**3. Cognitive dysfunction related to diabetes**

The negative effects of DM on retinal, renal, cardiovascular, and peripheral nervous systems are widely acknowledged, but less attention has received its effects on cognitive function and neurodevelopment. T1DM and T2DM are associated with reduced performance on numerous domains of cognitive function. The exact pathophysiology of cognitive dysfunction in diabetic patients is not well understood; nonetheless, vascular disease, hyper or hypoglycaemia, and insulin resistance seem to play significant roles [34].

Subjects with T1DM and T2DM can develop several microvascular (nephropathy, neuropathy, retinopathy) and macrovascular (coronary heart disease, peripheral arterial disease, cerebrovascular disease) complications that will contribute to cognitive dysfunction in adults; however, the major cause of mortality and morbidity in children with T1DM is the diabetic ketoacidosis, which cause cerebral injury along with haemorrhage or cerebral infarction in some cases, leading to cerebral edema (**Table 1**) [7, 8, 35].

Cognitive dysfunction in T1DM and T2DM share many similarities, but important differences do exist [7], specifically in the degree of cognitive dysfunction and in the manifestation of cognitive abnormalities [1]. Poorly managed diabetes due to chronic hyper and hypoglycaemia or elevated postprandial glucose may be common aetiological causes of the neurological complications of T1DM and T2DM or cognitive dysfunction [12, 36].

#### **3.1. Type 1 diabetes**

Different studies assessing cognition in children and adolescents with an early onset of diabetes (EOD) (6–7 years) have shown higher risk of developing more severe cognitive deficits, especially impairments in *memory, learning, intelligence* and *verbal fluency/language* [36, 37], as well as in *attention, executive function* [38], *psychomotor speed* [9], *slowing of information processing, problem solving, visuoconstruction, visual perception* and *mental flexibility* [7].

Patients with T1DM often perform within normal cognitive range; however, they may perform more poorly on some cognitive tasks compared to non-diabetic control subjects, such as *executive functions, short-term memory, psychomotor efficiency* and measure of *mental efficiency*, which predispose for more rapid deterioration of cognitive function later in life [1]. Kodl and Seaquist found different cognitive domains negatively affected in T1DM, specifically *information processing\*, psychomotor efficiency\*, attention\*, memory, learning, problem solving, motor speed, vocabulary, general intelligence, visuoconstruction\*, visual perception, somatosensory examination, motor strength, mental flexibility\** and *executive function*. According to the authors the domains

Advanced glycation end products, AGEs; cardiovascular, CV; central nervous system, CNS; high density lipoprotein cholesterol, HDL-c; hypothalamic-pituitary-adrenal, HPA; low density lipoprotein cholesterol, LDL-c. Adapted from

marked by asterisks have strong supporting data [34].

Metabolic factors • Chronic exposure to hyperglycaemia [1]

• Acute exposure to hypoglycaemia [11] • Recurrent exposure to hypoglycaemia [1] • Increased plasmatic concentration of AGEs [34]

• Endothelial dysfunction [17]

• Reduced fibrinolysis [14]

Hypertension [1]

Hyperleptinaemia

• Amyloid disposition

Disease onset • Early onset diabetes (6–7 years old) [9]

McCrimmon RJ, Ryan CM, Frier BM. Lancet, 2012 [7].

• Hyperinsulinaemia

• Impaired HPA axis activity [12] • Absence of C-Peptide [34] • Increased antidiuretic hormone

CNS factors • Genetic predisposition (*Absence of Apoε4 Allele*) [34]

• Increased oxidative stress [11]

• Depression and anxiety [2, 12] • Disrupted myelination [11]

• Dysfunctional synaptic plasticity [1]

• Changes in neuronal calcium homeostasis

• Increased apoptosis in oligodendrocyte precursor cells [11]

**Table 1.** Factors that contribute to the development of cognitive dysfunction in diabetic patients.

Endocrine factors • Insulin resistance [34]

*intercellular adhesion molecule 1*) [34] • Changes in blood–brain barrier permeability

CV factors • Microvascular complications (*nephropathy, neuropathy, retinopathy*) [8]

• Macrovascular complications (*coronary heart, peripheral arterial and cerebrovascular diseases*) [8]

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• Increased inflammatory markers (*C-reactive protein, α-1-antichymotrypsin, interleukin-6 and* 

• Dyslipidemia (*increased total cholesterol, LDL-c and triglycerides, and reduced HDL-c*) [14]


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].

