**1. Introduction**

### **1.1 Hippocampus**

The hippocampus in humans is a part of the cortical region that is connected to the limbic system and consists of two cortical structures: the hippocampal formation and the parahippocampal region. Hippocampal formation refers to a group of structures with a unique cellular structure and arrangement that accompany the hippocampus and include: dentate gyrus, hippocampus, subiculum, presubiculum, and parasubiculum [1, 2]. The main difference between these two structures is the number of cortical layers and their general connections. The hippocampus in the coronal sections is a C-shaped structure located into the lower horn of the lateral ventricle. Its general shape is similar to a seahorse (**Figure 1A**) [3].

The most common classification for the hippocampus in non-human primates and other laboratory animals is, the hippocampus is divided into 4 subfields, CA1-CA4. In humans, most parts of the hippocampal formation are located on the floor of the temporal horn of the lateral ventricle (**Figure 1B**). The part of the

**Figure 1.**

*Isolated hippocampus of human which is similar to seahorse (A). The shape and location of the hippocampus in humans (B).*

hippocampus that is located in the floor of the lateral ventricular temporal horn (most parts of CA1 and CA2 and the distal part of CA3) is about 4 cm long [1].

### *1.1.1 Evolution of hippocampal formation in humans*

By the ninth week of pregnancy, the primary hippocampus develops within the cerebral hemispheres but does not resemble an adult hippocampus. At the middle of the third trimester of pregnancy (weeks 19–15), immature dentate gyrus, the subiculum, and different areas of the hippocampus can be identified. The hippocampal groove deepens and different areas of the hippocampus appear to be more developed, at the end of the 25th week of pregnancy. Although cell layers are more pronounced in CA1 and CA2-CA3; But the boundary between CA1 and subiculum is not clear. By the last trimester of pregnancy (34 weeks), the hippocampal groove is narrower and the boundary between CA1 and subiculum is distinguishable; CA1, CA2, and CA3 are recognizable and seem the dentate gyrus has a mature appearance.

It should be noted that a decrease in hippocampal cell density is observed in the postnatal period, which is probably due to the apoptosis and the growth of neurons and filaments. No significant morphological changes are seen until puberty and, and the only myelination is gradually completed [4, 5].

### *1.1.2 Hippocampal functions*

The first theory suggested that the hippocampus has a key role in olfactory functions. But this theory was not accepted because Studies in later years showed that the hippocampus did not receive any nerve fibers directly from the olfactory bulb; However, the further study indicated that the hippocampus may be involved in olfactory responses, and in particular in olfactory memory [6]. In addition, Jeffrey Gray suggested that the hippocampus might play a role in anxiety [7].

Years later, three main ideas for hippocampal function were explained: response inhibition, learning and memory, and spatial cognition [8]. The majority of psychologists and neuroanatomists believe that the hippocampus plays a principal role in the formation of new memories about experienced events (episodic or autobiographical memory), which is part of the role of the hippocampus in its activity in discovering new events, places, and stimuli [9, 10]. Some researchers believe that the hippocampus is responsible for declarative memory in addition to episodic memory [11, 12]. Severe damage to the hippocampus can cause problems with the formation of new memory, as well as impairment of earlier formed memory.

### *The Impact of Diabetes on Hippocampus DOI: http://dx.doi.org/10.5772/intechopen.99895*

However, the memory from years before the hippocampal injury may remain intact, which appears to be due to the transfer of memory from the hippocampus to other parts of the brain over the years [8].

Interestingly, damage to the hippocampus does not affect some types of memory, such as motor memory and the ability to learn new motor and cognitive skills, such as playing a musical instrument and solving a variety of tables. This implies that these abilities depend on other types of memory called working memory, which involve different areas of the brain [13]. Several researchers distinguish between conscious recollection and familiarity which depends on the hippocampus and portions of the medial temporal lobe, respectively [14]. The hippocampus and related areas are necessary for the systematic formation and organization of memory, their retrieval, and the repetition of learned experiences. Hippocampal neurons encode a large amount of information received in the form of senses and experiences and are implicitly organized [9].

The hippocampal/internal temporal lobe (HC/MTL) complex seems to be necessary for the formation of spatial memory. This memory requires the interpretation and processing of sensory information received from the environment. In mammals in general, the proper functioning of the hippocampus, especially CA1, is essential for the formation and processing of space-related memory. Evidence suggests that the right hippocampus in humans plays a key role in spatial memory, and in rodents, the amount and accuracy of spatial memory are directly related to the number of hippocampal mossy fibers [15–17].

