maternal diabetes during pregnancy , also called gestational diabetes mellitus ( gdm ) , is an important risk factor for foetal overgrowth , termed macrosomia , which is influenced by maternal hyperglycemia and endocrine status through placental circulation . in humans , macrosomia has generally been defined as a birth weight greater than or equal to the 90th percentile birth weight for gestational age , that is , infants who weigh > 4000  g at delivery , regardless of gestational age or sex [ 24 ] .
infants born to diabetic mothers are at an increased risk for hypoglycaemia , respiratory distress syndrome , hyperbilirubinemia , and hypertrophic cardiomyopathy .
it seems that maternal hyperglycaemia leads to foetal hyperglycaemia , which stimulates foetal pancreatic islet cells and , consequently , induces foetal hyperinsulinaemia .
moreover , there exists a correlationship between maternal and foetal plasma cholesterol levels in 5 - 6-month - old human foetuses [ 5 , 6 ] .
it is noteworthy that several alterations in the metabolism of carbohydrates and lipids , observed in newborn babies of diabetic mothers , also persist postnatally [ 79 ] .
it is possible that foetal hyperinsulinaemia may be an endogenous teratogen factor during critical periods of foetal development , leading to permanent structural or functional changes and consequent programming of  metabolic memory . 
hyperinsulinemia in utero may affect the induction and activity of various hepatic enzymes associated with fat and carbohydrate metabolism .
this phenomenon may be accompanied , in placenta , by modifications in the expression of the transcriptional factors such as sterol regulatory element binding protein-1c ( srebp-1c ) , known to induce expression of genes involved in lipogenesis . in 1995
, barker   proposed that disproportionate foetal growth induced by foetal malnutrition , which could happen either in the middle or in a later period of the gestation , programmed coronary diseases in adulthood .
the in utero programming seems to create a kind of  metabolic memory  as the physiological abnormalities , observed during the gestational period , are responsible for the induction of diseases associated with the metabolic syndrome such as type 2 diabetes ( t2d ) and obesity in adulthood .
indeed , in human gdm , there exists a correlationship between gdm and 6-month - old foetal plasma cholesterol levels and other abnormal lipid parameters , including high concentrations of triglycerides ( tag ) , apob100 , very - low - density lipoprotein ( vldl ) , and low - density lipoprotein ( ldl ) , which often persist in macrosomia .
leptin , an adipocyte - derived hormone , by decreasing food intake and increasing energy expenditure , stabilizes body adiposity . a transient increase in leptin during neonatal life , called  neonatal leptin surge ,  has been shown to exert a neurotrophic effect and the development of energy - regulation circuits in mouse hypothalamus . furthermore ,
experimental premature leptin surge  from day 5.5 to day 10.5 of life  in mice pups led to decreased hypothalamic leptin sensitivity and accelerated weight gain when pups were fed a high - fat diet . in healthy women , both maternal and foetal leptin concentrations
reference   reported that leptin levels were always higher in overweight than in normal weight newborns , and plasma leptin level was correlated with birth weight .
hence , it is conceivable that foetal leptin plays a role in in utero programming . 
 in utero nutritional environment
epigenetic regulation is mediated by methylation and acetylation of histones . as far as foetal nutrition is concerned
, it has been reported that dietary methyl - group intake ( choline , methionine , and folate ) during critical periods of development can alter dna and histone methylation which may result in lifelong changes in gene expression .
hence , these epigenetic mechanisms might contribute to the development of macrosomia and its related adulthood pathologies such as obesity and t2d .
growth factors might be implicated in gdm and in the pathology of macrosomia via materno - foeto - placental axis .
we have conducted a clinical study in which we have determined circulating growth factors and the expressions of their genes in placenta in gdm mothers and their macrosomic babies .
we observed that serum concentrations of igf - i , igf - bp3 , egf , fgf-2 , and pdgf - b were higher in gdm dames and their macrosomic babies as compared to their respective controls . besides , the placental expression of the mrna of growth factors ( fgf-2 or pdgf - b ) and growth factor receptors , that is , igf - ir , egfr , and pdgfr - beta , was upregulated in gdm women compared to controls .
