Diabetes and its complications occur at high rates in the world population. Several epidemiological studies have associated perinatal adversities, such as nutritional disturbances or diseases during gestation and lactation, with the development of insulin resistance or failure on insulin secretion in the adult progeny. Only recently the mechanism by which this phenomenon occurs is being delineated through series of experimental studies and implies epigenetics changes as a main initializing event. In this review, the authors give a comprehensive report of the different models of fetal and developmental programming that can result either in insulin resistance or insulin inappropriate secretion, with the possible mechanistic explanation for these alterations. The changes in the female workforce, which implies in profound nutritional and hormonal changes, exposure to endocrine disruptor or addictive compounds during gestation and lactation, including the reduction of lactation period creates conditions that, are obesogenic for their progenies, increasing the risk of type 2 diabetes mellitus. Finally, neonatal insults might be an important ethiopathogenic factor for the development of metabolic disturbances in adulthood, including obesity and diabetes, contributing to the considerable increase in chronic diseases incidence in society.
Keywords: Diabetes; Programming; Epigenetics; Reprogramming
Generally, in the evolution of Type 2 Diabetes mellitus (T2D) there are two main steps. Insulin resistance is usually an initial step, which is compensated by hyperinsulinemia that can maintain normoglycemia. With the development of the disease hyperglycemia arises as a consequence of insulin secretion failure. This disease has genetic and environmental factors in its pathogenesis, and the latter may contributing more for the recent T2D increase in epidemic proportion. It seems that environmental factors are more effective in the beginning of life, such as on the fetal period and in the newborn. Dorner et al.  already in 1975, was the first to associate a possible epigenetic transmission of diabetes mellitus that were more related to maternal than paternal influence, suggesting a stronger environmental link occurring through uterine milieu and lactation. Other authors had confirmed this association [2,3].
During periods of rapid growth such as pregnancy, lactation, and the period of spurt growth that occurs at puberty, the body appears to be highly sensitive to influences of environmental stimuli. An unfavorable environment can disturb the process of cell proliferation and differentiation, leading to changes in the normal developmental pathways of tissues and organs. Events occurring in these critical periods of life, such as pregnancy, lactation and adolescence, are able to modify the epigenetic pattern (DNA methylation, histone acetylation and uncoded RNA) that does not change the DNA sequence but are mitotically and transgenerationally inherited, establishing adaptive phenotypes to meet environmental demands in the long term. This process is considered an adaptive response to ensure the maintenance of critical functions of tissues and survival to the insult. This phenomenon is called metabolic programming and more recently, developmental plasticity, since the phenomenon seems to be more probabilistic than deterministic, as programming could make us believe [4,5]. If this adverse condition is not permanent, the individual becomes more susceptible to developing metabolic disorders in adulthood, modulating the physiological function and susceptibility to disease (Figure 1). This concept was proposed for the first time in the 90’s from the XX century, in studies showing an association between adverse intrauterine conditions, for example, maternal malnutrition, with the later development of obesity, hypertension and cardiovascular disease . The intrauterine programming is more prone to cause morphological, besides functional alteration. When the programming occurs after birth, especially in early infant, the programming effect is more functional and can be different from those observed during gestation, even when the insult is similar.
Low Birth Weight (LBW) is associated with detrimental longterm metabolic consequences in humans. Several epidemiological studies have been investigating this new concept of the Developmental Origins of Health and Disease (DOHaD) hypothesis. The concept of developmental programming suggests that environmental insults during critical periods of development can trigger maladaptive changes in organ structure and function, thus increasing susceptibility to obesity, T2D, cardiovascular disease and metabolic syndrome in later life.
The aforementioned hypothesis emerged in the 80s of last century with studies in the UK, where was observed an association between LBW and obesity and diabetes mellitus at adulthood . Curiously, Indian babies with LBW when compared with the UK babies were shorter, thinner but fatter . Contrary to observe in western countries, where T2D patients had higher body mass index (BMI) and are obese, T2D patients in India were thinner but had higher central obesity . Thus, for the same kind of imprinting condition (LBW), postnatal nutritional conditions during development may produce different programming effects.
