Introduction

It is now believed that stimuli or insults induced during the perinatal period can have lifetime consequences, which is termed 'programming'. Programming stimuli may be generated endogenously, as in the case of hormonal signals, or they may be environmental. This 'programming' concept assumes that failure of a developing organism to progress from one stage of development to the next within the prescribed and preset time limits could lead to a permanent deficit (Susser & Levin, 1999). This is supported by several human observational studies which have reported effects in later life of exposures such as radiation (Stewart et al, 1958; MacMahon, 1962), famine (Stein et al, 1975) and viruses (Chess et al, 1971). This idea has been elaborated by Barker (1992), who suggested that impaired fetal growth might predispose to heart disease in later life. Coronary heart disease (CHD) is indeed common in men who were small at birth and at 1 y (Robinson, 2001). Inadequate fetal nutrition may result in fetal adaptations that programme future propensity to adult disease. The most unfavourable growth pattern is smallness and thinness at birth, continued slow growth in early childhood, followed by acceleration of growth so that height and weight approach the population means. A continuing rise in body mass index (BMI) above the mean has been shown to be associated with impaired glucose tolerance (IGT; Robinson, 2001). This type of growth pattern: initial under nutrition followed by better nutrition, is particularly relevant to developing countries such as India, where the incidence of type 2 diabetes (which is characterized by carbohydrate, protein and lipid metabolic abnormalities and long-term complications involving eyes, kidneys, nerves and blood vessels) and IHD are rising rapidly coinciding with increasing urbanization and obesity. Studies have documented striking differences between rural and urban populations with respect to the prevalence of obesity and type 2 diabetes mellitus in India. For instance, the prevalence of obesity (BMI>27) was reported as 3.6% in males and 6.6% in females in the rural population, but as high as 36.7% in males and 48.6% in females in the urban population. The prevalence of type 2 diabetes is higher in urban areas (10–13%) than in rural areas (approximately 2.8%; Krishnaswamy & Prasad, 2001). The exact reason for the difference in the prevalence of obesity and type 2 diabetes between the rural and urban populations is not clear, but it is relevant to note that the prevalence of breast-feeding is on the decline in India, especially in the urban areas. It is also interesting to note that Indian babies are exceptionally small, with a mean birth weight of 2700 g, and 30–35% have a birth weight of 2650 g or less (Robinson, 2001; Krishnaswamy & Prasad, 2001). The mothers of these children are short and underweight, with a mean BMI of only 18. These small babies have a low muscle mass, small viscera and a relative excess of fat—a body composition that is particularly suited to induce the development of insulin resistance. This is supported by the observation that lower birth weight and higher BMI in childhood are associated with IGT in these children (Robinson, 2001). These studies indicate that perinatal nutrition is an important determinant of adult diseases, an issue of major public health importance.

Tumour necrosis factor- and diabetes mellitus

There are mainly two types of diabetes mellitus (DM): type 1 and type 2. The immune-mediated destruction of -cells that occurs in type 1 DM involves both humoral and cell-mediated mechanisms. T and B lymphocytes, macrophages, granu-locytes and NK cells are activated to release interleukin-1 (IL-1) and tumour necrosis factor- (TNF-) and interferon- (IFN-) to destroy the -cell in type 1 DM (Mandrup-Poulsen et al, 1986; Dunger et al, 1996). Environmental agents such as drugs, chemicals and viruses increase the risk of genetically prone individuals developing type 1 DM. On the other hand, type 2 DM is characterized by insulin resistance and hyperinsulinaemia. Elevated plasma TNF- levels have been associated with obesity and insulin resistance, hypertriglyceridaemia and glucose intolerance (Hotamisligil, 1999; Jovinge et al, 1998; Das, 1999), which are seen in type 2 DM. Hence, methods designed to block or antagonize the actions of TNF- may prevent both type 1 and type 2 diabetes mellitus. One endogenous factor that has a negative feedback control on the production of TNF- and other pro-inflammatory cytokines is long chain polyunsaturated fatty acids (LCPUFAs; Kumar & Das, 1994; Kumar et al, 1992; Endres et al, 1989).

LCPUFAs and type 1 diabetes

Several case–control studies found a negative correlation between frequency and duration of breast-feeding and type 1 diabetes (Schrezenmeir & Jagla, 2000; Villalpando & Hamosh, 1998). This beneficial action has been attributed to reduced exposure to diabetogenic agents (especially viruses). Breast-feeding for 13 weeks reduced the incidence of gastrointestinal illness and respiratory illness during the first year of life (Wilson et al, 1998). It is likely that exclusive breast-feeding protects against bacterial and viral infections and prevents T-cell and humoral responses related to cow's milk proteins and thus protects from environmental factors that can trigger type 1 diabetes. Breast milk is a rich source of LCPUFAs (Fidler et al, 2000; Beijers & Schaafsma, 1996; de la Presa-Owens et al, 1996; Koletzko et al, 1988, 1992; see Table 1 for fatty acid composition of human breast milk). Hence, it is possible that these fatty acids are able to protect -cells and, thus, prevent diabetes. This is supported by the results of our animal studies in which it was observed that pre-treatment with LCPUFAs such as gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) prevents alloxan-induced destruction of cells both in vitro and in vivo (Mohan & Das, 2001; Suresh & Das, 2001; Das & Suresh, 2001). These results are supported by the work of Stene et al (2000), who showed in a population-based case–control study that cod liver oil, a rich source of EPA and DHA, taken during pregnancy was associated with reduced risk of type 1 diabetes in the offspring. This suggests that LCPUFAs, when present in adequate amounts, prior to or at the time of exposure to the diabetogenic agent can protect -cells and prevent type 1 diabetes. Although the exact mechanism by which LCPUFAs protect -cells is not known, both cyclo-oxygenase and lipoxygenase inhibitors did not block the beneficial action of LCPUFAs in vitro and in vivo (Mohan & Das, 2001; Suresh & Das, 2001; Das & Suresh, 2001) suggesting that fatty acids themselves are active. Further, LCPUFAs prevented alloxan-induced apoptosis of the pancreatic -cells (Suresh & Das, 2001). Mice deficient in poly (ADP-ribose) polymerase (PARP) activity are resistant to streptozotocin (both alloxan and streptozotocin have similar action on cells)-induced -cell death (Burkart et al, 1999). Hence, the possibility that LCPUFAs inhibit PARP activity and thus prevent DM is likely, but needs to be studied.