The negative effects of DM on retinal, renal, cardiovascular, and peripheral nervous systems are widely acknowledged, but less attention has received its effects on cognitive function and neurodevelopment. T1DM and T2DM are associated with reduced performance on numerous domains of cognitive function. The exact pathophysiology of cognitive dysfunction in diabetic patients is not well understood; nonetheless, vascular disease, hyper or hypoglycaemia,

Subjects with T1DM and T2DM can develop several microvascular (nephropathy, neuropathy, retinopathy) and macrovascular (coronary heart disease, peripheral arterial disease, cerebrovascular disease) complications that will contribute to cognitive dysfunction in adults; however, the major cause of mortality and morbidity in children with T1DM is the diabetic ketoacidosis, which cause cerebral injury along with haemorrhage or cerebral infarction in

Cognitive dysfunction in T1DM and T2DM share many similarities, but important differences do exist [7], specifically in the degree of cognitive dysfunction and in the manifestation of cognitive abnormalities [1]. Poorly managed diabetes due to chronic hyper and hypoglycaemia or elevated postprandial glucose may be common aetiological causes of the neurological

Different studies assessing cognition in children and adolescents with an early onset of diabetes (EOD) (6–7 years) have shown higher risk of developing more severe cognitive deficits, especially impairments in *memory, learning, intelligence* and *verbal fluency/language* [36, 37], as well as in *attention, executive function* [38], *psychomotor speed* [9], *slowing of information process-*

Patients with T1DM often perform within normal cognitive range; however, they may perform more poorly on some cognitive tasks compared to non-diabetic control subjects, such as *executive functions, short-term memory, psychomotor efficiency* and measure of *mental efficiency*, which predispose for more rapid deterioration of cognitive function later in life [1]. Kodl and

**3. Cognitive dysfunction related to diabetes**

and insulin resistance seem to play significant roles [34].

some cases, leading to cerebral edema (**Table 1**) [7, 8, 35].

**3.1. Type 1 diabetes**

126 Diabetes Food Plan

complications of T1DM and T2DM or cognitive dysfunction [12, 36].

*ing, problem solving, visuoconstruction, visual perception* and *mental flexibility* [7].

Advanced glycation end products, AGEs; cardiovascular, CV; central nervous system, CNS; high density lipoprotein cholesterol, HDL-c; hypothalamic-pituitary-adrenal, HPA; low density lipoprotein cholesterol, LDL-c. Adapted from McCrimmon RJ, Ryan CM, Frier BM. Lancet, 2012 [7].

**Table 1.** Factors that contribute to the development of cognitive dysfunction in diabetic patients.

Seaquist found different cognitive domains negatively affected in T1DM, specifically *information processing\*, psychomotor efficiency\*, attention\*, memory, learning, problem solving, motor speed, vocabulary, general intelligence, visuoconstruction\*, visual perception, somatosensory examination, motor strength, mental flexibility\** and *executive function*. According to the authors the domains marked by asterisks have strong supporting data [34].