the immune system is composed of two major subdivisions , the innate ( phagocytic cells and nk cells ) and adaptive immune responses . though the interactions between innate and adaptive immunity are complex , the innate mechanisms control both the initiation and the type of adaptive response ( th1/th2 ) .
it has been shown that the abnormalities in humoral and cell - mediated immunity in t1d females may persist during pregnancy and , hence , may complicate immune - foetal interaction .
though pancreatic autoimmunity does not seem to represent a typical marker of gdm , high prevalence of autoantibodies , such as anti - gad65 and anti - ia2 antibodies , has been observed in gdm subjects .
on the contrary , it has been reported that foetal exposure to maternal t2d protects offspring , during the first 2 decades of life , from the development of islet autoimmunity and diabetes in the later life .
this is explained by the fact that the immune systems of children receiving autoantibodies from their diabetic mothers are primed during foetal life . such priming
is demonstrated by an increase in mhc class ii positive lymphocytes in infants of diabetic mothers compared to controls . with regard to t - cell activation ,
fully activated t - cells are detected in the cord blood of infants and mothers with t1d , but not in infants from normal mothers .
have reported a decrease in t - cell proliferation , associated with a decrease of plasma levels of il-2 in the offspring of diabetic mothers , as compared to those of control mothers .
also , in rat model , probably because of their priming , ex vivo t - cell proliferation is significantly lower in diabetic pregnant rats and their macrosomic offspring , as compared to control animals .
this phenomenon may trigger a decrease in the number of circulating and thymus homing t - cells .
in addition , the number of t- and b - cells in the neonates of diabetic mothers was significantly decreased compared to the neonates of healthy mothers .
reported an increase in the number of lymphocytes but a decrease in natural killer ( nk ) subset in children from gdm mothers .
another alteration in lymphocyte subset pattern is observed in gdm mothers , who had high number of cd8 cells , expressing tcr gamma / delta , and low number of cd3 cells , expressing tcr alpha / beta .
also , infants born to gdm women had higher cd8 gamma / delta cells than control babies .
this immunological imbalance may correlate with a greater risk for developing t1d , later in life .
t helper ( th ) dichotomy in gdm and macrosomia has not yet been well explored . on the basis of production of cytokines , th cells can be classified into two principal populations , th1 and th2 ( figure 1 ) .
th1 cells support cell - mediated immunity and , as a consequence , promote inflammation , cytotoxicity , and delayed - type hypersensitivity , whereas th2 cells support humoral immunity and downregulate the inflammatory actions of th1 cells .
th1 cells secrete il-2 , ifn- , and tnf- while th2 cells secrete il-4 , il-5 , il-6 , il-10 , and il-13 .
analysis of t - cell markers in placenta showed an increase in t - cell infiltration that expresses gata3 , a marker of th2 phenotype , in placenta of gdm women . concerning experimental models of gdm
, we would like to mention that we have developed a model by administrating streptozotocin ( stz ) to wistar female rats [ 2 , 9 ] .
we confirmed in this model a decrease in th1 cells , as observed in human gdm .
furthermore , in gdm rat , the decrease in circulating ifn- was accompanied with an increase in il-10 ( th2 marker ) levels , as compared to control rats [ 34 , 35 ] .
, the shift from the th1 phenotype to the th2 , during pregnancy , has been shown to encourage vigorous production of antibodies which not only combat infections during pregnancy , but also offer passive immunity to foetus .
a low th1 profile in diabetic pregnant rats , associated with successful pregnancy , may also result from the elevated levels of reproductive hormones like human chorionic gonadotrophin ( hcg ) hormone , whose administration is known to diminish the production of the th1 cytokines . in rats ,
the upregulated th1 profile in macrosomic animals may be due to difference in physiological status between gdm dames and their offspring .
a study conducted on tunisian women with gdm and their macrosomic babies corroborates these experimental observations .
indeed , the comparison of th1/th2 ratio showed an increase in the th2 phenotype in gdm mothers , whereas an increase in th1 phenotype was observed in macrosomic infants .