### **1.2 Diabetes**

According to the World Health Organization (WHO), the term diabetes mellitus refers to a metabolic disorder with a variety of causes, including chronic hypoglycemia and impaired metabolism of carbohydrates, fats, and proteins due to impaired insulin secretion, insulin function, or both. Diabetes mellitus can have long-term effects and involve a variety of organs, including the central and peripheral nervous system, cardiovascular system, kidneys, and muscles. According to the World Health Organization, approximately 347 million people worldwide suffer from diabetes. However, 80% of these patients live in developing countries, and this number is increasing day by day [18, 19]. In addition, the number of people suffering from this metabolic disease in 2000 was 171 million, which will increase to 366 million in 2030 if proper prevention and treatment strategies are not implemented [20]. It is also estimated that by 2050 the incidence of diabetes in the world will increase by 198%, which will have a significant impact on increasing health care costs [20, 21]. As well as, global estimates suggest that by 2030, most people with diabetes will be 45 to 64 years old. The prevalence of type 2 diabetes is much faster than type 1, due to the increasing prevalence of obesity and reduced physical activity, which is one of the consequences of the industrialization of countries [22].

### *1.2.1 Diabetes can be divided into three general categories*

### *1.2.1.1 Type 1 diabetes (T1D)*

Type 1 diabetes, or insulin-dependent diabetes, is caused by the destruction of pancreatic beta cells as a result of insufficient insulin release. This type of diabetes is most common in adolescence and young adulthood and accounts for 10% of all diabetes cases [23].

### *1.2.1.2 Type 2 diabetes (T2D)*

Type 2 or non-insulin-dependent diabetes, which is more common than type 1 diabetes, occurs due to insensitivity and resistance to insulin in the body along with insufficient insulin release. This type of diabetes is more common in the elderly, especially women [22].

### *1.2.1.3 Gestational diabetes mellitus (GDM)*

Gestational diabetes mellitus is another type of diabetes that can be diagnosed during pregnancy and is defined as any amount of glucose intolerance that develops or is first diagnosed during pregnancy. However, in most cases, it is type 2 diabetes, which obviously leads to type 2 diabetes in 30 to 50 percent and in some cases has a similar course to type 1 diabetes [24]. According to this issue, diabetics and pregnant people can be divided into two groups: a group of people with diabetes who had diabetes before pregnancy (pre-existing diabetes) and may have one type of diabetes (T1D or T2D); The second group of people in whom gestational diabetes is diagnosed for the first time during pregnancy [25, 26].

### *1.2.2 Diabetes during pregnancy*

Diabetes mellitus is the most common and important metabolic complication in pregnancy that can affect maternal and fetal health [27]. According to studies, diabetes is seen in around 7% of pregnancies and its prevalence depends on the study population and diagnostic tests from 1 Up to 14% have also been reported [24, 28]. Gestational diabetes is one of the leading causes of mortality in pregnant women which can be elevating the risk for spontaneous abortion, stillbirth, congenital malformations, and perinatal morbidity and mortality [29]. It is well documented that maternal glycemic control during pregnancy can markedly decrease congenital malformation outcomes in the fetus. Studies have shown that infants born to diabetic mothers have a higher risk of congenital disorders in the nervous, cardiovascular, kidney, and gastrointestinal tracts [26, 30–32].

### *1.2.2.1 Pathophysiology of gestational diabetes on embryonic development*

In healthy mothers and under normal conditions, pregnancy causes hyperplasia of pancreatic beta cells and increases insulin levels in the mother's bloodstream [33]. On the other hand, at the beginning of pregnancy, insulin sensitivity is observed in pregnant women, which turns into insulin resistance as the pregnancy progresses. Maternal insulin resistance appears to occur due to the production of placental diabetogenic hormones such as growth hormone, placental lactogen, corticotropinreleasing hormone, and progesterone [33, 34]. This insulin resistance decreases after the placenta leaves the mother's body and increases the risk of hyperglycemia in mothers 7 to 15 weeks after delivery [35, 36].