Table 1 - PUFA composition of mature human milk.

Full table (16K)

LCPUFAs and type 2 diabetes mellitus

In Pima Indians, type 2 DM was less common among breast-fed children compared with those exclusively bottle-fed (Pettitt & Knowler, 1998; Pettitt et al, 1997). A strong association between the method of infant feeding in the first weeks after birth and glucose tolerance in adults aged 48–53 y was reported (Ravelli et al, 2000). Subjects who were bottle-fed had a higher mean 120 min plasma glucose concentration after a standard oral glucose tolerance test than those who were exclusively breast-fed. Breast-fed infants had a significantly higher percentage of DHA and total percentage of LCPUFAs in muscle phospholipids and lower plasma glucose levels compared with the formula-fed group (Baur et al, 1998). An inverse correlation between fasting plasma glucose and the percentage of both DHA and total LCPUFAs was reported (Borkman et al, 1993). The secretion of TNF-, which is cytotoxic to pancreatic cells (Dunger et al, 1996) and plays a major role in inducing insulin resistance (Hotamisligil, 1999; Jovinge et al, 1998; Das, 1999), is suppressed by LCPUFAs (Kumar & Das, 1992; 1994; Endres et al, 1989). Based on this, the beneficial action of breast-feeding in the prevention of type 1 DM, insulin resistance and type 2 diabetes can be attributed to the presence of significant amounts of LCPUFAs in human breast milk.

How do LCPUFAs prevent insulin resistance and type 2 DM? One possibility is that, when substantial amounts of LCPUFAs are incorporated into the cell membrane, the membrane becomes more fluid and enhances the number of insulin receptors on the membrane, and increases the affinity of insulin to its receptors, and insulin action (Das, 1994a; Ginsberg et al, 1982; Somova et al, 1999). This attenuates insulin resistance. However, other unknown mechanisms by which LCPUFAs may exert this beneficial action should also be kept in mind. EPA and DHA rich oil prevented insulin resistance and hypertension in a fructose-fed rat model (Huang et al, 1997). Purified EPA ethyl ester reduced insulin resistance and decreased the incidence of type 2 DM in OLETF and WBN/Kob rats respectively (models of spontaneous type 2 DM) by modifying the phospholipid fatty acid composition of the skeletal membrane (Mori et al, 1997; Nobukata et al, 2000). The observation that (a) there is a significant correlation between insulin secretion and action and AA (Pelikanova et al, 1989), (b) an inverse relationship exists between fasting plasma insulin and the percentage of AA in erythrocyte fatty acids (Clifton & Nestel, 1998), and (c) decreased insulin sensitivity is associated with decreased concentrations of PUFAs in skeletal muscle phospholipids in normal men (Borkman et al, 1993) suggests that PUFAs can modulate insulin sensitivity and insulin resistance. It was reported that long-term (6 months) fish oil (a rich source of EPA and DHA) supplementation to patients with type 2 DM did not produce any significant changes in blood glucose and insulin-mediated glucose uptake (Rivellese et al, 1996). This negative result could, in part, be due to a decrease in AA levels induced by increased intake of EPA, suggesting that a balanced intake of AA, EPA and DHA is important. Based on this, it is suggested that LCPUFAs prevent the development of insulin resistance, hypertension and DM but are ineffective once these diseases set in. This may also explain why breast-feeding (a rich source of LCPUFAs) is associated with decreased incidence of insulin resistance, hypertension and DM in the adult (Pettitt & Knowler, 1998; Pettitt et al, 1997; Ravelli et al, 2000; Singhal et al, 2001; Das, 2001a).

Ventromedial hypothalamic lesion and type 2 diabetes mellitus

Induction of lesions in the ventromedial hypothalamus (VMH) in rats induce instant hyperphagia and excessive weight gain (Axen et al, 1994), fasting hyperglycaemia, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance (Dube et al, 1999). Intraventricular administration of neuropeptide Y (NPY) antibodies abolished the hyperphagia and ob mRNA (leptin mRNA) in these animals. This suggests that increased release or action of NPY is responsible for hyperphagia and obesity seen in VMH-lesioned animals and that the ob gene might be up-regulated even in non-genetically obese animals (Dube et al, 1995; Funahashi et al, 1995). Streptozotocin-induced diabetic rats showed increase in NPY concentrations in the paraventricular and ventromedial (VMH) and lateral hypothalamic areas (Williams et al, 1989) whereas VMH-lesioned rats showed selectively decreased concentrations of norepinephrine and dopamine in the hypothalamus (Takahashi et al, 1994). Long-term infusion of norepine-phrine plus serotonin into the VMH impairs pancreatic islet function in as much as VMH norepinephrine and serotonin levels are elevated in hyperinsulinaemic and insulin-resistant animals (Ohtani et al, 1997). These changes in the hypothalamic neurotransmitters were restored to near normal concentrations after insulin therapy. Thus, dysfunction of VMH can impair pancreatic islet function and cause metabolic abnormalities similar to those seen in type 2 diabetes.

VMH-lesioned rats have suppressed splenic NK cell activity, especially when these animals were hyperphagic and obese (Katafuchi et al, 1994). The brain produces interferon- (IFN-), interleukin-1 (IL-1), IL-2 and several other cytokines including TNF in response to non-inflammatory and inflammatory stress (Horin et al, 1998; Tanebe et al, 2000). In rat brain slice preparations, TNF- decreased the firing rate of the VMH neurons (Katafuchi et al, 1997). Thus, a close association exists between hypothalamic monoamines, islet cell function and cytokines.

TNF- causes neuronal cell death (Venters et al, 1999, 2000), whereas LCPUFAs have significant neuroprotective action (Lauritzen et al, 2000) and inhibit the production of IL-1, IL-2 and TNF- both in vitro and in vivo (Kumar & Das, 1992, 1994; Endres et al, 1989). TNF- participates in the pathogenesis of both type 1 and type 2 diabetes. Breast milk is rich in LCPUFAs, especially AA, EPA and DHA, which also constitute a significant proportion of the total fatty acids in the brain, where they are predominantly associated with membrane phospholipids. It is possible that when the concentrations of LCPUFAs are inadequate, especially during the critical period of brain growth, which is from third trimester to 2 y post-term, TNF- levels tend to be high and this can cause damage to VMH neurons. This in turn leads to hyperphagia, hyperglycaemia, hyperinsulinaemia, hypertriglyceridaemia and IGT. This may explain the negative correlation observed between adequate breast-feeding and insulin resistance and type 2 and type 1 diabetes. It is also interesting to note the close relationship between LCPUFAs, insulin receptors in the brain and type 2 diabetes.