the regulatory t ( t - reg ) cells represent a specialized population of t - cells ( cd4cd25 ) , known for their properties as potent suppressors of inflammatory responses and for their ability to mediate immune tolerance .
t - reg cells induce immune tolerance throughout the production of two immunosuppressive cytokines : tgf- and il-10 .
both in humans   and in mice , t - regs cells increase very early in pregnancy , a period which coincides with an intense vascular activity .
the importance of t - reg cells in the success of pregnancy was demonstrated by aluvihare et al .   who reported that adoptive transfer of t - lymphocytes depleted of t - regs cells into pregnant t - cell - deficient mice led to the rejection of allogeneic foetal units .
furthermore , spontaneous abortion cases and patients with recurrent miscarriage are associated with lower systemic t - reg cells compared to normal pregnancies . in kuwaiti women ,
high number of t - cells expressing the activation - associated hla antigen ( cd4hla - dr ) , memory t - cells , and t - reg cells have been observed during gdm [ 46 , 47 ] .
the frequency of t - reg cells is significantly higher in children born to t1d mothers than in those born to gdm or normal women [ 48 , 49 ] . indeed ,
in the case of t1d , the maternal autoimmunity and the transplacental passage of auto - gad antibodies may influence the generation and expansion of foetal t - reg cells , which may suppress the gad65-specific t - cell responses . besides
, the t - reg cells of children born to t1d mothers exhibit a more pronounced memory phenotype ( increased ccr4 expression and downregulation of cd62l ) , suggesting an early activation of the foetal immune system , as a consequence of maternal autoimmunity .
it seems that the suppressive activity of t - reg cells was significantly reduced in gdm patients when compared to healthy pregnancy .
it is noteworthy that obesity - induced insulin resistance is associated with the development of a specialized t - reg population in visceral adipose tissue , called  vat resident t - reg  .
visceral adipose inflammation and insulin resistance have been associated with a dramatic reduction in vat t - reg cells in several animal models of obesity .
t - reg cells , by secreting il-10 , decrease the inflammatory state of adipose tissue and , thereby , improve insulin resistance .
loss - of - function and gain - of - function experiments demonstrated that vat t - reg cells are indispensable to reducing inflammation and increasing insulin sensitivity .
hence , the implication of vat resident t - reg cells deserves deep investigations in macrosomia .
during t - cell activation , an increase in intracellular free calcium concentrations , [ ca]i , is one of the earliest events which is triggered as a result of the hydrolysis of phosphatidylinositol - bisphosphate , catalyzed by the phospholipase c ( plc ) .
hence , plc gives rise to inositol trisphosphate , which recruits calcium from endoplasmic reticulum pool , and diacylglycerol which activates the protein kinase c. according to capacitive model of calcium entry , first calcium is released via t - cell receptor ( tcr ) activation from the endoplasmic reticulum ( er ) and then it is extruded into the extracellular medium . in turn
ionomycin opens calcium channels , leading to calcium influx from extracellular medium and thapsigargin ( tg ) recruits calcium which belongs to endoplasmic reticulum ( er ) pool .
interestingly , ionomycin - induced increases in [ ca]i in t - cells of gdm dames and their macrosomic offspring were greater than those in control rats . in 0% of calcium buffer , tg induces increases in [ ca]i exclusively from er pool and no influx occurs in the absence of calcium from the extracellular medium .
hence , both in 100% and in 0% calcium media , tg - induced increases in [ ca]i in t - cells are higher in gdm dames and macrosomic rats than those in control animals , demonstrating that t - cell calcium signaling is altered in these two pathological situations .
tnf- and il-6 represent the main inflammatory cytokines increased in the insulin - resistant states of obesity and t2d [ 26 , 54 ] . increasing evidence suggests that gdm is a proinflammatory state similarly to t2d .
monocyte chemotactic protein-1 ( mcp-1 ) is known to be elevated in inflammatory diseases like arthritis and lupus .
the elevation of mcp-1 in the third trimester of gdm suggests an association between inflammation and gdm . besides
, it has been suggested that hyperglycaemia and its related oxidative stress are usually associated with increased proinflammatory cytokines production [ 57 , 58 ] . increased concentrations of tnf- and il-6
might not only diminish insulin sensitivity by suppressing insulin signal transduction , but also interfere with the anti - inflammatory effect of insulin ( figure 2 ) [ 54 , 59 ] .