Observations in children from mothers exposed to Dutch famine during the nazi siege in World War II shows that the programming of diabetes mellitus is dependent on the period of gestation when the mother is exposed to malnutrition. The babies from mothers exposed to famine during early pregnancy did not presented LBW but were prone to develop obesity when adults and those who were exposed in late pregnancy had a LBW, tendency to develop glucose intolerance, despite lower risk to develop obesity . After WWII the nutritional conditions of Dutches improves. A similar nazi siege in Russia, with consequent famine to Leningrad citizens, failed to produce programming effects, probably because after the War the nutritional conditions did not have enough improvement .
Accelerated postnatal growth, or ‘catch-up growth’, following intra-uterine growth restriction (IUGR) has also been shown to be important in the programming of later metabolic disease risk as well as being an independent risk factor for overweight that can manifest as early as childhood . Babies with LBW have a rapid catch-up growth and a high risk to develop obesity and insulin resistance. Some studies show that children with high birth weight as well as children with LBW have higher chances of developing obesity in adulthood, demonstrating that the nutritional imbalance, both for more and for less, is able to programming for metabolic disorders in adult life. In fact, it seems that more important than the birth weight are the maternal conditions, such as body weight gain during pregnancy and the quality of the maternal diet during pregnancy and lactation .
The development of experimental programming models contributed to the advancement in understanding the mechanisms involved in the alterations found in glucose homeostasis. Experimental models using maternal malnutrition, such as protein or energy malnutrition, placental uterine artery ligation or glucocorticoids exposure are able to replicate findings related to LBW. On the other hand, maternal over nutrition usually given a high fat diet reproduces typical effects of maternal obesity that causes dysfunction in insulin secretion and glucose intolerance in offspring . Maternal diabetes is more complex, because can be also associated with high birth weight and childhood obesity, if moderate, but if severe can cause LBW . Interestingly, in most cases, offspring become obese in adulthood and therefore with a high risk of developing diabetes.
Some experiments show a programming effect increasing insulin sensitivity, such as maternal protein restriction during lactation, but most of the models of gestational or postnatal imprinting programs for insulin resistance and later insulin secretion failure with overt T2D. Below, were viewed some of the models more studied.
Maternal malnutrition (energy vs. protein malnutrition)
Nutrition has an important impact on some stages of life, especially during the fetal and early postnatal periods, having in some cases important consequences for health throughout the course of life. The growth of organs and tissues during the critical periods of development involves processes of differentiation, proliferation and migration of cells in organized structures. Although most of these processes occur during the intrauterine life, the neonatal phase is also considered a second important period for the physiological development. Thus, as it is well known that maternal malnutrition has a negative impact on the development of offspring, it is undisputable the merit of an adequate maternal nutrition during these stages of life.
Experimental studies with dietary restrictions on critical windows of development showed that depending of the type of diet restriction and the stage of life, in which the insult occur, the outcomes is different. Several models of maternal protein restriction were studied, some of them with drastic diet protein restriction (0% of protein) to moderate reduction (8 to 10%). Most of those studies were performed during gestation, but some were done during gestation and lactation, and a more reduced number only during lactation.
Maternal under nutrition during pregnancy is associated with obesity, hyperinsulinemia and leptin resistance at adulthood . Protein restriction in pregnant rats increases the risk of the offspring to develop higher blood pressure, obesity, hypertrophic adipocytes, higher insulin receptor expression and glucose metabolism alterations [19,20]. If protein restriction occurs only during lactation, the phenotype is different; the offspring shows low body weight, and higher insulin sensitivity in adult life [21-23]. It seems that this phase of higher insulin sensitivity turns in insulin resistance as the animal becomes older .
