**2. Early programming of diabetes**

plasma glucose levels. Currently, it is a major contributor to morbidity and mortality and is becoming an epidemic together with obesity worldwide. In fact, according to the WHO, the number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014; furthermore, WHO projects that diabetes will be the seventh leading cause of death in 2030. However, the most worrying fact is that the number of people who suffer diabetes will reach

Diabetes is classified into four clinical categories, T1DM, T2DM, gestational diabetes mellitus (GDM) and other specific types of diabetes due to other causes, such as genetic defects in β-cell function, genetic defects in insulin action or diseases of the exocrine pancreas, among others [6]. The two primary forms of diabetes are T1DM and T2DM. T1DM or insulin-dependent DM is an autoimmune disorder characterised by insulin deficiency (an absolute or near total loss of insulin secretion) caused by the destruction of the insulin-producing pancreatic β-cells; the onset occurs typically during childhood or early adulthood, between the ages of 8 and 12, although it could happen at early ages. This form of diabetes is fatal in the absence of insulin replacement therapy. T1DM represents approximately 5–10% of all diagnosed cases of diabetes [1, 3, 7–9], whereas T2DM or non-insulin-dependent diabetes, that accounts for 90–95% of all diagnosed cases. T2DM is characterised by decreased insulin sensitivity or insulin resistance in peripheral tissues and relative insulin deficiency; this pathology is commonly associated with other metabolic disturbances like obesity, hypercholesterolemia, hypertension and other features of the metabolic syndrome. The prevalence of this disturbance is increasing and

Cognitive dysfunction is a well-established consequence of diabetes. There is extensive literature which has demonstrated that diabetes, its microvascular complications (nephropathy, neuropathy and retinopathy), and its management with insulin and other drugs can induce mild to moderately severe neurocognitive dysfunction as a consequence of structural and functional changes in the central nervous system (CNS), and it will be especially harmful in infancy and childhood when it is under development. It is known that glycaemic extremes (hyper and hypoglycaemia) affect brain development. The subjects who develop diabetes early in life (6–7 years old) have an elevated risk of mild to moderately severe dysfunction that affects virtually all cognitive domains, including learning and memory. However, if the onset of the diabetes is after this critical period, the neurocognitive dysfunction will be less severe and more restricted. But, although "later onset" subjects show lower scores compared with their healthy siblings on tests of intelligence, sustained attention, visuospatial skills, psychomotor speed and executive functions, they show essentially normal learning and memory skills [9, 11]. Despite the fact that, poorly managed diabetes is associated with neurological

Therefore, the primary target of diabetic treatment is to achieve a good GC measured by the glycated haemoglobin A1c (HbA1c). HbA1c reflects average glycaemia during the last 3 months and has strong predictive value for diabetes-related complications. It has to be measured every 3 months in order to determine if patients´ glycaemic targets have been reached and maintained (HbA1c < 7.5% is recommended among all paediatric age-groups according to the American Diabetes Association; a lower goal <7% is recommended if it can be achieved

over half a billion by 2030, becoming a major public health issue [1–5].

is been diagnosed at increasingly younger ages [1–3, 7, 8, 10].

complications [4, 12, 13].

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Recent studies highlight the importance of the intrauterine environment in women with preexisting diabetes and obesity on the long-term health of the offspring. Thus, an intrauterine environment that exposes the foetus to excess of glucose, lipids, inflammation, growth factors, and cytokines may promote adipogenesis, alter appetite regulation, adversely affect pancreas development, and modify mitochondrial function, resulting in long-term metabolic risk to the offspring. The metabolic intrauterine environment is considered a critical risk factor for the development of adult diabetes and cardiovascular diseases [21]. As a consequence, any harm during critical developmental windows induces permanent adaptive programming in key organs, leading to persistent alterations in gene expression through epigenetic mechanisms. Nutrition constitutes the most significant environmental factor, being both a risk factor and the key in the prevention and protection against different metabolic disorders later in life [22].

*In utero* programming seems to create a *'metabolic memory'*, considering that physiological anomalies during the gestational period are responsible for the onset of T2DM and obesity associated with metabolic syndrome in the offspring at adulthood [23]. The periconceptional period has also been found as a critical period for nutritional effects on the ability of the foetus to respond to acute and chronic stressors, and for postnatal and adult metabolic health outcomes. It has been suggested that this period constitutes a critical time for nutritional effects on gene expression, with a potential preventive effect of postnatal risks related to prenatal maternal overconsumption and/or overweight, and DM or metabolic syndrome during pregnancy [22].