indeed , insulin exerts its anti - inflammatory effect by decreasing the production of reactive oxygen species ( ros ) from mononuclear cells and nuclear nf-b translocation .
the in vivo administration of insulin not only decreases the severity of t2d , but also diminishes the levels of mcp-1 and c - reactive protein ( crp ) , the two indicators of the inflammatory state .
il-6 promotes insulin resistance in liver cells   and negatively regulates insulin signaling and glucose metabolism in adipocytes .
it has been suggested that the increase in tnf- and il-6 in diabetic conditions might be a result of oxidative stress and inflammatory changes caused by hyperglycaemia . il-6 and tnf- are mainly produced by adipose tissues .
indeed , during insulin - resistant state , adipocytes secrete mcp-1 which favors the infiltration of macrophages that , consequently , produce il-6 and tnf- in high quantities ( figure 2 ) [ 66 , 67 ] .
we have reported that tnf- and il-6 are increased in gdm women . during pregnancy , il-6
secretion has been proposed to aggravate insulin resistance and participates in the pathogenesis of gdm .
adipocytes secrete a number of molecules , including adiponectin , leptin , and resistin , that modulate peripheral insulin sensitivity . from the immunological point of view , adiponectin exhibits anti - inflammatory properties   and leptin polarizes th cytokine production toward a proinflammatory ( th1 ) phenotype ( figure 1 ) .
since adipocytokines may play an important role in the early defects of t2d , women with gdm represent an ideal population model for studying this interrelationship .
depending on studies , elevated , constant , or decreased   levels of leptin have been observed in gdm women .
hence , in contrast to obesity which leads to an inflammatory th1 state , leptin does not play an important role in gdm , marked with th2 response , probably because of the hormonal status during pregnancy .
besides hyperglycaemia , chronic foetal hypoxia , detected in gdm , may also increase the inflammatory burden incurred by the foetus .
dietary n-3 pufas have been considered as immunosuppressors and , therefore , are used in the management of a number of inflammatory and autoimmune diseases , including rheumatoid arthritis and multiple sclerosis [ 75 , 76 ] , as these pathologies are characterized by the presence of activated t - cells and inflammatory cytokines either at the site of tissue injury [ 77 , 78 ] or in blood circulation [ 79 , 80 ] .
fat-1 transgenic mice , known to convert endogenous n-6 pufas to n-3 pufas , were protected from diabetes , because of low concentrations of tnf- and il-1 . generally , both in animal models and in humans , n-3 pufas decrease tnf- and il-6 production .
n-3 pufas exert their effect on the inflammatory gene expression through the inhibition of intracellular signaling pathways that lead to nf-b activation .
n-3 pufas have been shown to suppress mitogen - stimulated proliferation of lymphocytes isolated from lymph nodes , spleen , and lymphatic duct , in mice and human beings [ 75 , 85 ] .
feeding the n-3 pufa - diet corrected intracellular calcium homeostasis in t - cells of diabetic pregnant dames and their macrosomic obese rats .
we have assessed the th1/th2 dichotomy by dietary n-3 pufas in diabetic pregnancy and macrosomia .
we observed that the n-3 pufas - diet upregulated the th2 profile in gdm rats .
in macrosomic offspring , the th1 phenotype is upregulated and an n-3 pufas - diet downregulated this phenomenon . in agreement with our finding , wallace et al .  
have also observed that feeding fish oil to mice induced a shift in the ifn-/il-4 ratio , by a factor of four , as compared to animals fed the low fat diets .
we have investigated the molecular mechanisms by which n-3 pufas - diet controls t - reg cell suppressive capacity .
we used docosahexaenoic acid ( dha ) , the end product of -linolenic acid metabolism in animal tissues , and observed that the exposure of t - reg cells to this fatty acid or its in vivo supplementation upregulated tgf- but downregulated il-10 in these cells , suggesting that dha might be orienting the t - reg cell differentiation toward a th3 phenotype .