An insulin-resistant phenotype has been observed in both male and female adult rats born of dams fed a low-protein diet throughout pregnancy and lactation [24,25]. This was associated with impaired expression of key insulin-signalling proteins. Adipocytes isolated from low-protein offspring had significantly higher basal and insulinstimulated glucose uptakes than controls. This may be related to a threefold increase in insulin receptors in low-protein adipocytes. Consistent with these observed changes in glucose transport, adipocytes from low-protein animals had higher basal and insulinstimulated Insulin Receptor Substrate (IRS)-1-associated with phosphatidylinositol 3-kinase (PI 3-kinase) activities . Recently, some studies, such as of Berends et al. , used cross-fostering to recuperate after birth, the pups whose mothers were protein restricted during gestation. The recuperated 3 months old male offspring had lower IRS-1, PI3K p110β and Akt phosphorylation in epididymal adipose tissue, but not significant changes in insulinemia or glycemia. By the contrary, the 3 months old offspring whose mothers were protein-restricted (0% protein) during the first ten days of lactation presented constitutively higher adipocyte levels of Akt, mTOR and GLUT4 that not respond to in vitro insulin administration .
Most of the experimental studies were done with rodents, mainly rats or some transgenic mice, and yet few studies with sheep that are more close to humans in relation to the type of gestation and lactation, since those animals usually produce only one offspring, instead of the 10-12 pups produced at each rat parturition. However, the results obtained with sheep are still controversial to characterize a true insulin resistance when maternal malnutrition occurs during pregnancy or lactation. George et al.  showed that the female offspring of energy malnourished ewes during gestation, develops when adults, higher insulin secretion, insulin resistance as well as lipid and glycogen liver accumulation. While, Costello et al.  showed an altered AKT and GLUT 4 in muscles of adult male offspring of undernourished mothers during pregnancy, but the glucose tolerance was normal, indicating an adaptive mechanism.
Glucocorticoid exposure or maternal stress
It is well described in literature that early life stress, i.e. exposure to glucocorticoid excess, induces important alterations in emotional and social functioning increasing the risk for the development of aggressive behaviors in animal models or human studies. The hypothalamicpituitary- adrenocortical (HPA) axis is one of the main pathways to respond to a stressor [31-34].
It is well known that glucocorticoids cause hyperglycemia by increasing insulin resistance and inhibiting glucose-stimulated insulin release from pancreatic beta cells . Concerning the programming for metabolic and endocrine disorders, changes in the secretion of HPA axis and/or in glucocorticoid action are good candidate mechanism in animals and humans to link LBW with cardiometabolic risk factors, such as obesity, dyslipidemia, hypertension and glucose intolerance [36-38]. In fact, prenatal glucocorticoid administration to women at risk of preterm delivery has adverse long-term effects on offspring metabolic health, as hyperinsulinemia at 30 years old .
The postnatal manipulations, such as different forms of maternal deprivation have been investigated in rodents, including early handling, early deprivation and single or repeated maternal separation [40-49] which gave new insights in the effects of early life stressors on future alterations in HPA status and glucocorticoid action. In part, these effects seem to be mediated by epigenetically-induced changes in neuroendocrine function. Liu et al.  have shown that offspring from mothers with low maternal care (for eg., low licking and grooming) are more anxious, and have a lower corticosterone response to stress and a lower Glucocorticoid Receptor (GR) expression in the hippocampus at adulthood compared with offspring from mothers with high maternal care. By the contrary, neonatal stress, such as maternal separation and followed by needle puncture is associated with higher visceral fat mass and hyperinsulinemia. If those animals were mechanically tactile stimulated those programmed changes were prevented .
To date DNA methylation is the most common mechanism investigated, because methylation patterns are established during development. This issue will be better addressed in item 5.2 of this review . Few studies in humans evidence that methylation of genes involved in glucocorticoid action are altered by the early life environment, and concerning these recent findings on epigenetic issues, more information has been published in several recent reviews [53-55].