LCPUFAs, insulin receptors in the brain and type 2 diabetes mellitus

Insulin signalling plays an important role in the regulation of food intake, neuronal growth and differentiation, regulates neurotransmitter release and synaptic plasticity in the CNS (Wan et al, 1997; Bruning et al, 2000). In mice with neuron-specific disruption of the insulin receptor gene (NIRKO mice), brain development and neuronal survival were normal. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, insulin resistance, hyperinsulinaemia and hyper-triglyceridaemia, features that are seen in type 2 diabetes mellitus. This suggests that decrease in the number of insulin receptors, a defect in the function of insulin receptors, insulin lack or resistance in the brain can lead to the development of type 2 diabetes even when pancreatic cells are normal both qualitatively and quantitatively. These results are supported by the observation that intraventricular injection of insulin inhibits food intake (Bruning et al, 2000).

LCPUFAs have important effects on cell membrane and cellular properties of neural tissue. In infants, LCPUFAs are preferentially accumulated by the brain during the last tri-mester of pregnancy and the first months of life. Adequate amounts of AA and DHA are essential for optimal development and function of central nervous system (reviewed in Salem et al, 1996). Infants as small as 2 kg and 32 weeks of gestation are capable of elongation and desaturation of EFAs, LA and ALA, and form AA and DHA, respectively. However, vegetable oil-based infant feed formulas lead to sub-optimal neural development and performance due to decrease in brain DHA content (Salem et al, 1993; Farquharson et al, 1995).

Human infants accumulate AA, EPA and DHA from maternal/placental transfer, consumption of human milk, and synthesis from LA and ALA. It is known that AA stimulates glucose uptake in cerebral cortical astrocytes and thus may play a role in the regulation of energy metabolism in the cerebral cortex (Yu et al, 1993). Glucose, in turn, is known to enhance ACh release in the brain (Ragozzino et al, 1996). Since AA enhances glucose uptake and, in turn, glucose augments ACh release, it is reasonable to assume that AA can enhance ACh release (Das, 2001b). Indeed, DHA, another LCPUFA increases cerebral ACh levels and improves learning ability in rats (Minami et al, 1997). In brain, ACh modulates neuronal functions including long-term potentiation and synaptic plasticity in neuronal circuits that are involved in learning and memory, and interacts with dopamine receptor in hippocampus (Hersi et al, 2000). This is interesting since decreased numbers of dopamine receptors or dopamine concentrations have a role in obesity (Wang et al, 2001), a condition that is frequently associated with type 2 diabetes.

The brain is rich in insulin receptors (Bruning et al, 2000; Hill et al, 1986; Das, 2001e). Insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of synapses in the CNS (Abott et al, 1999). Insulin and energy restriction enhance the activities of desaturases (reviewed in Das, 1991, 2000a) and so can increase the formation of LCPUFAs from their respective precursors (see Figure 1). TNF--induced neuronal death can be antagonized by IGF-1 and insulin (Venters et al, 1999, 2000). AA, DHA and other LCPUFAs have significant neuroprotective action (Lauritzen et al, 2000) and inhibit the production of IL-1, IL-2 and TNF- both in vitro and in vivo (Kumar & Das, 1992; 1994; Endres et al, 1989). Both insulin and LCPUFAs regulate superoxide anion generation and enhance the production of eNO (endothelial NO) (Das, 1994b, 2000b, 2001c, d, 2002a; Satomi et al, 1985; Boichot et al, 1999). NO has anti-inflammatory actions under certain circumstances (Guidot et al, 1996) and can quench free radicals. IGF-I and, possibly, insulin enhance ACh release from rat cortical slices (Nilsson et al, 1988). ACh in turn has anti-inflammatory actions (Borovikova et al, 2000) and is also a potent stimulator of eNO synthesis (Xu et al, 1996). Based on this, it is suggested that the concentrations of LCPUFAs are increased in the brain by the action of insulin and IGF-I on desaturases, which in turn enhances the brain ACh (this is in addition to the ability of insulin and IGF-I to directly enhance ACh levels in the brain) and suppress the production of TNF-, a neurotoxic molecule. Insulin, ACh and LCPUFAs suppress the production of TNF- and augment the synthesis of eNO. Both ACh and eNO in addition to their neuroprotective action interact with other neurotransmitters. Thus, insulin, IGF-I, ACh and LCPUFAs protect brain from insults induced by TNF- and other molecules.

Figure 1.

The metabolism of essential fatty acids and various co-factors that can either enhance or inhibit their metabolism. inhibition of -6- and -5-desaturase enzyme activities; enhancement of their activity. COX, cyclo-oxygenase enzyme; LO, Lipoxygenase enzyme.

Full figure and legend (46K)

Since LCPUFAs enhance the number of insulin receptors and attenuate insulin resistance (Burkart et al, 1999; Pettitt & Knowler, 1998; Pettitt et al, 1997; Ravelli et al, 2000; Baur et al, 1998; Borkman et al, 1993), one important function of LCPUFAs in the brain could be to ensure the presence of adequate number of insulin receptors. This assumes added significance in the light of the observation that NIRKO mice showed all the features of type 2 diabetes (Bruning et al, 2000). Thus, a defect in the metabolism of LCPUFAs or when adequate amounts of LCPUFAs are not incorporated into the neuronal cell membranes during the fetal development and infancy may lead to a defect in the expression and/or function of insulin receptors in the brain. This may lead to type 2 diabetes as seen in NIRKO mice.

