animal study (Soulimane-Mokhtari et al., 2008), diabetic and control rats were fed a control diet or diet rich in EPA and DHA. During pregnancy of the diabetic rats, VLDL- and LDL-cholesterol were significantly decreased in the intervention group. Moreover, similar changes were seen in the macrosomic offspring: maternal fish oil diet significantly decreased VLDL- and LDLcholesterol. As n-3 LCPUFA supplementation during pregnancy restored tissue lipase activities to normal range and ameliorated long-term prognosis of macrosomia, n-3 fatty acid supplementation may be beneficial for mothers with GDM.

Maternal diabetes during pregnancy (characterised by hyperglycaemia, hyperlipidaemia, hyperlipoproteinaemia and altered T-cell function) may result in metabolic programming of the offspring causing obesity, impaired glucose tolerance, hyperlipidaemia and hyperlipoproteinaemia during adulthood (Khan, 2007). In Chinese children of mothers with GDM, significantly higher systolic and diastolic blood pressures and lower HDL-cholesterol levels were seen than in controls at the age of 8 years. High umbilical cord insulin was an independent risk factor of both abnormal glucose tolerance and obesity; hence, in utero hyperinsulinaemia and hyperglycaemia may have long-term effects on developing type 2

Fatty Acid Supply in Pregnant Women with Type 1 Diabetes Mellitus 451

GDM and control groups had lower LA and higher AA and DHA than their mothers. As umbilical venous blood comes from placental capillaries, these higher proportions of AA and DHA in umbilical venous than in maternal blood may indicate that the placental transfer remained unimpaired. However, the decreased n-3 and n-6 LCPUFA values might

**4.3 Differences between fatty acid supply in pregnant women with type 1 diabetes** 

Senovilla et al. from Madrid, finally Wijendran et al. from Hartford.

We found ten studies about fatty acid supply of pregnant women with either T1DM or GDM. Five different research groups performed human investigations: Chen CH et al. from Cleveland, Chen X et al. from New Jersey, Min et al. from London (Min, Thomas), Ortega-

To the best of our knowledge, only one study investigated the LCPUFA supply in pregnant women with T1DM. In this study no differences were found in n-3 and n-6 EFA values, while the most important n-3 metabolite, DHA was lower in all lipid fractions. In GDM most of the studies found decreased or unchanged ALA values, while LA values remained in most cases stable. In case of LCPUFAs, the results are less unambiguous and there was a difference between plasma and erythrocyte LCPUFA values. In general we can say, that plasma LCPUFAs in most cases were higher in mothers with GDM than in controls or it remained unchanged. In contrast, in erythrocyte membrane lipids LCPUFAs were either lower or unchanged in women with GDM compared to healthy controls except for one

Although we found only one study about fatty acid supply of pregnant women with T1DM, it seems, that diabetes had no influence on the EFA supply in mothers. In contrast, GDM may diminish EFA supply during pregnancy. T1DM significantly lowered the LCPUFA values in both plasma and erythrocyte membrane lipids, while there was a discrepancy in the effect of GDM: in plasma lipids it rather increased while in erythrocyte membrane lipids

**4.4 Differences between fatty acid supply in neonates from mothers with type 1** 

There were seven human studies investigating the fatty acid supply in cord blood or blood from infants born from mother with either T1DM or GDM. Four different research groups have data about blood lipid fatty acid composition of these offspring: Min et al. from London (Ghebremeskel, Min, Thomas), Ortega-Senovilla et al. from Madrid, Wijendran et al.

In contrast to maternal data, four studies investigated the fatty acid composition of newborns or infants of mothers with T1DM. Findings of EFA values are rather unequivocal: values of LA and ALA are either higher or lower or remained unchanged in the T1DM group. However, result are more clear in the case of LCPUFAs, all three studies found significantly lower AA and/or DHA values in plasma lipids, while erythrocyte membrane DHA values were either lower or similar to AA values, they remained unchanged in the

Looking at the results about the effect of GDM, in most cases EFA values remained stable, while LCPUFAs, predominantly DHA was significantly lower in the GDM group. In cord blood there was no deviation between plasma and erythrocyte LCPUFA values: AA and

indicate enhanced utilization of these fatty acids.

**mellitus and with gestational diabetes** 

study (Wijendran et al., 2000).

offspring of T1DM mothers.

decreased the availability of LCPUFAs.

**diabetes mellitus and with gestational diabetes** 

from Hartford, finally Winkler et al., from Munich.

diabetes and metabolic syndrome (Tam et al., 2008). Type 2 diabetes was diagnosed at younger ages if the patients were exposed to maternal diabetes intrauterine, whereas this difference wasn't seen in the onset of type 1 diabetes (Pettitt et al., 2008). This finding suggests, that intrauterine hyperglycaemia predisposes to an earlier onset of type 2 diabetes, while type 1 diabetes is little influenced by the intrauterine milieu.

