**10. The Barker hypothesis: disputes and joint effects of insulin and cortisol**

Hormonal equilibrium and adjustment are needed for an adequate anabolism and development [16, 17, 19, 37, 50]. This equilibrium is under nutritional and genetic regulation [7, 50]. Maternal glucocorticoids have relevant effects on the foetal metabolites and corticoid levels. They have opposite effects to those of other anabolic and growth mediators such as insulin or IGF-1 [38, 44]. Glucocorticoids are key hormones for adequate foetal development and maturation [16, 17], but at high concentrations they induce IUGR with a great affectation of glucose homeostasis, brain development and maturation and thus, all the processes regulated by this complex organ. Fortunately there are mechanisms regulating the concentration of active corticoids [7, 16], palliating, at least in part, the negative effects of the excess amount of these hormones.

Fifty years ago, it was assessed that children with marasmic malnutrition presented low insulinaemia and a high cortisol/insulin ratio [51]. However, these children kept a normal glucose tolerance [51] suggesting an increased insulin resistance. In animal models, the tissue-insulin hypersensitivity induced by protein-energy malnutrition was confirmed [52, 53]. This disagrees with the thrifty phenotype theory [4–6], which supposes less glucose consumed by peripheral tissues because of an insulin resistance status, allowing an adequate glucose transfer to the brain even in nutritional restriction conditions.

**Figure 4.** Insulin and lipoprotein programming during pregnancy. Foetal malnutrition influencing growth and pancreas capacities. Notice that the glucose and nutrient availability affect glucocorticoid concentrations and the flux of new cells originating lower pancreatic cell growth and less insulin production. This fact is counterbalanced by increasing insulin sensitivity and cholesterol synthesis. High food amount availabilities would induce adaptive mechanisms addressing glucose intolerance, diabetes mellitus, and/or dyslipidaemia and coronary heart disease (CHD) in this "programmed" body later in life. \*Non-definitive evidence. Modified from Sánchez-Muniz et al. [1].

Inadequate nutrition in human foetuses negatively affects pancreatic development, leading to a smaller β-cell population [54] or a decreased ability for insulin production [55]. This situation makes pancreas unable to adequately respond to some metabolic and stress conditions in adult life. Foetal effects of this programming are less known, but it seems that malnutrition, placental insufficiency and GD alter the islets development in the perinatal period, increasing the risk of suffering diabetes in the future (**Figure 4**). There is no agreement on the results obtained as malnutrition effects on insulin secretion ability have been associated with alterations in the secretion mechanism or hormone biosynthesis, or other factors such as the amount of hormone in each islet and the insulin availability by modifying the expression of the insulin production and translation genes [56].

It is well known that pancreatic β-cells release adequate amounts of insulin as a response to nutrients, hormones and nervous stimuli in order to keep glucose levels in a narrow range and assure optimum tissue functioning [38, 39, 57]. Glycaemia is the main insulin-secretion regulator [38, 39, 57] (**Figure 3**). In the foetus, insulin synthesis is regulated by glucose, and it has been described a slight foetal β-cell immaturity in the face of glucose. This seems paradoxical as glucose is the main metabolic substrate in the foetus [38, 58]. The "thrifty phenotype" hypothesis proposed by Hales and Barker [5] suggests that type 2 diabetes is due to the action of unknown factors that reduce foetal growth, islet β cell ontogeny and insulin sensitivity during the prenatal period. This hypothesis supposes a foetal programming where the HPA axis is involved under hormonal and nutritional regulation. This programming is induced as an adaptation mechanism of the future being to its limited environment in order to guarantee its own survival and is more prevalent in low birthweight individuals [7].

tissue-insulin hypersensitivity induced by protein-energy malnutrition was confirmed [52, 53]. This disagrees with the thrifty phenotype theory [4–6], which supposes less glucose consumed by peripheral tissues because of an insulin resistance status, allowing an ade-

**Figure 4.** Insulin and lipoprotein programming during pregnancy. Foetal malnutrition influencing growth and pancreas capacities. Notice that the glucose and nutrient availability affect glucocorticoid concentrations and the flux of new cells originating lower pancreatic cell growth and less insulin production. This fact is counterbalanced by increasing insulin sensitivity and cholesterol synthesis. High food amount availabilities would induce adaptive mechanisms addressing glucose intolerance, diabetes mellitus, and/or dyslipidaemia and coronary heart disease (CHD) in this

Inadequate nutrition in human foetuses negatively affects pancreatic development, leading to a smaller β-cell population [54] or a decreased ability for insulin production [55]. This situation makes pancreas unable to adequately respond to some metabolic and stress conditions in adult life. Foetal effects of this programming are less known, but it seems that malnutrition, placental insufficiency and GD alter the islets development in the perinatal period, increasing the risk of suffering diabetes in the future (**Figure 4**). There is no agreement on the results obtained as malnutrition effects on insulin secretion ability have been associated with alterations in the secretion mechanism or hormone biosynthesis, or other factors such as the amount of hormone in each islet and the insulin availability by modifying the expression of the insulin production

It is well known that pancreatic β-cells release adequate amounts of insulin as a response to nutrients, hormones and nervous stimuli in order to keep glucose levels in a narrow range and

"programmed" body later in life. \*Non-definitive evidence. Modified from Sánchez-Muniz et al. [1].

and translation genes [56].

quate glucose transfer to the brain even in nutritional restriction conditions.

78 Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

However, there are different studies in neonates showing that even in adequate *intra utero* growth situations, there is a wide dispersion in the hormonal results [59], suggesting that more factors than malnutrition may be involved. Moreover, our group has found that normoweight neonates whose mothers had an adequate adherence to the Mediterranean diet (MDA) during pregnancy showed insulin resistance markers lower than those whose mothers followed a diet far from the Mediterranean pattern [12, 13].

The hormonal imbalance associated with hypercortisolaemia, hyperinsulinaemia and reduced levels of GH and testosterone is a typical fact of the metabolic syndrome [40, 60]. However, this association has never been suggested in neonates and thus studied by our research group.