Neuroimaging studies have found morphological abnormalities, cortical atrophy, lower grey matter volume and density in left temporal-occipital junction, white matter hyper-intensities and reduced white matter densities, concretely white matter microstructural deficits, as well as neuroanatomical changes in the hippocampal region. However, other studies did not find volumetric changes in the hippocampus [12, 36, 37]. In fact, Ho et al., have reported that measuring subfields of the hippocampus with high resolution magnetic resonance imaging may provide a way to specifically target the neurogenic regions of the hippocampus and may show different effects of diabetes on different parts of the hippocampus. It should be noted that studies carried out in rodents with T1DM have shown reductions in hippocampal cell proliferation and survival, leading to learning and memory deficits compared to control rodents (**Figure 2**) [3].

hypoglycaemia harms neurons in cerebral cortex, medial temporal region, including hippocampus, basal ganglia and brain stem with unknown individual consequences [36]. Hypoglycaemic episodes in T1DM children lead to significant declines in *verbal abilities, memory skills* and *ability to organise* and *recall information*. Severe hypoglycaemia may result in persistent electroencephalography (EEG) changes, with 80% of EEG abnormalities observed in diabetic children with history of severe hypoglycaemia compared with 30% of abnormalities in diabetic subjects without severe hypoglycaemia and 24% in healthy control children [39]. In presence of severe hypoglycaemia in T1DM, children show mildly reduced intelligence

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Children and adults with T1DM have worse performance in executive function, full IQ and motor speed; in presence of hyperglycaemia negative effects on memory function were observed in children. Moreover, higher HbA1c levels were associated with worse *motor speed* and *psychomotor efficiency* [41]. Additionally, chronic hyperglycaemia has been associated with reductions in grey matter volume and multiple posterior brain regions, including the cerebellum. Adolescents with three or more symptomatic hyperglycaemic episodes showed reductions in white matter integrity, specifically in superior parietal lobule, corpus callosum, posterior limb of the internal capsule, and grey matter integrity, concretely in thalamus and putamen, whereas children (4–10 years old) showed microstructural abnormalities in white matter with lower IQ scores [40]. A lifetime exposure to hyperglycaemia reduces occipital/parietal grey and matter volume; after 2 years with T1DM, a reduction in the whole brain grey matter has been observed [11]. Large effects have been observed in T1DM patients regarding *visuospatial ability, motor speed, writing, sustained attention* and

It is worth noting that a late onset of diabetes (LOD) entails several cognitive dysfunctions, although these impairments are less severe compared to those subjects with EOD. In subjects with a LOD, it has been found lower *overall cognition, intelligence, visual learning* and *memory, motor speed* and *visual motor integration, sustained attention* and *executive function* compared to

Finally, several studies have shown that gender influences neurocognitive function in T1DM. In a study with children and adolescents (aged 7–16 years), boys presented decline in *verbal intelligence*, which was correlated with worse GC. This was not seen in girls of similar ages. It should be noted that most human studies do not distinguish between genders when

The prevalence of childhood obesity has increased dramatically worldwide, leading to a variety of health problems, including T2DM, which previously was seen only in adults. The Centres for Disease Control (CDC) and Prevention foresee that the prevalence of T2DM in those under 20 years of age will quadruple in 40 years, assuming a 2.3% annual increase [6]. In the United States, up to 1 in 3 new cases of diabetes diagnosed in subjects younger than 18 years old is T2DM, occurring most commonly in children and adolescents between 10 and

quotient (IQ), as well as adverse effects in general, verbal and performance IQ [40].

*reading* [40, 42].

their healthy siblings [9, 38].

**3.2. Type 2 diabetes**

describing results of neurocognitive testing [34].

Additionally, glycaemic extremes (hyper and hypoglycaemia) affect brain development. Severe hypoglycaemia during a lifetime exposure decreases lateral temporal–parietal-occipital grey matter volume, whereas after 2 years with T1DM showed a greater reduction in the regional white matter volume in the precuneus/cuneus region [11]. Furthermore, severe

**Figure 2.** Effect of glycaemic extremes on the development of congestive dysfunction.

hypoglycaemia harms neurons in cerebral cortex, medial temporal region, including hippocampus, basal ganglia and brain stem with unknown individual consequences [36]. Hypoglycaemic episodes in T1DM children lead to significant declines in *verbal abilities, memory skills* and *ability to organise* and *recall information*. Severe hypoglycaemia may result in persistent electroencephalography (EEG) changes, with 80% of EEG abnormalities observed in diabetic children with history of severe hypoglycaemia compared with 30% of abnormalities in diabetic subjects without severe hypoglycaemia and 24% in healthy control children [39]. In presence of severe hypoglycaemia in T1DM, children show mildly reduced intelligence quotient (IQ), as well as adverse effects in general, verbal and performance IQ [40].