Conclusion and therapeutic implications

The negative correlation observed between breast-feeding and insulin resistance and DM can be related to the presence of significant amounts of LCPUFAs in the human breast milk. I suggest that the increased prevalence of type 2 diabetes mellitus seen in certain populations recently could be due to a concomitant decrease in breast-feeding. This possibility can be verified by studying whether there is a negative correlation between breast-feeding and the incidence of DM in these populations. Formula feeds contain only linoleic acid (LA) and alpha-linolenic acid (ALA), which are essential fatty acids (EFAs), but not their longer chain metabolites GLA, DGLA, AA, EPA, DPA (docosapentaenoic acid, 22:5 -3) and DHA, which are present in the human milk. This is an important difference. Although infants have the capability to synthesize these longer chain fatty acids from LA and ALA, the rate of formation appears to be not adequate in the early stages of life, especially in pre-term infants (Carlson et al, 1985; Cunnane et al, 2000). Hence, the amounts of LCPUFAs formed may be inadequate to support the optimal neural development. As a result, the development, expression and maintenance of insulin receptors will be low, whereas the concentrations of pro-inflammatory cytokines such as TNF-, which participates in neuronal plasticity and neurodegenerative conditions (Mattson et al, 2001), will be high. This leads to a decrease in the expression and number of insulin receptors in the brain and thus the onset of obesity, insulin resistance and diabetes mellitus as seen in the NIRKO mice. Thus, a marginal deficiency of LCPUFAs during the critical phases of fetal and infant growth can have a profound effect on subsequent health (see Figure 2).

Figure 2.

The possible relationship between LCPUFAs, neural development, insulin, IGFs, neurotransmitters, maternal protein deficiency, -cell function and type 2 diabetes mellitus. inhibition of secretion, action, synthesis or damage to cells; increase in synthesis, action, secretion or protection of cells. For further details see the text.

Full figure and legend (46K)

Impaired fetal growth seems to increase the risk for adult diseases: insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, hypertension and coronary heart disease (Robinson, 2001). The hypothesis proposed by Barker (1992) predicts that coronary heart disease and impaired glucose tolerance will be more common in populations that are undergoing transition from sparse to better nutrition such as India, where the incidence of insulin resistance, type 2 diabetes mellitus, hypertension and coronary heart disease is assuming epidemic proportions (Krishnaswamy & Prasad, 2001). However, the relationship relating birth-weight to later outcomes has been disputed (Lucas et al, 1999). It was suggested that much of what was claimed to be fetal in origin may, in fact, relate to postnatal nutrition and growth (Lucas et al, 1999). It is possible that both fetal and postnatal nutrition and growth play a significant role in adult diseases. If this is true, what is the most significant perinatal nutritional factor(s) that can induce lifetime effects on metabolism, growth, and neurodevelopment and on major adult diseases? I suggest that this nutritional factor could be the LCPUFA content of human breast milk. It is true that breast milk contains several bioactive factors in addition to LCPUFAs. Breast-fed infants showed decreased incidence of obesity (Das, 2001b; von Kries et al, 2000), insulin resistance (Baur et al, 1998), hypertension (Das, 2001a; Singhal et al, 2001), diabetes mellitus (Schrezenmeir & Jagla, 2000; Pettitt et al, 1997), and CHD (Fall et al, 1992) in later life. LCPUFAs have beneficial actions in all these conditions (reviewed in Mohan & Das, 2001; Suresh & Das, 2001; Stene et al, 2000; Borkman et al, 1993; Das, 1994a, 2000c, 2001a, b, e). In view of this overlap of actions between breast-feeding and LCPUFAs, it is reasonable to suggest that some of the beneficial actions of human breast milk can be attributed to their content of LCPUFAs. These LCPUFAs when fed (either through breast milk or externally) during the critical periods of growth (third trimester to 2 y post-term) will accumulate not only in the specified areas of the brain but also in vessel walls including endothelium, kidney, heart and other tissues and, thus, may counteract the pathological mechanisms that tend to induce diabetes mellitus, insulin resistance, hypertension and CHD (Das, 2002b). Clearly, more studies are needed to confirm or refute this suggestion.

It is known that children born to women with gestational diabetes mellitus (GDM) have a higher incidence of diabetes. Wijendran et al (2000) reported that umbilical cord vein erythrocyte phospholipid AA and DHA concentrations were significantly lower in women with GDM in comparison to healthy pregnant women. Maternal HbA_1c (glycosylated hemoglobin) was inversely correlated to fetal erythrocyte phospholipid DHA and AA in GDM. This indicates that there is impairment in fetal accretion of DHA and AA in GDM. This supports the proposal that decreased accumulation of perinatal LCPUFAs increases the incidence of DM. However, studies relating the incidence of diabetes in children born of GDM women as function of breast-feeding have not been performed. If the hypothesis presented here is correct, it is expected that the incidence of diabetes in those who were breast-fed will be low.

A close association between poor fetal growth and adult diseases (Robinson, 2001; Barker, 1992) has been suggested. Could this be explained in terms of the hypothesis presented here?

Ozanne et al (1998) showed that growth retardation due to maternal protein restriction induced a decrease in the ratio of DHA to DPA in both muscle and liver in their offspring. The -5-desaturase activity in hepatic microsomes showed a reduction in the low-protein offspring, which was negatively correlated with fasting plasma insulin levels compared to controls. This suggests that fetal growth retardation inhibits the activity of -5-desaturase, a key enzyme involved in the formation of LCPUFAs in the body. This is interesting in the light of the observation that in pre-term infants fed commercial formulas with LA, AA in plasma and erythrocyte phospholipids declined for months after birth and remained low for 5 months. In these infants, AA status correlated with one or more measures of normalized growth until 12 months. Dietary AA improved first year growth of pre-term infants (Carlson et al, 1985). Studies performed both in experimental animals and humans showed that excess EPA and DHA inhibited both ⁶ and 5 desaturases (Raz et al, 1997), causing a depletion in AA, which led to impaired growth, resulting in lower weight, length and head circumference (Hamosh, 1998; Amusquivar et al, 2000). On the other hand, studies done in the fish-eating community of the Faroe Islands suggested that intake of seafood rich in long-chain -3 fatty acids increased birth weight by prolonging gestation (Olsen et al, 1986) and/or by increasing the fetal growth rate (Olsen et al, 1987, 1990). These studies imply that a balanced intake of AA, EPA and DHA is essential for proper growth and development of the fetus and for post-natal development. This is supported by the fact that breast milk, the most ideal food for the newborn, contains substantial amounts of AA, EPA and DHA (see Table 1).

It is also important to note that many co-factors are necessary for optimal EFA metabolism. There are also factors that can interfere with the metabolism of LA and ALA such that their long-chain metabolites are not formed in adequate amounts (see Figure 1). In view of this, it is important that infants receive adequate amounts of the co-factors that are necessary for optimal EFA metabolism. Hence, it is suggested that infant feed formula should contain adequate amounts of various LCPUFAs (similar to the composition as is present in human milk) and co-factors that are necessary for the proper metabolism of EFAs. When such balanced supplementation is given to infants from birth until 2 y post-term, it may reduce the incidence of diabetes mellitus (both type 1 and type 2).