Maternal obesity and diabetes
The prevalence of maternal obesity has risen in worldwide at an alarming rate in the last two decades. In the UK, around one in five pregnant women is obese while in the USA, approximately 64% of women of reproductive age are overweight and 35% are obese . Often, obese women give birth to large for gestational age babies, increasing the short-term risk complications during delivery as well as long-term influences on offspring health, either by direct effects of shared environmental or genetic factors or by programming effects .
In humans, maternal obesity has been associated with some longterm adverse health offspring outcomes during infancy, adolescence and even adulthood, including risk of obesity and other dysfunctions as insulin resistance, dyslipidemia and hypertension [58-60]. In fact, Catalano et al.  were the first group who demonstrated that the fetuses of obese mothers had greater insulin resistance than fetuses of lean women, but the mechanisms by which the programming effects of maternal obesity are mediated are less well understood, for eg, compared with maternal undernutrition.
Despite the mechanism of action is not yet completely known, evidence from experimental studies (with rodents and primates) has indicated that maternal obesity or fat diet exposure programs offspring for an increased risk of adult obesity and diabetes . In mice, studies have shown that a maternal obesogenic diet (16% fat, 33% sugar) for 6 weeks before mating and throughout pregnancy and lactation leads the 6 months-old offspring to higher adiposity, hypertension, hyperglycemia and hyperinsulinemia . In addition, more recently it was reported that at 17 days of gestation, the fetuses from female mice fed with high fat diet (60 kcal % fat) for 4 weeks before mating and throughout pregnancy presented higher plasma glucose and insulin .
Gestational diabetes predisposes offspring to develop diabetes later in life  and this could have a transgeneration transmission independent of genetic causes [66,67]. The association of diabetes in offspring of diabetic mothers was twice than with diabetic fathers [68,69]. It is difficult to separate the genetic factors from the environmental factors, since the diabetic mothers have the genes that can be transmitted to the offspring. However, an elegant epidemiological study in Pima Indians community showed a 3.7- fold higher prevalence of diabetes in the progeny of diabetic mothers after they develop diabetes than their siblings before their mothers developed diabetes .
In experimental models, gestational diabetes may induce pancreatic islet dysfunctions on the offspring and increase risk of diabetes in adult . In rats, mild maternal diabetes is induced by administration of streptozotocin at the beginning of gestation and continuous glucose infusion at the last week of pregnancy. The fetus from these mothers develops pancreatic beta-cells hyperplasia and hyperinsulinemia, which explains why those fetus are macrossomic, but at adulthood despite beta-cells mass is normalized, in vivo and in vitro glucose-stimulated insulin secretion was deficient followed by glucose intolerance [72,73]. However, hyperglycemic mothers had microsomic newborns, which also presented beta-cells hyperplasia, but with marked degranulation, suggesting an early exhaustion of their secretory capacity, confirmed by hypoinsulinemia . After birth there is a normalization of betacells mass, but when the animals grow older the beta-cells suffer hyperplasia, with a higher insulin response to glucose-stimulation and insulin resistance . The female offspring transmit to their progeny (second generation) the same phenotype characteristics of the offspring of mild diabetic mothers, such as glucose intolerance and insulin secretion defect at adulthood, and the second generation transmit to a third generation. However, the male are incapable to transmit those phenotype to their progeny [65,73].
Overnutrition by early overfeed
Overnutrition in rats is a well-characterized model for neonatal and childhood obesity. Overnutrition may be induced by reducing the litter size, which increases body fat content, triglycerides, insulin, leptin and glucose serum levels at weaning [76,77]. Early overfed rats’ exhibit structural and functional hypothalamic changes, which impairs their response to both insulin  and leptin . These changes may contribute to a higher risk of obesity-related diseases in adulthood. We recently, showed an altered liver oxidative stress and insulin resistance in this model . Several studies have attributed this profile to neonatal hyperleptinemia, hyperinsulinemia and hyperglycaemia at weaning, which may cause a malprogramming throughout life. We failed to find any change in glycemia, insulinemia or leptinemia in the adult animal programmed by early neonatal overfeeding .