Children and adults with T1DM have worse performance in executive function, full IQ and motor speed; in presence of hyperglycaemia negative effects on memory function were observed in children. Moreover, higher HbA1c levels were associated with worse *motor speed* and *psychomotor efficiency* [41]. Additionally, chronic hyperglycaemia has been associated with reductions in grey matter volume and multiple posterior brain regions, including the cerebellum. Adolescents with three or more symptomatic hyperglycaemic episodes showed reductions in white matter integrity, specifically in superior parietal lobule, corpus callosum, posterior limb of the internal capsule, and grey matter integrity, concretely in thalamus and putamen, whereas children (4–10 years old) showed microstructural abnormalities in white matter with lower IQ scores [40]. A lifetime exposure to hyperglycaemia reduces occipital/parietal grey and matter volume; after 2 years with T1DM, a reduction in the whole brain grey matter has been observed [11]. Large effects have been observed in T1DM patients regarding *visuospatial ability, motor speed, writing, sustained attention* and *reading* [40, 42].

It is worth noting that a late onset of diabetes (LOD) entails several cognitive dysfunctions, although these impairments are less severe compared to those subjects with EOD. In subjects with a LOD, it has been found lower *overall cognition, intelligence, visual learning* and *memory, motor speed* and *visual motor integration, sustained attention* and *executive function* compared to their healthy siblings [9, 38].

Finally, several studies have shown that gender influences neurocognitive function in T1DM. In a study with children and adolescents (aged 7–16 years), boys presented decline in *verbal intelligence*, which was correlated with worse GC. This was not seen in girls of similar ages. It should be noted that most human studies do not distinguish between genders when describing results of neurocognitive testing [34].

#### **3.2. Type 2 diabetes**

**Figure 2.** Effect of glycaemic extremes on the development of congestive dysfunction.

Neuroimaging studies have found morphological abnormalities, cortical atrophy, lower grey matter volume and density in left temporal-occipital junction, white matter hyper-intensities and reduced white matter densities, concretely white matter microstructural deficits, as well as neuroanatomical changes in the hippocampal region. However, other studies did not find volumetric changes in the hippocampus [12, 36, 37]. In fact, Ho et al., have reported that measuring subfields of the hippocampus with high resolution magnetic resonance imaging may provide a way to specifically target the neurogenic regions of the hippocampus and may show different effects of diabetes on different parts of the hippocampus. It should be noted that studies carried out in rodents with T1DM have shown reductions in hippocampal cell proliferation and survival, leading to learning and memory deficits compared to control rodents (**Figure 2**) [3].

128 Diabetes Food Plan

Additionally, glycaemic extremes (hyper and hypoglycaemia) affect brain development. Severe hypoglycaemia during a lifetime exposure decreases lateral temporal–parietal-occipital grey matter volume, whereas after 2 years with T1DM showed a greater reduction in the regional white matter volume in the precuneus/cuneus region [11]. Furthermore, severe

> The prevalence of childhood obesity has increased dramatically worldwide, leading to a variety of health problems, including T2DM, which previously was seen only in adults. The Centres for Disease Control (CDC) and Prevention foresee that the prevalence of T2DM in those under 20 years of age will quadruple in 40 years, assuming a 2.3% annual increase [6]. In the United States, up to 1 in 3 new cases of diabetes diagnosed in subjects younger than 18 years old is T2DM, occurring most commonly in children and adolescents between 10 and

19 years of age [43]. It is difficult to distinguish between T1DM and T2DM in children, given the current obesity epidemic worldwide. The rapid emergence of childhood T2DM means that health professionals have to treat a disease in children, which previously was encountered only in adults. This represents several challenges, because most of diabetes education materials are designed and directed to children with T1DM, but not to T2DM and probably obese patients. Another problem is that most medications used for T2DM have been tested for safety and efficacy in subjects older than 18 years old, because ethical reasons. Therefore, there is scarce scientific data for optimal management of children with T2DM [6, 43].