th3 phenotypes that infiltrate decidua are known to prevent abortion and contribute to the success of pregnancy .
furthermore , dha diminished the suppressive activity of t - reg cells on effector t - cell proliferation
. it is now becoming clear that the interaction of foxp3 with other transcription factors ( like naft or runx-1 ) or histone deacetyltransferase and class ii histone deacetylase is critical for the repression of the transcription of il-2 gene by foxp3 .
hence , we hypothesized that dha might downregulate t - reg cell activity , by interfering with the critical downstream components of the foxp3-driven suppressor pathway .
furthermore , dha reduced the migration of t - reg cells toward chemokines by downregulating the expression of chemokines receptors ( ccr-4 and cxcr-4 ) in these cells .
t - reg cell migration and activity have been found to be associated with mitogen - activated protein kinase ( mapk ) , that is , erk1/2 , activation .
besides erk1/2 , the phosphatidylinositol-3-kinase ( pi3k ) and akt / protein kinase b ( hence referred to as akt ) play a critical role in the t - cell survival , expansion , and differentiation . erk1/2 and
akt phosphorylation controls the expression of p27 , an inhibitor of cycline / cyclind kinase 2 that regulates cell cycle .
we noticed that dha significantly diminished the mapk phosphorylation in activated t - reg cells , and this phenomenon was associated with an increase of p27 in t - reg cells .
hence , dha seems to reinforce the anergic state of t - reg cells . concerning the molecular mechanism of action of n-3 pufas
, we have previously shown that dietary n-3 pufas are incorporated into plasma membrane phospholipids .
hence , we assume that dietary n-3 pufas may exert their beneficial action by modulating cell signaling .
we have recently shown that t - cell activation and t - cell calcium signaling are altered in diabetic pregnancy and macrosomia , and dietary fish oils , particularly eicosapentaenoic acid ( epa ) and dha , restore these t - cell abnormalities . during cell activation ,
a modification in the intracellular ph also plays an important role in the cell cycle progression and , hence , dha and epa have been shown to modulate this phenomenon .
dietary n-3 pufas , incorporated into plasma membrane , may also give rise to diacylglycerols which , in turn , may modulate cell activation .
it has been shown that diacylglycerols , containing epa and dha , modulate pkc activation , calcium signaling , and erk1/erk2 phosphorylation .
the incidence of gdm and macrosomia continues to grow worldwide and represents a major public health challenge . except for genetic factors , physical inactivity and high caloric food
are the major causing factors for these pathologies . based on clinical studies , the dietary guidelines for americans
2005 report   and several international and professional organizations   have made recommendations for consumption of at least two meals , containing fish , per week or from 0.250  g to 1  g of epa and dha daily with a 5  :  1 ratio of n-6 fatty acid / n-3 fatty acid .
there is no doubt concerning the beneficial effects of n-3 pufas in the improvements of hypertriglyceridemia and the reduction of cardiovascular risk .
thus , the use of these fatty acids in combination with genuine drugs ( lipid - lowering , anti - inflammatory , etc . ) represents a new therapeutic strategy in fighting against diabetes and obesity .
 th ( t helper ) cells are differentiated into either th1 or th2 phenotype . it is generally considered that th1 phenotype is proinflammatory , whereas th2 phenotype exerts anti - inflammatory or protective effects . 
 gestational diabetes mellitus ( gdm ) has been associated with a decreased th1 phenotype , whereas macrosomia is marked with high expression of th1 cytokines . besides , these two pathological situations are marked with high concentrations of inflammatory mediators like tumor necrosis factor- ( tnf- ) and interleukin-6 ( il-6 ) , known to play a pivotal role in insulin resistance . 
 dietary n-3 polyunsaturated fatty acids ( n-3 pufas ) may exert a beneficial effect by shifting th1/th2 balance to a th2 phenotype and increasing insulin sensitivity . in this paper , we shed light on the role of t - cell malfunction that leads to an inflammatory and pathophysiological state , related to insulin resistance in gdm and macrosomia . 
 we will also discuss the nutritional management of these pathologies by dietary n-3 polyunsaturated fatty acids ( pufas ) . 