High carbohydrate milk formula until the time of weaning resulted in chronic hyperinsulinemia and adult-onset obesity (HC phenotype) in these rats supported by hypersecretory capacity of HC islets and hypothalamic alterations predisposing to hyperphagia . Insulin secretion by pancreatic islets is under the control of peripheral (circulating blood glucose concentrations) and central Autonomic Nervous System (ANS) mechanisms. The Parasympathetic Nervous System (PNS) and the Sympathetic Nervous System (SNS) are the two opposing limbs of the ANS that extensively innervate the pancreas and regulate insulin secretion. The stimulatory effect of the PNS is exerted via acetylcholine, whereas the inhibitory effect of the SNS is exerted via norepinephrine. In vivo and in vitro studies on the insulin secretory capacity of islets from HC rats indicated an augmented response to cholinergic stimulation and a reduced sensitivity to adrenergic inhibition, suggesting that an altered ANS regulation contributes to the hypersecretory capacity of the HC islet cells .
Nicotine or tobacco smoke exposure
In early life, exposure to environmental chemicals seems to be one of the causes of world epidemic of obesity, acting as an obesogenic factor, and contributing to high levels of obesity and disorders closely associated with her, such as diabetes.
Recently, it has been shown that the critical windows are also sensitive to low doses of chemicals compounds. These agents, during the period of tissues organogenesis, are able to alter metabolic homeostasis, increasing the risk to develop obesity and diabetes .
The hypothesis is that lipophilic substances would be more diluted in obese individuals due to their greater content of fat mass compared to lean individuals. Adipose tissue gain over time furthers the dilution effect to lower serum levels independently of the chemical’s elimination. The temporal dilution of chemical compounds by mass gain is important in children because their rapid growth. The metabolism of chemicals in obese is delayed and its half-lives is extended . Thus, chemical concentration in blood may be lower in obese people due to dilution but it cumulative exposure may be higher because the extended half-life. Furthermore, as it is accumulated in the adipose tissue, it may exert toxicity due to their high tissue concentrations. Chemical’s pharmacokinetics and pharmacodynamics seems to be altered in the obese, modifying for example the capacity of the peroxisome proliferator-activated receptor (PPAR)-γ binding, which alters the process of adipocyte differentiation, and consequently adipose tissue metabolism.
Studies have shown the ability of maternal smoking to promote epigenetic changes in perinatal life and thus act as an important agent of programming including the development of glucose homeostasis dysfunction . Perinatal maternal smoking increases the risk of obesity and diabetes in adult life [86-93].
Cigarette smoke exposure in early life influences significantly the infant development. The relationship between childhood smoke exposure and metabolic changes include the risk of developing atherosclerosis and diabetes in childhood. Epidemiological studies have demonstrated in children exposed to cigarette smoke a decrease in HDL-C, hyperleptinemia, increase in C-reactive protein and IL-6, and decreased adiponectin [94,95]. Similarly, smoke exposure is associated with the presence of autoantibodies to pancreatic islet cells, which can be the first step in the development of type 1 diabetes .
Experimental findings showed an association between fetal nicotine exposure and obesity, hypertension and glucose homeostasis change. In utero exposure to tobacco smoke from the partner may truly have an impact on the fetus, and is associated with obesity in women at adulthood .
Adult offspring from mothers exposed to nicotine during pregnancy and lactation is programmed not only to obesity but also to insulin resistance, glucose intolerance, cold intolerance, reduced spontaneous physical activity and high risk of cardiovascular disease [93,97,98].