Previous studies have illustrated that increase in the level of maternal blood glucose and a decrease in insulin is the main reason for diabetes during pregnancy [37]. In the above conditions, glucose can easily pass through the placenta into the fetal bloodstream, leading to fetal hyperglycemia. During the first few weeks of pregnancy, fetal islet cells (beta cells) cannot release enough insulin in response to hyperglycemia, which is the main cause of fetal hyperglycemia. In response to this condition, after week 20, the fetal pancreas is stimulated and the pancreatic beta cells begin to hypertrophy and hyperplasia, which eventually leads to increased fetal insulin levels. In addition to impairing the development of various organs, this

### *The Impact of Diabetes on Hippocampus DOI: http://dx.doi.org/10.5772/intechopen.99895*

complication can be followed by hypoglycemia and hyperinsulinemia in the first few days after birth [30, 37–39].

Results from previous experiments have shown that insulin can influence carbohydrate, fats, and protein metabolism, membrane transport of glucose, amino acids, and ion exchange in cells as well as protein and DNA synthesis. In addition, insulin can stimulate or inhibit the activity of certain enzymes and regulate gene expression [40]. On the other hand, alters and reduction of ions transfer can lead to the reduction level of some vital ions such as zinc. Thereby, this process has a negative effect on the migration of marginal layer cells in the fetus of diabetic mothers which increases defects in the central nervous system [41]. In this regard, some studies indicate that high concentrations of beta-hydroxybutyric acid, which occurs in diabetes mothers, can delay the development of the central nervous system of the fetus [42–44].

Although hyperglycemia is believed to be the most important teratogenic element in diabetic pregnancy; Some researchers suggest that changes in maternal metabolic status (i.e., triglyceride and β-hydroxybutyrate levels and branched-chain amino acids) lead to disrupted fetal metabolism of inositol, sorbitol, prostaglandins, and arachidonic acid could have a teratological effect and therefore be important for the incidence of fetal disorders. An excess of fetal reactive oxygen species (ROS) has also been linked to the etiology of congenital malformations induced by diabetes. These free radicals may cause increasing neuronal death by oxidizing proteins, damaging DNA, and inducing the lipoperoxidation of cellular membranes. In vitro and in vivo studies have shown that the disturbed development of embryos in a diabetic milieu can be normalized by treatment with different antioxidant factors [27, 45–47].

### *1.2.3 The effects of gestational diabetes on fetal development and infant health*

It is well documented that fetuses of mothers with diabetes during pregnancy are in a completely different environment than a healthy mother. Glucose, alanine, and free fatty acids are transported in large quantities from the mother's blood to the fetus. As a result, the concentration of insulin in the amniotic fluid increased, which indicates a compensatory response of the fetus to an increase in these factors [48]. Hyperglycemia in the first trimester of pregnancy increases significantly the risk of congenital malformations and stillbirth [49].

Several studies have shown that maternal hyperglycemia during pregnancy causes fetal hyperglycemia and neonatal hypoglycemia; Because circulating glucose simply crosses the placenta by facilitating diffusion, resulting in fetal hyperglycemia [35, 37]. In contrast, to compensate for this event, the fetal pancreas is stimulated and the pancreatic beta cells begin to hypertrophy, which causes increased fetal insulin levels. Due to the inability of the growing beta cells in the pancreas to secrete enough insulin, this condition soon leads to fetal hypoinsulinemia [37, 50]. Although this complication is temporary; However, studies show that fetuses from mothers with diabetes develop hyperinsulinemia in the last trimester of pregnancy. This condition in the fetus, in addition to affecting various organs, puts infants at risk for hypoglycemia in the few first days after birth, which is one of the most important causes of infant mortality in diabetic mothers [51, 52]. Previous studies report that gestational diabetes can increase the risk of impaired fetal and neonatal development, mortality, and also problems in infancy, childhood, and adulthood [31, 32]. Abundant human studies have identified type 1 diabetes during pregnancy as an important factor in the development of fetal and neonatal complications such as stillbirth, fetal macrosomia, respiratory distress syndrome, diabetes, jaundice, asphyxia, hypertension, neonatal hyperglycemia, hypocalcemia and hypomagnesemia, cardiac abnormalities, hypoxia, and neonatal polycythemia [53–55].

Studies have also shown that diabetes can have teratogenic effects and also negative effects on embryogenesis, organogenesis, and fetal growth [56]. The frequency of the mentioned problems is the same for both types of diabetes and the incidence of these complications depends directly on the severity of maternal diabetes [57]. Studies have shown that in gestational diabetes, there is a linear relationship between maternal glucose levels in early pregnancy and the incidence of birth defects [58].
