**3. Effect of type 1 diabetes mellitus on fatty acid supply**

T1DM disturbs not only the carbohydrate, but also the lipid metabolism. The most extensively studied experimental animal model of T1DM is the alloxane or streptozotocininduced diabetic rat or mouse. The results of animal studies are quite unequivocal: in diabetic animals significantly higher LA contents were found in liver, renal cortex and heart lipids (Ramsammy et al., 1993), in liver microsomes and erythrocyte membranes (Shin et al., 1995) as well as in plasma, liver and skeletal muscle phospholipids (Mohan & Das, 2001), while its most important metabolite, AA was significantly decreased in diabetic animals. These results can be explained with the diminished activity of -5 (Ramsammy et al., 1993) and -6 desaturase enzymes in T1DM (Ramsammy et al., 1993; Shin et al., 1995). On the basis of these animal studies, insulin is considered as the most potent activator of both -5 and -6 desaturase enzymes (Brenner, 2003).

Human studies are even less unambiguous than animal observations. Some studies found significantly higher LA values in diabetic patients (Decsi et al., 2002, 2007; Tilvis & Miettinen, 1985), while others found no significant differences (Ruiz-Gutierrez et al., 1993; Seigneur et al., 1994). On the other hand, most studies report significantly lower AA (Decsi et al., 2002; Ruiz-Gutierrez et al., 1993) and DHA values (Decsi et al., 2002; Ruiz-Gutierrez et al., 1993; Tilvis & Miettinen, 1985) in diabetic patients than in controls. In one study (Tilvis et al., 1986), diabetic patients treated with continuous insulin infusion therapy had significantly lower LA, and significantly higher AA and DHA values both in plasma and erythrocyte membrane lipids than patients with conventional insulin therapy. These results suggest that better diabetic control may improve the activity of -6 desaturase enzyme.

After a longer period, hyperglycaemia and hypoinsulinemia may lead to several complications in diabetic patients. Several studies investigated the relationship between disturbed fatty acid status in diabetic patients and a number of complications, like diabetic neuropathy, nephropathy and retinopathy. These relationships and the potential role of n-3 fatty acid supplementation in diabetic patients are reviewed elsewhere (Szabó et al., 2010b).

#### **3.1 Fatty acid supply during pregnancy in women with type 1 diabetes mellitus: Maternal effects**

T1DM disturbs the fatty acid supply, therefore maternal LCPUFA stores may be compromised compared to healthy pregnant women. Disturbed fatty acid supply and metabolism may influence the course of pregnancy and delivery and may lead both to maternal and fetal complications. Nevertheless, we found only two human studies investigating the fatty acid supply during pregnancy in women with T1DM and four studies investigating fatty acid supply in cord blood lipids of newborns born from mothers with T1DM (Table 4).

Ghebremeskel et al. (Ghebremeskel et al., 2002) induced diabetes with streptozotocin in pregnant rats and investigated the liver fatty acid composition. They found significantly higher essential fatty acid values (ALA and LA) as well as n-3 and n-6 LCPUFA values (AA, EPA, DPA and DHA) in the TG and NEFA fractions. In an earlier study (Chen CH et al.,

Fatty Acid Supply in Pregnant Women with Type 1 Diabetes Mellitus 445

synthesis is rather slow and can't meet the requirements of the fetus. As T1DM disturbs the fatty acid supply of pregnant women, newborns of mothers with diabetes may have inadequate in utero n-3 and n-6 LCPUFA supply. In contrast to the lack of data on maternal fatty acid supply, cord blood lipids in neonates of mothers with T1DM were published from

Chen CH et al. (Chen CH et al., 1965) found no differences between cord blood LA values between newborns of diabetic and control mothers. Cord blood of newborns from mothers with T1DM and healthy controls was analysed in detail in an English study (Ghebremeskel et al., 2004). In the plasma CPG fraction there were significantly higher LA and ALA values in cord blood of neonates from diabetic mothers, while their long-chain metabolites, AA and DHA were lower in both plasma CPG and sterin esther (STE) fractions, which may reflect impaired placental transfer of the n-3 and n-6 LCPUFAs. The authors speculated that the effect of T1DM and pregnancy-induced metabolic changes together with the Western diet might have resulted in decreased AA and DHA levels in pregnant women with T1DM. In another study, cord blood samples of newborns of mothers with T1DM contained significantly lower ALA, DPA and DHA in the plasma TG fraction and significantly lower AA and DHA in the plasma CPG fraction (Min et al., 2005a). However, only DHA values

were decreased in the erythrocyte PE fraction in the cord blood of the T1DM group.