In the pioneer study published in 1965 by Chen CH et al. (Chen CH et al., 1965) newborns of mothers with GDM were also analysed and no differences were found in LA values between the diabetic and control groups. Wijendran et al. analysed not only the maternal diet and fatty acid composition of maternal erythrocyte PL, but also the fatty acid composition of cord blood erythrocyte membrane lipids (Wijendran et al., 2000). Though in the maternal blood only DHA differed between mothers with GDM and controls, in the cord blood several differences were found. Values of AA and n-6 PUFAs as well as DHA and n-3 PUFAs were significantly lower in the GDM group than in controls. The DHA sufficiency index calculated from DHA divided with C22:5n-6 was also decreased. This impaired AA and DHA supply in cord blood suggested the impaired fetal accretion of these LCPUFAs in pregnancy with GDM. The authors also correlated maternal and fetal fatty acids both in the GDM group and controls. Though in controls significant positive correlations were found between maternal plasma PL AA and DHA and cord blood plasma PL AA and DHA, these correlations were lost in the GDM group. In controls also an enrichment of AA and DHA in fetal erythrocyte was found, while in the GDM group fetal DHA was lower than maternal, and no difference in AA values were found. These alterations raised the possibility that placental transfer of maternal LCPUFAs during the third trimester may be altered in GDM. Maternal HbA1c was also significantly and inversely correlated to fetal AA and DHA values. Although mothers had their HbA1c values between 4-6%, these values were significantly higher than in controls suggesting a moderate impairment of glucose control. This altered glucose control may also have a negative impact on fetal LCPUFA accretion.

Min et al. (Min et al., 2005b) investigated cord blood samples of newborns from mothers with and without GDM in London and found significantly decreased ALA, LA, DHA and AA values in the plasma TG fraction. In contrast, in the plasma CPG fraction only DHA values were significantly lower in the diabetic group. Similarly, in the PC fraction of erythrocyte membrane lipids significantly decreased DHA values were found. This altered cord blood fatty acid supply may suggest the compromised placental fatty acid transport and/or fetal lipid metabolism.

In another English study (Thomas et al., 2005) also significantly lower DHA values were found in the cord blood plasma CPG lipids in the diabetic group. DHGLA was also decreased in plasma CPG and STE fractions. Values of LA, ALA and AA were not significantly different between the two groups in the plasma TG, CPG and STE fractions, but values of AA were reduced. Although mothers with GDM consumed more DHA, their neonates had reduced levels of both DHA and AA, suggesting that mothers with GDM have impaired placental transfer of LCPUFAs. Mead acid, which is considered as an indicator of shortage of EFAs, was increased in the plasma CPG and TG fractions. The elevated Mead acid values in the cord plasma TG and CPG fraction suggested fetal EFA deficiency.

In a recent study (Ortega-Senovilla et al., 2009) umbilical arterial and venous plasma fatty acid composition was analysed in women with GDM and controls who underwent elective caesarean section. While there were no significant differences in umbilical venous blood fatty acids between the two groups, in the umbilical arterial blood significantly lower AA, n-6 PUFA, DHA and n-3 PUFA values were found. Umbilical arterial and venous blood of both

diabetes and metabolic syndrome (Tam et al., 2008). Type 2 diabetes was diagnosed at younger ages if the patients were exposed to maternal diabetes intrauterine, whereas this difference wasn't seen in the onset of type 1 diabetes (Pettitt et al., 2008). This finding suggests, that intrauterine hyperglycaemia predisposes to an earlier onset of type 2 diabetes,

In the pioneer study published in 1965 by Chen CH et al. (Chen CH et al., 1965) newborns of mothers with GDM were also analysed and no differences were found in LA values between the diabetic and control groups. Wijendran et al. analysed not only the maternal diet and fatty acid composition of maternal erythrocyte PL, but also the fatty acid composition of cord blood erythrocyte membrane lipids (Wijendran et al., 2000). Though in the maternal blood only DHA differed between mothers with GDM and controls, in the cord blood several differences were found. Values of AA and n-6 PUFAs as well as DHA and n-3 PUFAs were significantly lower in the GDM group than in controls. The DHA sufficiency index calculated from DHA divided with C22:5n-6 was also decreased. This impaired AA and DHA supply in cord blood suggested the impaired fetal accretion of these LCPUFAs in pregnancy with GDM. The authors also correlated maternal and fetal fatty acids both in the GDM group and controls. Though in controls significant positive correlations were found between maternal plasma PL AA and DHA and cord blood plasma PL AA and DHA, these correlations were lost in the GDM group. In controls also an enrichment of AA and DHA in fetal erythrocyte was found, while in the GDM group fetal DHA was lower than maternal, and no difference in AA values were found. These alterations raised the possibility that placental transfer of maternal LCPUFAs during the third trimester may be altered in GDM. Maternal HbA1c was also significantly and inversely correlated to fetal AA and DHA values. Although mothers had their HbA1c values between 4-6%, these values were significantly higher than in controls suggesting a moderate impairment of glucose control. This altered

while type 1 diabetes is little influenced by the intrauterine milieu.

glucose control may also have a negative impact on fetal LCPUFA accretion.

and/or fetal lipid metabolism.