It was reported that the calculated transfer of dietary LA and AA into breast milk was 32.818.0% and 11.86.6% respectively, whereas AA originating from conversion of dietary LA contributed only 1.1% to the total milk AA secreted (Prado et al, 2001). Thus, it was observed that little milk AA originates from conversion of LA and that 70% of LA and 90% of AA secreted in human breast milk is not derived from direct intestinal absorption, indicating that maternal body stores are the major source of milk LA and AA in the lactating women (Prado et al, 2001). This indirectly emphasizes the importance of providing various LCPUFAs from external sources to all women so that their body stores of LCPUFAs are adequately replenished so that when they are pregnant the fetus will be able to receive adequate amounts of these fatty acids. Infant feed formula may be supplemented with adequate amounts of various LCPUFAs (similar to the composition of human milk) from birth to 2 y post-term so that the incidence of diabetes mellitus is likely to be reduced. It is important that these LCPUFAs may also be provided to all pregnant females so that the fetus receives adequate amounts of these fatty acids (Koletzko et al, 2001). Since the brain keeps producing neurons even in adulthood (Barinaga et al, 1998), it may be necessary to supplement LCPUFAs even after infancy, keeping in view the possible adverse effects of excess intake of these fatty acids.

References

1. Abott, MA, Wells, DG & Fallon, JR (1999). The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J. Neurosci., 19, 7300–7308. | PubMed | ISI | ChemPort |
2. Amusquivar, E, Ruperez, FJ, Barbas, C & Herrera, E (2000). Low arachidonic acid rather than -tocopherol is responsible for the delayed postnatal development in offspring of rats fed fish oil instead of olive oil during pregnancy and lactation. J. Nutr., 130, 2855–2865. | PubMed | ChemPort |
3. Axen, KV, Li, X, Fung, K & Sclafani, A (1994). The VMH-dietary obese rat: a new model of non-insulin dependent diabetes mellitus. Am. J. Physiol., 266, (3 Pt 2)R921–R928.
4. Barinaga, M (1998). No-new-neurons dogma loses ground. Science, 279, 2041–2042.
5. Barker, DJPed. (1992). Fetal and Infant Origins of Adult Disease, London: BMJ
6. Baur, LA, O'Connor, J, Pan, DA, Kriketos, AD & Storlien, LH (1998). The fatty acid composition of skeletal muscle membrane phospholipid: its relationship with the type of feeding and plasma glucose levels in young children. Metabolism, 47, 106–112. | Article | PubMed | ISI | ChemPort |
7. Beijers, RJ & Schaafsma, A (1996). Long-chain polyunsaturated fatty acid content in Dutch preterm breast milk; differences in the concentrations of docosahexaenoic acid and arachidonic acid due to length of gestation. Early Hum. Devl., 44, 215–223.
8. Boichot, E, Sannomiya, P & Escofier, N et al (1999). Endotoxin-induced acute lung injury in rats: role of insulin. Pulmon. Pharmac. Ther., 12, 285–290.
9. Borkman, M, Stolien, LH, Pan, DA, Jenkins, AB, Chisholm, DJ & Campbell, LV (1993). The relation between insulin sensitivity and the fatty acid composition of skeletal muscle phospholipids. New. Engl. J. Med., 328, 238–244. | Article | PubMed | ChemPort |
10. Borovikova, LV, Ivanova, S, Zhang, M, Yang, H, Botchkina, GI, Watkins, LR, Wang, H, Abumrad, N, Eaton, JW & Tracey, KJ (2000). Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature, 405, 458–462. | Article | PubMed | ISI | ChemPort |
11. Bruning, JC, Gautam, D, Burks, DJ, Gillette, J, Schubert, M, Orban, PC, Klein, R, Krone, W, Muller-Wieland, D & Kahn, CR (2000). Role of brain insulin receptor in control of body weight and reproduction. Science, 289, 2122–2125. | Article | PubMed | ISI | ChemPort |
12. Burkart, V, Wang, Z-Q, Radons, J, Heller, B, Herceg, Z, Stingl, L, Wagner, EF & Klb, H (1999). Mice lacking the poly (ADP-ribose) polymerase gene are resistant to beta-cell destruction and diabetes development induced by streptozotocin. Nat. Med., 5, 314–319. | Article | PubMed | ISI | ChemPort |
13. Carlson, SE, Rhodes, PG & Ferguson, MG (1985). DHA status of preterm infants at birth and following feeding with human milk or formula. Am. J. Clin. Nutr., 44, 798–804.
14. Chess, S, Korn, SJ & Fernandez, PB (1971). Psychiatric Disorders of Children with Congenital Rubella, New York: Brunner–Mazel
15. Clifton, PM & Nestel, PJ (1998). Relationship between plasma insulin and erythrocyte fatty acid composition. Prostaglandins Leukot. Essen. Fatty Acids, 59, 912–919.
16. Cunnane, SC, Francescutti, V, Brenna, T & Crawford, MA (2000). Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoic accumulation than formula-fed infants not consuming dietary docosahexaenoate. Lipids, 35, 105–111.
17. Das, UN (1991). Essential fatty acids: Biology and their clinical implications. Asia Pacific J. Pharmac., 6, 317–330.
18. Das, UN (1994a). Insulin resistance and hyperinsulinemia: Are they secondary to an alteration in the metabolism of essential fatty acids?. Med. Sci. Res., 22, 243–245.
19. Das, UN (1994b). Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network. Prostaglandins Leukot. Essen. Fatty Acids, 51, 207–213.
20. Das, UN (1999). GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus. Prostaglandins Leukot. Essen. Fatty Acids, 60, 13–20.
21. Das, UN (2000a). Possible beneficial action(s) of glucose–insulin–potassium regimen in acute myocardial infarction and inflammatory conditions: a hypothesis. Diabetologia, 43, 1081–1082.