Neuroimaging studies have shown deficits in hippocampal-based cognitive performance, which may be attributed to changes in brain structure and volume, leading to deficits in *attention, learning* and *memory* [1]. T2DM subjects have similar morphological abnormalities than T1DM patients, such as cortical atrophy and white matter lesions. Moreover, it has been shown a reduction in the microstructural integrity of white matter and grey matter. The reductions in grey matter volumes have been observed in the prefrontal cortex, amygdala and hippocampus [12]. Additionally, greater cortical atrophy, more lesions in deep white matter and hippocampal (susceptible to acute metabolic changes, such as hypoglycaemia) atrophy,

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Hippocampal atrophy is one of the neuroanatomical characteristics that differs between people with T1DM and T2DM, both have reduced grey matter density and white matter lesions. Nevertheless, cortical atrophy is more pronounced in T2DM, possibly because the subjects are older on average. Moreover, the hippocampus is more affected in T2DM, is unclear why, because this area is susceptible to acute metabolic change, which is more prominent in T1DM. This suggests that age, sex, the associated comorbidities and the presence of macrovascular disease or insulin resistance might be important risk factors for hippocampal atrophy (**Figure 2**). T2DM subjects perform worse than healthy control on learning and memory tests, unlike those with T1DM, who rarely have deficits in these domains [7]. However, the results are inconclusive, because other studies have found deficits in *learning* and *memory* in T1DM patients, but Kodl and Seaquist confirmed that there is no strong evidence to suggest this [34].

**4. Glycaemic index and dietetic management in diabetic children and** 

symptoms. This is called *'hypoglycaemia unawareness'* [6].

At present, nutritional interventions, physical activity and weight control remain the main pillars of effective diabetes management. Despite modern approaches to intensive insulin therapy and other drugs for the management of diabetes, dietary management remains as the main important action of diabetes treatment [48]. There is not an ideal nutritional intervention for the management of diabetes. A poor GC in subjects with T1DM and T2DM has been related with the onset of diabetes complications. Therefore, it is vital to develop new strategies in order to maintain a good GC. Current standards for diabetes management reflect the need to lower glucose as safely as possible, without increasing the risk or hypoglycaemic episodes. It should receive special consideration the risk of hypoglycaemia in young children (aged <6 years or EOD), because usually they are unable to recognise and/or manage the

There are different dietetic approaches aimed at the improvement of the GC in children and adolescents with T1DM and T2DM, among them it is worth noting low GI diets, diets rich in antioxidants, carbohydrate exchange diets, high-cereal fibre diet, traditional Mediterraneanstyle dietary pattern, low carbohydrate Mediterranean style diet, low carbohydrate diets and

**adolescents**

low fat diets.

leading to impairments in *immediate memory*, have been observed (**Figure 2**) [7].

The comorbidities, such as obesity, hypertension and dyslipidaemia, may be present at the time of diagnosis in youth with T2DM, which contribute to the severity of the disease. The cause of diabetes-related cognitive dysfunction is difficult to establish, because of the prevalence of several comorbidities in the same individual, which might affect cognitive function [6, 7].