The association between poor psychosocial health, the risk of obesity and T2DM is well established. DynaHEALTH EU project hypothesises that factors determining glucose metabolism and insulin sensitivity on one hand, and the neuroendocrine response resulting from exposure to psychosocial stress on the other, should be incorporated as a single health indicator, named *'gluco-psychosocial axis'* (GPA) [24]. It is proposed that long-term GPA status could be established during developmental windows throughout early stages of life, via programming. The metabolic and psychosocial environments in early stages of life play an important role in the structural and functional development of the GPA components. Several studies have demonstrated the importance of the prenatal environment in determining long-term health and the ageing process [24].

sexually driven. This could be due to inherent gender differences in hypothalamic development, or gender specificity of the adaptive response to environmental challenges. In fact, there is higher risk of T2DM in women who were exposed to high maternal BMI during foetal life. Thus, in the future it will be vital to take into account sex differences for the establishment of recommendations, health guidelines and in the design of new therapeutic interventions [24, 33]. Either pre-existing diabetes (T1DM/T2DM) or GDM are associated with macrosomia in the offspring. Alterations in macrosomic infants persist postnatally, leading to insulin resistance, obesity, diabetes and metabolic syndrome at adulthood [23]. Maternal programming creates a vicious cycle by which maternal diet, weight or glycaemic status can increase offspring susceptibility to metabolic disease. These offspring during their pregnancies will have their own children; also exposed to an adverse *in utero* environment, perpetuating the burden of such

Influence of Glycaemic Control on Cognitive Function in Diabetic Children and Adolescents

http://dx.doi.org/10.5772/intechopen.75562

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The molecular mechanisms involved in foetal programming in diabetic women are far from understood [31]. It is essential that all diabetic women receive a proper management, including preconception counselling about weight management and weight loss (if they are overweight),

**Figure 1.** Vicious cycle of metabolic disease perpetuation to future generations and critical windows for intervention.

conditions to future generations (**Figure 1**) [25, 33].

Adapted from Dearden and Ozanne [33].

Epidemiological evidence suggests impaired glucose metabolism begins much earlier in life [24]. According to clinical studies pre-pregnancy diabetes or GDM, together with maternal obesity, have been associated with higher risk in the offspring of developing obesity, insulin resistance and T2DM later in life [25]. Complications in the offspring might appear even with gestational glucose levels below the thresholds of GDM; even borderline high blood glucose levels increase the risk of infants of being large for gestational age, early adiposity rebound and higher prevalence of metabolic syndrome, especially if they become obese [22]. Infants born from mothers who developed DM before pregnancy had higher risk to develop obesity, higher blood glucose and HbA1c levels, as well as lower HDL cholesterol concentrations and were more prone to DM during childhood, compared to those infants born from mothers who developed DM after pregnancy [25]. Furthermore, different studies have demonstrated that both, GDM or pre-gestational diabetes are related to delayed brain maturation, deficiencies in fine/gross motor development, cognitive deficiencies, and higher risk to develop Attention Deficit Hyperactivity Disease (ADHD) in the offspring, especially when there was a bad control of the maternal illness (HbA1c > 7.5%) during pregnancy [26–28].

T2DM burden is currently increasing in young people; higher maternal body mass index (BMI) during pregnancy is associated with higher all-cause mortality, higher cardiovascular morbidity and mortality, and increased risk of T2DM among offspring [24]. Data from PREOBE project have demonstrated that infants born from obese mothers had significantly higher birth weight and waist circumference, and those born from mothers with GDM had higher waist/height index compared to the healthy controls [29]. Maftei et al. reported that maternal pre-pregnancy BMI is related to offspring's insulin resistance at 9–10 years old, independently of GDM, and gestational weight gain does not appear to affect insulin resistance in children [30]. Other studies, showed that both foetal hyperglycaemia and hyperinsulinaemia in GDM increase the obesity and diabetes rates in the offspring, independently of maternal genetic influence [31]. Additionally, Westermeier et al., found that maternal obesity and neonatal insulin resistance are associated with long-term development of obesity, DM, and increased global cardiovascular risk in the offspring, involving deleterious mechanisms of intrauterine programming [32].

The DynaHEALTH EU project is testing how offspring's diseases later in life and their own GPA status is established in early life in response to metabolic and stress factors and partly related to maternal GPA status in pregnancy [24].