In the BABYDIET study, newborns with increased genetic and familiar risk for T1DM were investigated (Winkler et al., 2008). Erythrocyte membrane PC and PE were determined in infants of mothers with and without T1DM at the age of 3 and 12 months. No differences were found in the values of the most important LCPUFAs, AA and DHA in the PC fraction, while significantly lower DPA values were found in the infants of diabetic mothers at the age of 3 months, than in those of the healthy controls. In contrast, comparing only the exclusively breastfed infants of mothers with and without T1DM, no differences were found in the values of n-3 and n-6 PUFAs. At the age of 12 months, infants from mothers with T1DM had significantly higher essential fatty acid (ALA and LA) values, but DHA values

As newborns of mothers with diabetes may have diminished AA and DHA supply, the neurodevelopment of these infants may also be affected. In an experimental animal study (Zhao et al., 2009), diabetes was induced in rats who were divided into two groups, one with good and one with poor diabetic control and were fed either with AA or control diet. After one week the animals were mated and the neurodevelopment of the pups was investigated. Maternal dietary AA supplementation through pregnancy and lactation resulted in improved sensorimotor and developmental performances of the offspring of both healthy controls and poorly controlled diabetic dams. Maternal AA supplementation also improved

Maternal diabetes may disturb fetal fatty acid supply, however, from the epidemiological point of view the longer term effects are more important. Offspring of diabetic mothers may develop different malformations such as spina bifida, at birth they might be macrosomic and develop hypoglycaemia. The potential role of fatty acids in hyperglycaemia-induced teratogenesis was studied in an experimental animal model (Goldman et al., 1985). Diabetic pregnant rats without insulin treatment received subcutaneous AA injection during the period of organogenesis and although maternal glucose concentration didn't change, there was a significant decrease in the incidence of neural tube defects (from 11% to 3.8%), micrognathia (from 7% to 0.8%) and cleft palate (from 11% to 4%). These data suggest that beside good diabetes control also AA supplementation in diabetes might reduce the

several studies.

were decreased in the PE fraction.

teratogenetic effect of hyperglycaemia.

the AA supply of the offspring's liver, but not in the brain.


1965), only LA was determined and no significant differences were found in plasma NEFA fraction between diabetic and control mothers.

\* a.) = age of 3 months; b.) = age of 12 months

Abbreviations: AA: arachidonic acid, ALA: alpha-linolenic acid, CPG: choline phosphoglycerol, DHA: docosahexaenoic acid, DHGLA: dihomo-gamma-linolenic acid, DPA: docosapentaenoic acid, EFAs: essential fatty acids, EPA: eicosapentaenoic acid, LA: linoleic acid, LCPUFAs: long-chain polyunsaturated fatty acids, NEFA: non-esterified fatty acid, PC: phosphatidylcholine, PE: phosphatidylethanolamine, pl.: plasma, PL: phospholipid, RBC: erythrocyte, SM: sphyngomyeline, STE: sterol esther, T1DM: type 1 diabetes mellitus, TG: triacylglycerol

Table 4. Change in essential fatty acid and long-chain polyunsaturated fatty acid values compared to controls in pregnant women with type 1 diabetes mellitus and newborns from mothers with type 1 diabetes mellitus

Plasma and erythrocyte membrane fatty acid composition was studied in women with and without T1DM at midgestation (Min et al., 2005a). In the maternal plasma only choline phosphoglyceride (CPG) DHA was found to be decreased in diabetic patients, while in the erythrocyte membrane lipids more pronounced differences were found. Both the phosphatidylcholine (PC) fraction and in the phosphatidylethanolamine (PE) fraction significantly lower DHA values were found in mothers with T1DM than in healthy pregnant women. The authors hypothesised that this difference might be due to the synergistic effect of diabetes and pregnancy.

#### **3.2 Fatty acid supply in newborns of mothers with type 1 diabetes mellitus: Fetal effects**

AA and DHA play an important role in the maturation of the fetal nervous system. Although the developing fetus can synthesise AA and DHA from their precursors, this

1965), only LA was determined and no significant differences were found in plasma NEFA

RBC PC, PE: LA, ALA ↔

a.) RBC PC, PE: LA, ALA ↔ b.) RBC PE: LA, ALA ↑ RBC PC: LA, ALA ↔

Abbreviations: AA: arachidonic acid, ALA: alpha-linolenic acid, CPG: choline phosphoglycerol, DHA: docosahexaenoic acid, DHGLA: dihomo-gamma-linolenic acid, DPA: docosapentaenoic acid, EFAs:

phosphatidylethanolamine, pl.: plasma, PL: phospholipid, RBC: erythrocyte, SM: sphyngomyeline, STE:

Plasma and erythrocyte membrane fatty acid composition was studied in women with and without T1DM at midgestation (Min et al., 2005a). In the maternal plasma only choline phosphoglyceride (CPG) DHA was found to be decreased in diabetic patients, while in the erythrocyte membrane lipids more pronounced differences were found. Both the phosphatidylcholine (PC) fraction and in the phosphatidylethanolamine (PE) fraction significantly lower DHA values were found in mothers with T1DM than in healthy pregnant women. The authors hypothesised that this difference might be due to the synergistic effect

Table 4. Change in essential fatty acid and long-chain polyunsaturated fatty acid values compared to controls in pregnant women with type 1 diabetes mellitus and newborns from

**3.2 Fatty acid supply in newborns of mothers with type 1 diabetes mellitus: Fetal** 

AA and DHA play an important role in the maturation of the fetal nervous system. Although the developing fetus can synthesise AA and DHA from their precursors, this

essential fatty acids, EPA: eicosapentaenoic acid, LA: linoleic acid, LCPUFAs: long-chain polyunsaturated fatty acids, NEFA: non-esterified fatty acid, PC: phosphatidylcholine, PE:

pl. CPG: LA, ALA ↑ pl. TG: LA, ALA ↓ pl. STE: LA, ALA ↔

pl. TG: ALA ↓ pl. CPG: LA, ALA ↔ RBC PC, PE: LA, ALA ↔ pl. CPG: DHA ↓ RBC PC: DPA, DHA ↓ RBC PE: DHA ↓

pl. TG: DHGLA ↓ pl. STE: AA, DHA ↓

DHA ↓

pl. CPG: AA, DPA, DHA ↓

pl. TG: DHGLA, DPA,

pl. CPG: AA, DHA ↓ RBC PC: AA, DHA ↔ RBC PE: DHA ↓

a.) RBC PC: DPA ↓ RBC PE: AA, DHA ↔ b.) RBC PE: DHA ↓ RBC PC: AA, DHA ↔

Author Number Change in EFAs Change in LCPUFAs

Chen CH et al., 1965 n = 3 pl. NEFA: LA ↔ no data

Chen CH et al., 1965 n = 4 pl. NEFA: LA ↔ no data

Min et al., 2005a n = 32 pl. TG, CPG: LA, ALA <sup>↔</sup>

a.) n = 23

b.) n = 25

sterol esther, T1DM: type 1 diabetes mellitus, TG: triacylglycerol

fraction between diabetic and control mothers.

**T1DM: maternal** 

**T1DM: fetal effects** 

Ghebremeskel et al.,

Winkler et al., 2008\*

**effects**

<sup>2004</sup>n = 31

Min et al., 2005a n = 26

\* a.) = age of 3 months; b.) = age of 12 months

mothers with type 1 diabetes mellitus

of diabetes and pregnancy.

**effects** 

synthesis is rather slow and can't meet the requirements of the fetus. As T1DM disturbs the fatty acid supply of pregnant women, newborns of mothers with diabetes may have inadequate in utero n-3 and n-6 LCPUFA supply. In contrast to the lack of data on maternal fatty acid supply, cord blood lipids in neonates of mothers with T1DM were published from several studies.

Chen CH et al. (Chen CH et al., 1965) found no differences between cord blood LA values between newborns of diabetic and control mothers. Cord blood of newborns from mothers with T1DM and healthy controls was analysed in detail in an English study (Ghebremeskel et al., 2004). In the plasma CPG fraction there were significantly higher LA and ALA values in cord blood of neonates from diabetic mothers, while their long-chain metabolites, AA and DHA were lower in both plasma CPG and sterin esther (STE) fractions, which may reflect impaired placental transfer of the n-3 and n-6 LCPUFAs. The authors speculated that the effect of T1DM and pregnancy-induced metabolic changes together with the Western diet might have resulted in decreased AA and DHA levels in pregnant women with T1DM.

In another study, cord blood samples of newborns of mothers with T1DM contained significantly lower ALA, DPA and DHA in the plasma TG fraction and significantly lower AA and DHA in the plasma CPG fraction (Min et al., 2005a). However, only DHA values were decreased in the erythrocyte PE fraction in the cord blood of the T1DM group.

In the BABYDIET study, newborns with increased genetic and familiar risk for T1DM were investigated (Winkler et al., 2008). Erythrocyte membrane PC and PE were determined in infants of mothers with and without T1DM at the age of 3 and 12 months. No differences were found in the values of the most important LCPUFAs, AA and DHA in the PC fraction, while significantly lower DPA values were found in the infants of diabetic mothers at the age of 3 months, than in those of the healthy controls. In contrast, comparing only the exclusively breastfed infants of mothers with and without T1DM, no differences were found in the values of n-3 and n-6 PUFAs. At the age of 12 months, infants from mothers with T1DM had significantly higher essential fatty acid (ALA and LA) values, but DHA values were decreased in the PE fraction.