22. Das, UN (2000b). Newer uses of glucose–insulin–potassium regimen. Med. Sci. Monit., 6, 1053–1055.
23. Das, UN (2000c). Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how?. Prostaglandins Leukot. Essen. Fatty Acids, 63, 351–362.
24. Das, UN (2001a). Can perinatal supplementation of long chain polyunsaturated fatty acids prevent hypertension in adult life?. Hypertension, 38, e6–e8.
25. Das, UN (2001b). Is obesity an inflammatory condition?. Nutrition, 17, 953–966. | Article | PubMed | ISI | ChemPort |
26. Das, UN (2001c). Is insulin an anti–inflammatory molecule?. Nutrition, 17, 409–413.
27. Das, UN (2001d). Can glucose–insulin–potassium regimen suppress inflammatory bowel disease?. Med. Hypoth., 57, 183–185.
28. Das, UN (2001e). The brain–lipid–heart connection. Nutrition, 17, 276–279.
29. Das, UN (2002a). Insulin and the critically ill. Critical Care, 6, 262–263.
30. Das, UN (2002b). A Perinatal Strategy to Prevent Adult Diseases: the Role of Long-chain Polyunsaturated Fatty Acids. Boston, MA: Kluwer Academic
31. Das, UN & Suresh, Y (2001). Prevention of alloxan-induced cytotoxicity and diabetes mellitus by -linolenic acid and other polyunsaturated fatty acids both in vitro and in vivo. In:-Linolenic Acid: Recent Advances in Biotechnology and Clinical Applications, ed. Y-S Huang & VA Zibohpp.112–125, Champaign, IL: AOCS Press
32. de la Presa-Owens, S, Lopez-Sabater, MC & Rivero-Urgell, M (1996). Fatty acid composition of human milk in Spain. J. Pediatr. Gastroenterol. Nutr., 22, 180–185. | PubMed |
33. Dube, MG, Kalra, PS, Crowley, WR & Kalra, SP (1995). Evidence of a physiological role for neuropeptide Y in ventromedial hypothalamic lesion-induced hyperphagia. Brain Res., 690, 275–278. | PubMed |
34. Dube, MG, Xu, B, Kalra, PS, Sninsky, CA & Kalra, SP (1999). Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats. Brain Res., 816, 38–46. | Article | PubMed | ChemPort |
35. Dunger, A, Cunnigham, JM & Delaney, CA et al (1996). Tumor necrosis factor-alpha and interferon-gamma inhibit insulin secretion and cause DNA damage in unweaned rat islets: Extent of nitric oxide involvement. Diabetes, 45, 183–189.
36. Endres, S, Ghorbani, R & Kelley, VE et al (1989). The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. New Engl. J. Med., 320, 265–271. | PubMed | ChemPort |
37. Fall, CHD, Barker, DJP, Osmond, C, Winter, PD, Clark, PMS & Hales, CN (1992). Relation of infant feeding to adult serum cholesterol concentration and death from ischemic heart disease. Br. Med. J., 304, 801–805. | ChemPort |
38. Farquharson, J, Jamieson, EC, Abbasi, KA, Patrick, WJA, Logan, RW & Cockburn, F (1995). Effect of diet on the fatty acid composition of the major phospholipids of infant cerebral cortex. Arch. Dis. Child., 72, 198–203.
39. Fidler, N, Salobir, K & Stibilj, V (2000). Fatty acid composition of human milk in different regions of Slovenia. Ann. Nutr. Metab., 44, 187–193.
40. Funahashi, T, Shimomura, I, Hiraoka, H, Arai, T, Takahashi, M, Nakamura, T, Nozaki, S, Yamashita, S, Takemura, K & Tokunaga, K et al (1995). Enhanced expression of rat obese (ob) gene in adipose tissues of ventromedial hypothalamus (VMH)-lesioned rats. Biochem. Biophys. Res. Commun., 211, 469–475. | Article | PubMed | ISI | ChemPort |
41. Ginsberg, BH, Jabour, J & Spector, AA (1982). Effect of alterations in membrane lipid unsaturation on the properties of the insulin receptor of Ehrlich ascites cells. Biochim. Biophys. Acta., 690, 157–164.
42. Guidot, DM, Hybertson, BM, Kitlowski, RP & Repine, JE (1996). Inhaled nitric oxide prevents IL-1 induced neutrophil accumulation and associated acute edema in isolated rats lungs. Am. J. Physiol., 271, L225–L229. | PubMed | ISI | ChemPort |
43. Hamosh, M (1998). Long-chain polyunsaturated fatty acids: who needs them. Biochem. Soc. Trans., 26, 96–103.
44. Hersi, AI, Kitaichi, K, Srivastava, LK, Gaudreau, P & Quirion, R (2000). Dopamine D-5 receptor modulates hippocampal acetylcholine release. Brain Res. Mol. Brain Res., 76, 336–340. | Article | PubMed |
45. Hill, JM, Lesniak, MA, Pert, CB & Roth, J (1986). Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience, 17, 1127–1138. | Article | PubMed | ChemPort |
46. Horin, T, Katafuchi, T, Take, S & Shimizu, N (1998). Neuroimmunomodulatory actions of hypothalamic interferon-alpha. Neuroimmunomodulation, 5, 172–177. | Article | PubMed | ChemPort |
47. Hotamisligil, GS (1999). The role of TNFalpha and TNF receptors in obesity and insulin resistance. J. Intern. Med., 245, 621–625. | Article | PubMed | ISI | ChemPort |
48. Huang, Y-J, Fang, VS, Chou, Y-C, Kwok, C-F & Ho, L-T (1997). Amelioration of insulin resistance and hypertension in a fructose-fed rat model with fish oil supplementation. Metabolism, 46, 1252–1258.
49. Jovinge, S, Hamsten, A & Tomvall, P et al (1998). Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism, 47, 113–118. | Article | PubMed | ChemPort |
50. Katafuchi, T, Okada, E, Take, S & Hori, T (1994). The biphasic changes in splenic natural killer cell activity following ventromedial hypothalamic lesions in rats. Brain Res., 652, 164–168.
51. Katafuchi, T, Motomura, K, Baba, S, Ota, K & Hori, T (1997). Differential effects of tumor necrosis factor-alpha and -beta on rat ventro-medial hypothalamic neurons in vitro. Am. J. Physiol., 272, (6 Pt 2)R1966–R1971.