Nevertheless, developmental programming in humans is not limited to the *in utero* environment, the nutritional status during post-natal period has a considerable impact on later life health. As well, gender differences in developmental programming have been largely ignored and it has been suggested that offspring responses to the early metabolic environment are highly sexually driven. This could be due to inherent gender differences in hypothalamic development, or gender specificity of the adaptive response to environmental challenges. In fact, there is higher risk of T2DM in women who were exposed to high maternal BMI during foetal life. Thus, in the future it will be vital to take into account sex differences for the establishment of recommendations, health guidelines and in the design of new therapeutic interventions [24, 33].

named *'gluco-psychosocial axis'* (GPA) [24]. It is proposed that long-term GPA status could be established during developmental windows throughout early stages of life, via programming. The metabolic and psychosocial environments in early stages of life play an important role in the structural and functional development of the GPA components. Several studies have demonstrated the importance of the prenatal environment in determining long-term health

Epidemiological evidence suggests impaired glucose metabolism begins much earlier in life [24]. According to clinical studies pre-pregnancy diabetes or GDM, together with maternal obesity, have been associated with higher risk in the offspring of developing obesity, insulin resistance and T2DM later in life [25]. Complications in the offspring might appear even with gestational glucose levels below the thresholds of GDM; even borderline high blood glucose levels increase the risk of infants of being large for gestational age, early adiposity rebound and higher prevalence of metabolic syndrome, especially if they become obese [22]. Infants born from mothers who developed DM before pregnancy had higher risk to develop obesity, higher blood glucose and HbA1c levels, as well as lower HDL cholesterol concentrations and were more prone to DM during childhood, compared to those infants born from mothers who developed DM after pregnancy [25]. Furthermore, different studies have demonstrated that both, GDM or pre-gestational diabetes are related to delayed brain maturation, deficiencies in fine/gross motor development, cognitive deficiencies, and higher risk to develop Attention Deficit Hyperactivity Disease (ADHD) in the offspring, especially when there was a bad con-

T2DM burden is currently increasing in young people; higher maternal body mass index (BMI) during pregnancy is associated with higher all-cause mortality, higher cardiovascular morbidity and mortality, and increased risk of T2DM among offspring [24]. Data from PREOBE project have demonstrated that infants born from obese mothers had significantly higher birth weight and waist circumference, and those born from mothers with GDM had higher waist/height index compared to the healthy controls [29]. Maftei et al. reported that maternal pre-pregnancy BMI is related to offspring's insulin resistance at 9–10 years old, independently of GDM, and gestational weight gain does not appear to affect insulin resistance in children [30]. Other studies, showed that both foetal hyperglycaemia and hyperinsulinaemia in GDM increase the obesity and diabetes rates in the offspring, independently of maternal genetic influence [31]. Additionally, Westermeier et al., found that maternal obesity and neonatal insulin resistance are associated with long-term development of obesity, DM, and increased global cardiovascular risk in the offspring, involving deleterious mechanisms of

The DynaHEALTH EU project is testing how offspring's diseases later in life and their own GPA status is established in early life in response to metabolic and stress factors and partly

Nevertheless, developmental programming in humans is not limited to the *in utero* environment, the nutritional status during post-natal period has a considerable impact on later life health. As well, gender differences in developmental programming have been largely ignored and it has been suggested that offspring responses to the early metabolic environment are highly

trol of the maternal illness (HbA1c > 7.5%) during pregnancy [26–28].

and the ageing process [24].

124 Diabetes Food Plan

intrauterine programming [32].

related to maternal GPA status in pregnancy [24].

Either pre-existing diabetes (T1DM/T2DM) or GDM are associated with macrosomia in the offspring. Alterations in macrosomic infants persist postnatally, leading to insulin resistance, obesity, diabetes and metabolic syndrome at adulthood [23]. Maternal programming creates a vicious cycle by which maternal diet, weight or glycaemic status can increase offspring susceptibility to metabolic disease. These offspring during their pregnancies will have their own children; also exposed to an adverse *in utero* environment, perpetuating the burden of such conditions to future generations (**Figure 1**) [25, 33].

The molecular mechanisms involved in foetal programming in diabetic women are far from understood [31]. It is essential that all diabetic women receive a proper management, including preconception counselling about weight management and weight loss (if they are overweight),

**Figure 1.** Vicious cycle of metabolic disease perpetuation to future generations and critical windows for intervention. Adapted from Dearden and Ozanne [33].

proper weight gain during pregnancy, the critical importance of optimising GC (HbA1c < 6.5), by self-monitoring blood glucose levels, medication (if needed), medical nutrition therapy (eating a healthy diet) and optimal individualised exercise [21, 31]. Therefore, prevention of foetal programming by tight GC will be essential in order to break the vicious cycle of obesity, diabetes and related-complications in future generations [31]. In order to develop effective intervention strategies, it is important to understand the programming effects of maternal nutrition during pregnancy and the post-natal period both separately and combined, as well as to define clearly the critical developmental periods in order to establish an appropriate time intervention [33].