Nicotine exposure from conception until lactation results in permanent β-cell depletion and subsequent impaired glucose tolerance . According to Holloway et al. , fetal and neonatal exposure to nicotine results in disorders in the offspring that are common to those observed in T2D, and that adverse glucose metabolism observed in rats exposed to nicotine during fetal and neonatal life, can influence the metabolic risk in subsequent generations.
As nicotine is transferred through breast milk , becomes important to know its effects on the infant’s development when exposure occurs during lactation. To assess whether exposure to nicotine would impact in metabolism of offspring, if it happened only during lactation, our group decided to expose lactating rats to nicotine and to study the metabolism of their offspring when they were adult. We found no changes in fasting blood glucose or adiponectin in adult rats exposed to nicotine during lactation. However, we detected hyperinsulinemia and a higher insulin resistance index in these animals. Moreover, when we calculated the ratio of adiponectin to white adipose tissue mass, we observed lower adiponectin production per gram of adipose tissue, suggesting that a relative adiponectin insufficiency may be related to the development of insulin resistance in these animals , but it seems that the development of classical diabetes requires that nicotine exposure occurs in both gestation and lactation periods.
It is important to reinforce that not only the active smokers are exposed to developing smoking-related diseases. Environmental tobacco exposure (or second-hand exposure) is also associated with death for heart disease, lung cancer and other disorders. Cigarette smoke when inhaled by non-smokers can act on endocrine-metabolic system, and parameters related to metabolic syndrome have been associated with exposure to environmental tobacco exposure, such as hypertriglyceridemia, central obesity, decreased HDL-C and increased fasting serum insulin .
Rats and mice exposed to environmental tobacco smoke during lactation presented normoglycemia, hypoinsulinemia and lower HOMA-β suggesting deficiency in pancreatic insulin secretion, which may be an explanation for the hypoinsulinemia [103-105]. This lower pancreatic insulin secretion is consequent of a reduction in mass of pancreatic β cells that was previously observed in rats exposed to nicotine during pregnancy and lactation  or even an inhibitory effect of nicotine on pancreatic secretion of insulin . Adult offspring exposed to cigarette smoke during lactation showed hyperglycemia and normoinsulinemia, suggesting the development of glucose intolerance associated with higher adiposity in these animals when adults, reinforcing the idea of a higher risk of metabolic syndrome development in individuals exposed to smoke cigarette [102,105].
Role of prolactin and leptin
Therefore, both in excess as in deficiency of nutrients happens specific physiological responses that when occurring in critical periods of life will be able to modify epigenetic mechanisms and to act as metabolic imprinting factors. In metabolic programming models, the accumulation of adipose tissue appears to function as a determinant factor to development of glucose homeostasis disorders, especially if this accumulation occurs in the abdominal region. The mechanistic basis may involve an imbalance in the production of adipocytokines that modulate insulin sensitivity. In obesity, the adipose tissue produces more adipokines that cause insulin resistance, and less adipocytokine that improves insulin sensitivity. This imbalance in cytokine production has been proposed as a marker for diabetes mellitus, making the quantification of adipocytokine profile useful in clinical practice [107,108]. Thus, it is interesting to evaluate how adipocytokines, such as leptin, during the imprinting period of gestation or lactation can affect the hypothalamic and ANS neural development affecting the control of insulin secretion and action.