52. Koletzko, B, Mrotzek, M & Bremer, HJ (1988). Fatty acid composition of mature human milk in Germany. Am. J. Clin. Nutr., 47, 954–959. | PubMed | ISI | ChemPort |
53. Koletzko, B, Thiel, I & Abiodun, PO (1992). The fatty acid composition of human milk in Europe and Africa. J. Pediatr., 120, (4 Pt 2)S62–S70. | PubMed | ISI | ChemPort |
54. Koletzko, B, Agostoni, C, Carlson, SE, Clandinin, T, Hornstra, G, Neuringer, M, Uauy, R, Yamashiro, Y & Willatts, P (2001). Long chain polyunsaturated fatty acids (LC-PUFAs) and perinatal development. Acta Paediatr., 90, 460–464.
55. Krishnaswamy, K & Prasad, MPR (2001). The changing epidemiologic scene: malnutrition versus chronic diseases in India. Nutrition, 17, 166–167.
56. Kuboki, K, Jiang, ZY, Takahara, N, Ha, SW, Igarashi, M, Yamauchi, T, Feener, EP, Herbert, TP, Rhodes, CJ & King, GL (2000). Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation, 101, 676–681. | PubMed | ISI | ChemPort |
57. Kumar, SG & Das, UN (1994). Effect of prostaglandins and their precursors on the proliferation of human lymphocytes and their secretion of tumor necrosis factor and various interleukins. Prostaglandins Leukot. Essen. Fatty Acids, 50, 331–334.
58. Kumar, SG, Das, UN, Kumar, KV, Tan, BKH & Das, NP (1992). Effect of n-6 and n-3 fatty acids on the proliferation and secretion of TNF and IL-2 by human lymphocytes in vitro. Nutr. Res., 12, 815–823.
59. Lauritzen, I, Blondeau, N, Heurteaux, C, Widmann, C, Romey, G & Lazdunski, M (2000). Polyunsaturated fatty acids are potent neuroprotectors. EMBO J., 19, 1784–1793. | Article | PubMed | ISI | ChemPort |
60. Lucas, A, Fewtrell, MS & Cole, TJ (1999). Fetal origins of adult disease-the hypothesis revisited. Br. Med. J., 319, 245–249.
61. MacMahon, B (1962). Prenatal X ray exposure and childhood cancer. J. Natl Cancer Inst., 28, 1173–1191.
62. Mandrup-Poulsen, T, Bendtzen, K & Nerup, J et al (1986). Affinity purified human interleukin-1 is cytotoxic to isolated islets of Langerhans. Diabetologia, 29, 63–67. | PubMed |
63. Mattson, MP & Camandola, S (2001). NF-kB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest., 107, 247–254. | PubMed | ISI | ChemPort |
64. Minami, M, Kimura, S, Endo, T, Hamaue, N, Horafuji, M, Togashi, H, Matsumoto, M, Yaoshioka, M, Saito, H, Watanabe, S, Kobayashi, T & Okuyama, H (1997). Dietary docosahexaenoic acid increases cerebral acetylcholine levels and improves passive avoidance performance in stroke-prone spontaneously hypertensive rats. Pharmac. Biochem. Behav., 58, 1123–1129.
65. Mohan, IK & Das, UN (2001). Prevention of chemically induced diabetes mellitus in experimental animals by polyunsaturated fatty acids. Nutrition, 17, 126–151. | PubMed |
66. Mori, Y, Murakawa, Y, Katoh, S, Hata, S, Yokoyama, J, Tajima, N, Ikeda, Y, Nobukata, H, Ishikawa, T & Shibutani, Y (1997). Influence of highly purified eicosapentaenoic acid ethyl ester on insulin resistance in the Otsuka Long–Evans Tokushima fatty rat, a model of spontaneous non-insulin dependent diabetes mellitus. Metabolism, 46, 1458–1464. | Article | PubMed | ISI | ChemPort |
67. Nilsson, L, Sara, VR & Norberg, A (1988). Insulin-like growth factor 1 stimulates the release of acetylcholine from rat cortical slices. Neurosci. Lett., 88, 221–226.
68. Nobukata, H, Ishikawa, T, Obata, M & Shibutani, Y (2000). Long-term administration of highly purified eicosapenatenoic acid ethyl ester prevents diabetes and abnormalities of blood coagulation in male WBN/Kob rats. Metabolism, 49, 912–919.
69. Ohtani, N, Ohta, M & Sugano, T (1997). Microdialysis study of modification of hypothalamic neurotransmitters in streptozotocin-diabetic rats. J. Neurochem., 69, 1622–1628. | PubMed |
70. Olsen, SF & Hansen, HS (1987). Marine fat, birthweight, and gestational age: a case report. Agents Actions, 22, 373–374.
71. Olsen, SF, Hansen, HS, Sorensen, TI, Jensen, B, Secher, NJ & Sommer, S et al (1986). Intake of marine fat, rich in (n-3)-polyunsaturated fatty acids, may increase birthweight by prolonging gestation. Lancet, 2, 367–369. | Article | PubMed | ISI | ChemPort |
72. Olsen, SF, Olsen, J & Frische, G (1990). Does fish consumption during pregnancy increase fetal growth? A study of the size of the newborn, placental weight and gestational age in relation to fish consumption during pregnancy. Int. J. Epidemiol., 19, 971–977. | PubMed | ISI | ChemPort |
73. Ozanne, SE, Martensz, ND, Petry, CJ, Loizou, CL & Hales, CN (1998). Maternal low protein diet in rats programmes fatty acid desaturase activities in the offspring. Diabetologia, 41, 1337–1342.
74. Pelikanova, T, Kohout, M, Valek, J, Base, J & Kazdova, L (1989). Insulin secretion and insulin action related to the serum phospholipid fatty acid pattern in healthy men. Metabolism, 38, 188–192.
75. Pettitt, DJ & Knowler, WC (1998). Long-term effects of the intrauterine environment, birth weight and breast-feeding in Pima Indians. Diabetes Care, 21, (Suppl 2)B138–B141.
76. Pettitt, DJ, Forman, MR, Hanson, RL, Knowler, WC & Bennett, PH (1997). Breastfeeding and incidence of non-insulin-dependent diabetes mellitus in Pima Indians. Lancet, 350, 166–168. | Article | PubMed | ChemPort |
77. Prado, MD, Villalpando, S, Elizondo, A, Rodriguez, M, Demmelmair, H & Koletzko, B (2001). Contribution od fietary and newly formed arachidonic acid to human milk lipids in women eating a low-fat diet. Am. J. Clin. Nutr., 74, 242–247.