As newborns of mothers with diabetes may have diminished AA and DHA supply, the neurodevelopment of these infants may also be affected. In an experimental animal study (Zhao et al., 2009), diabetes was induced in rats who were divided into two groups, one with good and one with poor diabetic control and were fed either with AA or control diet. After one week the animals were mated and the neurodevelopment of the pups was investigated. Maternal dietary AA supplementation through pregnancy and lactation resulted in improved sensorimotor and developmental performances of the offspring of both healthy controls and poorly controlled diabetic dams. Maternal AA supplementation also improved the AA supply of the offspring's liver, but not in the brain.

Maternal diabetes may disturb fetal fatty acid supply, however, from the epidemiological point of view the longer term effects are more important. Offspring of diabetic mothers may develop different malformations such as spina bifida, at birth they might be macrosomic and develop hypoglycaemia. The potential role of fatty acids in hyperglycaemia-induced teratogenesis was studied in an experimental animal model (Goldman et al., 1985). Diabetic pregnant rats without insulin treatment received subcutaneous AA injection during the period of organogenesis and although maternal glucose concentration didn't change, there was a significant decrease in the incidence of neural tube defects (from 11% to 3.8%), micrognathia (from 7% to 0.8%) and cleft palate (from 11% to 4%). These data suggest that beside good diabetes control also AA supplementation in diabetes might reduce the teratogenetic effect of hyperglycaemia.

Fatty Acid Supply in Pregnant Women with Type 1 Diabetes Mellitus 447

Author Number Change in EFAs Change in LCPUFAs

Chen X et al., 2010 n = 49 pl.: LA, ALA ↑ pl.: AA, EPA, DHA ↑

pl. CPG: ALA ↓ RBC PC: ALA ↓ RBC PE: ALA ↑

pl. TG: LA, ALA ↔ pl. CPG: ALA ↓

pl. TG: LA, ALA ↔ pl. PC: ALA ↓ pl. SM: LA ↔

RBC SM: LA ↔

pl. CPG: ALA ↓ pl. TG: LA ↑ pl. STE: ALA ↓

Wijendran et al., 1999 n = 15 pl. PL: ALA <sup>↓</sup> pl. PL: DHGLA, DPA ↓,

pl. TG: LA, ALA ↓ pl. CPG: LA, ALA ↔ RBC PC, PE: LA, ALA ↔

b.) pl.: LA, ALA ↔

Wijendran et al., 2000 n = 13 RBC PL: LA, ALA ↔ RBC PL: AA, DHA ↓

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

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

pl. CPG, STE: LA, ALA ↔

<sup>2009</sup>n = 15 pl.: LA, ALA <sup>↔</sup> pl.: AA, DHA <sup>↔</sup>

Wijendran et al., 2000 n = 13 RBC PL: ALA ↓ RBC PL: DHA ↑

Chen CH et al., 1965 n = 9 pl. NEFA: LA ↔ no data

2009\* n = 15 a.) pl.: LA, ALA <sup>↔</sup>

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

Thomas et al., 2005 n = 37 pl. TG: ALA <sup>↓</sup>

mothers with gestational diabetes mellitus (GDM)

RBC PC, PE: LA, ALA ↔

RBC PC, PE: LA, ALA ↔

pl. CPG: AA ↑

DHA ↓

RBC PC: DHGLA, AA, EPA, DPA, DHA ↓ RBC PE: DHGLA, DPA,

pl. TG: AA, DHA ↔ pl. CPG: AA ↑ RBC PC: AA ↓ RBC PE: AA, DHA ↔

pl. TG: AA, DHA ↔ pl. PC: DHA ↑ pl. SM: AA, DHA ↔ RBC PC: AA ↓ RBC PE: AA ↓

RBC SM: AA, DHA ↔

pl. TG: AA, DHA ↔ pl. CPG: DHA ↓ RBC PC: DHA ↓ RBC PE: AA, DHA ↔

a.) pl.: AA, DHA ↔ b.) pl.: AA, DHA ↓

pl. CPG: DHGLA, DHA ↓ pl. STE: DHGLA ↓ pl. TG: AA, DHA ↔

pl. CPG: AA ↑ pl. TG: DHA ↑ pl. STE: AA ↑

DHA ↑

Chen CH et al., 1965 n = 8 pl. NEFA: LA ↔ no data

**GDM: maternal effects** 

Min et al., 2004 n = 53

Min et al., 2005b n = 40

Min et al., 2006 n = 12

Thomas et al., 2004 n = 44

Min et al., 2005b n = 40

Ortega-Senovilla et al.,

**GDM: fetal effects** 

Ortega-Senovilla et al.,