Our group showed that pups´ leptin secretion during lactation can be affect by maternal malnutrition, showing lower levels at the beginning and mid-lactation and being higher at the end of lactation . Then, we tested how leptin administration during this period of life could affect the future body composition and food intake and, we showed for the first time that leptin can program for higher body weight and food intake, when directly injected in the pups . Later, independently Pinto et al.  and Bouret et al.  showed in elegant experiments that leptin can alter the hypothalamic neural plasticity if injected in ob/ob mice, decreasing the number and functionality of NPY neurons and increasing POMC neurons. However, this effect was only possible in the neonatal period . Leptin may be important for the normal proliferation of pancreatic β-cells in the neonatal period, because increases the viability of isolated rat pancreatic islets by suppressing apoptosis and increasing islet cell proliferation . This could be the mechanistic basis, why leptin injected in this critical period of life could permanently alter food behavior, glucose homeostasis and insulin secretion. We showed that leptin injected on the pups during the first ten days of life caused a leptin surge at 30 days of life concomitantly with an insulin surge, and hypoadiponectinemia [114,115]. Then, those animals develop at adulthood hyperleptinemia and hyperinsulinemia, without changes in glycemia, but with hypertriglyceridemia. Trevenzoli et al.  showed in this model of neonatal hyperleptinemia that besides the hyperinsulinemia, the adult animals develop hypoadiponectinemia and liver microesteatosis. Vickers et al.  also found in male rats an effect of neonatal leptin treatment in increasing insulinemia in the adult animal. It seems that those effects are gender dependent, since in female neonatal leptin treatment seems to be protective to the effects of maternal under nutrition . More recently, Itoh et al.  showed glucose intolerance in 4 months old mice treated with leptin from postnatal day 5.5 to 10.5. Curiously, if the secondary surge of leptin that occurs after weaning is blocked by leptin antibody, the programming effects of leptin on body weight, glucose homeostasis and hypertriglyceridemia is abolished . However, the treatment of normal animals either with leptin antibody  or leptin antagonist  reproduces some of the alterations induced by leptin treatment during lactation. Thus, it seems that normal leptin levels at the neonatal period are necessary to a normal body weight and glucose homeostasis during development.
Malnutrition during lactation also is associated with low maternal prolactinemia . Since prolactin is important for the maintenance of pancreatic beta-cell mass , we pharmacologically blocked the maternal prolactin at the last 3 days of lactation with bromocriptine and observed hyperglycemia and hypoadiponectinemia in the 180 days old offspring, despite normoinsulinemia . The same kind of alteration on glucose homeostasis was observed when the suckling was interrupted by mechanical device, using a bandage in the mothers at the last 3 days of lactation .
Epigenetic alterations - DNA methylation, histone acetylation and interference RNA
In almost all countries, the epidemic of obesity has been rising inexorably since 1980 decade. In 1997, WHO accepted that this was a major public health problem . Nowadays, interactions between genes and environment provide a promising explanation to the idea of future development of disease risk, as adult obesity and diabetes. In this sense, epigenetics, that is the study of functional modifications to the genome without altering the underlying DNA sequence, has emerged as a relevant field combining experimental, epidemiological, clinical, and public health research [127,128].
Some populations, particularly in Latin America and Asia, are prone to developing central obesity, T2D and hypertension. Currently these features are being close related to epigenetic programming of gene expression in terms of metabolic/endocrine regulation that can induce a complex combination of adult health-related disorders . In fact several studies strongly support the idea that epigenetic processes of gene expression patterns such as DNA methylation, histone modifications and small interference RNAs (siRNA or microRNAs), which are involved in chromatin remodeling, are affected by the environment and can display key roles in the developmental programming of adult disease [126,128,129]. DNA methylation is more stable and this change can be transferred to next generation, while histone modifications and microRNA are more self-limited alterations in gene transcriptionand it was not reported yet in transgenerational studies .
As schematized in Figure 2, different imprinting factors during a critical window of development, as gestation or lactation periods, can act through different epigenetic mechanisms. It appears that these factors can activate the processes of DNA methylation and histones acetylation or deacetylation, or increase the levels of some siRNA, which may inhibit some genes related to normal insulin secretion and signaling, thereby affecting the developmental plasticity of the pancreas or insulin-dependent tissues, such as skeletal muscle, adipocyte and liver .