78. Ragozzino, ME, Unick, KE & Gold, PE (1996). Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc. Natl Acad. Sci. USA, 93, 4693–4698. | Article | PubMed | ChemPort |
79. Ravelli, AC, van der Meulen, JH, Osmond, C, Barker, DJ & Bleker, OP (2000). Infant feeding and adult glucose tolerance, lipid profile, blood pressure, and obesity. Arch. Dis. Child., 82, 248–252. | Article | PubMed | ChemPort |
80. Raz, A, Kamin-Belsky, N, Przedecki, F & Obukowicz, MG (1997). Fish oil inhibits delta 6 desaturase activity in vivo: Utility in a dietary paradigm to obtain mice depleted of arachidonic acid. J. Nutr. Biochem., 8, 558–565.
81. Rivellese, AA, Maffettone, A, Iovine, C, Di Marino, L, Annuzzi, G, Mancin, M & Riccardi, G (1996). Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care, 19, 1207–1213. | Article | PubMed | ChemPort |
82. Robinson, R (2001). The fetal origins of adult disease. Br. Med. J., 322, 375–376.
83. Salem, NJr, Wegher, B, Mena, P & Uauy, R (1996). Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc. Natl Acad. Sci. USA, 93, 49–54. | Article | PubMed | ChemPort |
84. Satomi, N, Sakurai, A & Haranaka, K (1985). Relationship of hypoglycemia to tumor necrosis factor production and antitumor activity: role of glucose, insulin and macrophages. J. Natl Cancer Inst., 74, 1255–1260.
85. Schrezenmeir, J & Jagla, A (2000). Milk and diabetes. Am. J. Coll. Nutr., 19, 176S–190S.
86. Singhal, A, Cole, TJ & Lucas, A (2001). Early nutrition in preterm infants and later blood pressure: two cohorts after randomized trials. Lancet, 357, 413–419. | Article | PubMed | ISI | ChemPort |
87. Somova, L, Moodley, K, Channa, ML & Nadar, A (1999). Dose-dependent effect of dietary fish-oil (n-3) polyunsaturated fatty acids on in vivo insulin sensitivity in rat. Meth. Find. Exp. Clin. Pharmac., 21, 275–278.
88. Stein, Z, Susser, M, Saenger, G & Marolla, F (1975). Famine and Human Development: the Dutch Hunger Winter of 1944–45, New York: Oxford University Press
89. Stene, LC, Ulriksen, J, Magnus, P & Joner, G (2000). Use of cod liver oil during pregnancy associated with lower risk of type 1 diabetes in the offspring. Diabetologia, 43, 1093–1098. | Article | PubMed | ISI | ChemPort |
90. Stewart, A, Webb, J & Hewitt, DA (1958). A survey of childhood malignancies. Br. Med. J., i, 1445–1508.
91. Suresh, Y & Das, UN (2001). Protective action of arachidonic acid against alloxan-induced cytotoxicity and diabetes mellitus. Prostaglandins Leukot. Essen. Fatty Acids, 64, 37–52.
92. Susser, M & Levin, B (1999). Ordeals for the fetal programming hypothesis. Br. Med. J., 318, 885–886.
93. Takahashi, A, Ishimaru, H, Ikarashi, Y & Maruyama, Y (1994). Aspects of hypothalamic neuronal systems in VMH lesion-induced obese rats. J. Auton. Nerv. Syst., 48, 213–219.
94. Tanebe, K, Nishijo, H, Muraguchi, A & Ono, T (2000). Effects of chronic stress on hypothalamic interleukin-1beta, interleukin-2, and gonadotrophin-releasing hormone gene expression in overiectomized rats. J. Neuroendocrinol., 12, 13–21. | Article | PubMed | ISI | ChemPort |
95. Venters, HD, Tang, Q & Liu, Q et al (1999). A new mechanism of neurodegeneration: proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl Acad. Sci. USA, 96, 9879–9884. | Article | PubMed | ChemPort |
96. Venters, HD, Dantzer, R & Kelley, KW et al (2000). A new concept in neurodegeneration: TNFalpha is a silencer of survival signals. Trends Neurosci., 23, 175–180. | Article | PubMed | ISI | ChemPort |
97. Villalpando, S & Hamosh, M (1998). Early and late effects of breast-feeding: does breast-feeding really matter?. Biol. Neonate, 74, 177–191. | PubMed |
98. von Kries, R, Kolletzko, B, Sauerwald, T & von Mitius, E (2000). Does breast-feeding protect against childhood obesity?. Adv. Exp. Med. Biol., 478, 29–39. | PubMed | ISI | ChemPort |
99. Wan, Q, Xiong, ZG, Man, HY, Ackerley, CA, Braunton, J, Lu, WY, Becker, LE, MacDonald, JF & Wang, YT (1997). Recruitment of functional GABA_A receptors to postsynaptic domains by insulin. Nature, 388, 686–690. | Article | PubMed | ISI | ChemPort |
100. Wang, G-J, Volkow, ND, Logan, J, Pappas, NR, Wong, CT, Zhu, W, Netusil, N & Fowler, JS (2001). Brain dopamine and obesity. Lancet, 357, 354–357. | Article | PubMed | ISI | ChemPort |
101. Wijendran, V, Bendel, RB, Couch, SC, Philipson, EH, Cheruku, S & Lammi-Keefe, CJ (2000). Fetal erythrocyte phospholipid polyunsaturated fatty acids are altered in pregnancy complicated with gestational diabetes mellitus. Lipids, 35, 927–931. | PubMed |
102. Williams, G, Gill, JS, Lee, YC, Cordoso, HM, Okpere, BE & Bloom, SR (1989). Increased neuropeptide Y concentrations in specific hypothalamic regions of streptozotocin-induced diabetic rats. Diabetes, 38, 321–327. | PubMed | ISI | ChemPort |
103. Wilson, AC, Forsyth, JS, Greene, SA, Irvine, L, Hau, C & Howie, PW (1998). Relation of infant diet to childhood health: seven year follow up of cohort of children in Dundee infant feeding study. Br. Med. J., 316, 21–25. | ChemPort |
104. Xu, Z, Tong, C & Eisenach, JC (1996). Acetylcholine stimulates the release of nitric oxide from rat spinal cord. Anesthesiology, 85, 107–111.
105. Yu, N, Martin, J-L, Stella, N & Magistretti, PJ (1993). Arachidonic acid stimulates glucose uptake in cerebral cortical astrocytes. Proc. Natl Acad. Sci. USA, 90, 4042–4046. | Article | PubMed | ChemPort |