Min et al. (Min et al., 2005b) investigated cord blood samples of newborns from mothers with and without GDM in London and found significantly decreased ALA, LA, DHA and AA values in the plasma TG fraction. In contrast, in the plasma CPG fraction only DHA values were significantly lower in the diabetic group. Similarly, in the PC fraction of erythrocyte membrane lipids significantly decreased DHA values were found. This altered cord blood fatty acid supply may suggest the compromised placental fatty acid transport

In another English study (Thomas et al., 2005) also significantly lower DHA values were found in the cord blood plasma CPG lipids in the diabetic group. DHGLA was also decreased in plasma CPG and STE fractions. Values of LA, ALA and AA were not significantly different between the two groups in the plasma TG, CPG and STE fractions, but values of AA were reduced. Although mothers with GDM consumed more DHA, their neonates had reduced levels of both DHA and AA, suggesting that mothers with GDM have impaired placental transfer of LCPUFAs. Mead acid, which is considered as an indicator of shortage of EFAs, was increased in the plasma CPG and TG fractions. The elevated Mead

acid values in the cord plasma TG and CPG fraction suggested fetal EFA deficiency.

In a recent study (Ortega-Senovilla et al., 2009) umbilical arterial and venous plasma fatty acid composition was analysed in women with GDM and controls who underwent elective caesarean section. While there were no significant differences in umbilical venous blood fatty acids between the two groups, in the umbilical arterial blood significantly lower AA, n-6 PUFA, DHA and n-3 PUFA values were found. Umbilical arterial and venous blood of both GDM and control groups had lower LA and higher AA and DHA than their mothers. As umbilical venous blood comes from placental capillaries, these higher proportions of AA and DHA in umbilical venous than in maternal blood may indicate that the placental transfer remained unimpaired. However, the decreased n-3 and n-6 LCPUFA values might indicate enhanced utilization of these fatty acids.

#### **4.3 Differences between fatty acid supply in pregnant women with type 1 diabetes mellitus and with gestational diabetes**

We found ten studies about fatty acid supply of pregnant women with either T1DM or GDM. Five different research groups performed human investigations: Chen CH et al. from Cleveland, Chen X et al. from New Jersey, Min et al. from London (Min, Thomas), Ortega-Senovilla et al. from Madrid, finally Wijendran et al. from Hartford.

To the best of our knowledge, only one study investigated the LCPUFA supply in pregnant women with T1DM. In this study no differences were found in n-3 and n-6 EFA values, while the most important n-3 metabolite, DHA was lower in all lipid fractions. In GDM most of the studies found decreased or unchanged ALA values, while LA values remained in most cases stable. In case of LCPUFAs, the results are less unambiguous and there was a difference between plasma and erythrocyte LCPUFA values. In general we can say, that plasma LCPUFAs in most cases were higher in mothers with GDM than in controls or it remained unchanged. In contrast, in erythrocyte membrane lipids LCPUFAs were either lower or unchanged in women with GDM compared to healthy controls except for one study (Wijendran et al., 2000).

Although we found only one study about fatty acid supply of pregnant women with T1DM, it seems, that diabetes had no influence on the EFA supply in mothers. In contrast, GDM may diminish EFA supply during pregnancy. T1DM significantly lowered the LCPUFA values in both plasma and erythrocyte membrane lipids, while there was a discrepancy in the effect of GDM: in plasma lipids it rather increased while in erythrocyte membrane lipids decreased the availability of LCPUFAs.

#### **4.4 Differences between fatty acid supply in neonates from mothers with type 1 diabetes mellitus and with gestational diabetes**

There were seven human studies investigating the fatty acid supply in cord blood or blood from infants born from mother with either T1DM or GDM. Four different research groups have data about blood lipid fatty acid composition of these offspring: Min et al. from London (Ghebremeskel, Min, Thomas), Ortega-Senovilla et al. from Madrid, Wijendran et al. from Hartford, finally Winkler et al., from Munich.

In contrast to maternal data, four studies investigated the fatty acid composition of newborns or infants of mothers with T1DM. Findings of EFA values are rather unequivocal: values of LA and ALA are either higher or lower or remained unchanged in the T1DM group. However, result are more clear in the case of LCPUFAs, all three studies found significantly lower AA and/or DHA values in plasma lipids, while erythrocyte membrane DHA values were either lower or similar to AA values, they remained unchanged in the offspring of T1DM mothers.

Looking at the results about the effect of GDM, in most cases EFA values remained stable, while LCPUFAs, predominantly DHA was significantly lower in the GDM group. In cord blood there was no deviation between plasma and erythrocyte LCPUFA values: AA and

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DHA were either lower or no significantly different in the offspring of GDM mothers than in controls.

To sum it up: T1DM has no clear effect on EFA status of the offspring, while GDM might lower it. In contrast, both T1DM and GDM lowered the availability of LCPUFAs in newborns and infants of diabetic mothers.