Epidemiological data of adults exposed to intrauterine energy restriction during the Dutch Hunger in World War II were the first to show DNA hypomethylation at the imprinted IGF2 region in mononuclear cells . Those undernourished babies developed into overweight adults who had a higher cardiovascular risk, confirming the hypothesis that the early life nutritional status can induce epigenetic changes that persist throughout life and provide a mechanistic base for the DOHaD theory.
Sinclair et al.  provide the first experimental evidence that reductions in specific dietary lead to epigenetic alterations to DNA methylation in offspring, and change adult health-related phenotypes. In this study, it was showed that a restricted supply of vitamin B12, folate and methionine around conception to mature sheep changed the methylation status of 4% of CpG islands in the liver offspring and resulted in higher adiposity, lower lean mass, insulin resistance and higher blood pressure at adulthood. In addition, Indian evidence indicates that insulin resistance at birth is linked to LBW and increased body fat with selective vitamin B12 deficiency and abnormalities of one carbon pool metabolism potentially responsible and affecting 75% of Indians and many populations in the developing world .
Other issues related to epigenetic changes have been presented in recent reviews [133-135] as well as, particularly, concerning the recent advances in the epigenetic mechanisms in the development and function of the endocrine pancreas and type 2 diabetes programming [136-138].
After a series of studies addressing the mechanisms involved in the metabolic programming phenomenon, currently the attention turns to strategies based in the knowledge about this mechanism and aimed controlling or preventing metabolic changes that underlie the programming, especially disorders in glucose metabolism and diabetes.
Both in humans as in animals, the caloric restriction, but not causing malnutrition, are capable of improving in a consistent form the insulin resistance . In patients with overweight and insulin resistance, both calorie restriction and physical exercise reverse these disorders . However, important changes in lifestyle seem to be a difficult practice in humans, especially when these new habits must be followed long-term. Therefore, new therapeutics ways, such as drugs and nutrients with bioactive properties, have been studied for obesity control and its metabolic disorders, especially T2D.
There is a wide range of bioactive components with aim to reprogramming or prevent the programmed insulin resistance or diabetes. Anti-oxidant compounds, rich in polyphenols such as resveratrol and yerba-mate, have shown beneficial effects on obesity and glycemic control, becoming a possible treatment option for T2D. Several studies have shown that yerba mate is capable of correcting serum glucose, triglycerides and LDL-C [141-143], improves significantly the glucose intolerance , even when combined with high-fat diets . Another bioactive component that seems to have beneficial effects on metabolic alterations of obesity is resveratrol, a polyphenol extract mainly from red grapes. In experimental models, chronic treatment with resveratrol improves glucose tolerance , prevents obesity, and reduces oxidative stress and the risk of hypertension, dyslipidemia and liver steatosis in adult rats with programmed obesity . The possible mechanism by which resveratrol improves glucose dysfunctions, seems be through increasing of GLUT4 translocation and enhancing of Akt phosphorylation, stimulating the glucose uptake by skeletal muscle . These findings suggest an important role of these bioactive components in the management of obesity and its related disorders.
Literature shows the influence of dairy products in the energetic metabolism regulation. In patients, calcium-rich diet potentiates the beneficial effect of hypocaloric diet in decrease adiposity and improves the lipid profile, hypertension and insulin sensitivity . Recently, our group showed that calcium supplementation is a good strategy to obesity and glucose intolerance treatment in early weaned rats and offspring from nicotine-exposed mothers [150,151].
Another possible strategy to prevent the development of glucose intolerance is to try to revert the hormonal alterations associated with malnutrition, such as hyperleptinemia or hypoprolactinemia or early weaning. In the first case, the use of leptin antibodies or antagonists may be promising [120,121].
Notwithstanding, neonatal insults might be an important ethiopathogenic factor for the development of metabolic disorders in adult life, including obesity and diabetes, contributing to the considerable increase in chronic diseases incidence in society. Thus, it is important to know the epigenetics mechanisms that are responsible for the imprinting process and subsequent programming effects to design effective strategies to prevent or treat the alarming increase in diabetes prevalence.