Lamport et al. [44], performed a systematic review in adults, concluding that T2DM is associated with cognitive impairments. In the present longitudinal review we found many studies relating an accelerated cognitive decline in adults with T2DM; however, it is difficult to conclude that these reported cognitive impairments are independently associated to abnormalities in glucose tolerance or due to the associated comorbidities present in these patients (cerebrovascular and cardiovascular diseases, obesity, hypertension and hypercholesterolemia) [44]. Some studies suggest that cognitive performance does not differ in T2DM subjects in relation to non-diabetic controls when it is taken into account the influence of age, premorbid IQ, BMI and depression [1]. Unlike the studies in T1DM patients, most studies suggest that T2DM subjects experience cognitive decline. T2DM most often is associated with deficits in cognitive domains, *declarative memory, attention* and *executive function*, alterations also seen in children and adolescents with Metabolic Syndrome or obesity and glycaemic disorders [45, 46]. The GC, the disease duration and cerebrovascular complications are considered risk factors that influence the magnitude of the cognitive decline [12]. *Learning* and *memory* deficits are the cognitive abnormalities that most clearly differentiate patients with T2DM from T1DM patients [7].

Kodl and Seaquist, established that the cognitive domains that are negatively affected in adults with T2DM are *memory\* (verbal memory, visual retention, working memory, immediate recall, delayed recall), psychomotor speed\*, executive function\*, processing speed, complex motor function, verbal fluency, attention* and it seems to be related with the development of diabetes. According to the authors, the domains marked by asterisks have strong supporting data [34]. Additionally, Sweat et al., in a study carried out in 162 adolescents (aged 19.53 ± 1.53 years), found that obese adolescents showed slower *processing speed* maintaining equivalent *executive functioning* compared with their healthy siblings [46]. Whereas, a recent systematic review performed Barkin et al., showed a consistent inverse association between obesity and *executive function* in children and adolescents, emphasising that in future research is necessary to use a standardised method of *executive function* measurement in order to establish causality with obesity and develop new and more effective intervention strategies [47].

Neuroimaging studies have shown deficits in hippocampal-based cognitive performance, which may be attributed to changes in brain structure and volume, leading to deficits in *attention, learning* and *memory* [1]. T2DM subjects have similar morphological abnormalities than T1DM patients, such as cortical atrophy and white matter lesions. Moreover, it has been shown a reduction in the microstructural integrity of white matter and grey matter. The reductions in grey matter volumes have been observed in the prefrontal cortex, amygdala and hippocampus [12]. Additionally, greater cortical atrophy, more lesions in deep white matter and hippocampal (susceptible to acute metabolic changes, such as hypoglycaemia) atrophy, leading to impairments in *immediate memory*, have been observed (**Figure 2**) [7].

19 years of age [43]. It is difficult to distinguish between T1DM and T2DM in children, given the current obesity epidemic worldwide. The rapid emergence of childhood T2DM means that health professionals have to treat a disease in children, which previously was encountered only in adults. This represents several challenges, because most of diabetes education materials are designed and directed to children with T1DM, but not to T2DM and probably obese patients. Another problem is that most medications used for T2DM have been tested for safety and efficacy in subjects older than 18 years old, because ethical reasons. Therefore,

The comorbidities, such as obesity, hypertension and dyslipidaemia, may be present at the time of diagnosis in youth with T2DM, which contribute to the severity of the disease. The cause of diabetes-related cognitive dysfunction is difficult to establish, because of the prevalence of several comorbidities in the same individual, which might affect cognitive function

Lamport et al. [44], performed a systematic review in adults, concluding that T2DM is associated with cognitive impairments. In the present longitudinal review we found many studies relating an accelerated cognitive decline in adults with T2DM; however, it is difficult to conclude that these reported cognitive impairments are independently associated to abnormalities in glucose tolerance or due to the associated comorbidities present in these patients (cerebrovascular and cardiovascular diseases, obesity, hypertension and hypercholesterolemia) [44]. Some studies suggest that cognitive performance does not differ in T2DM subjects in relation to non-diabetic controls when it is taken into account the influence of age, premorbid IQ, BMI and depression [1]. Unlike the studies in T1DM patients, most studies suggest that T2DM subjects experience cognitive decline. T2DM most often is associated with deficits in cognitive domains, *declarative memory, attention* and *executive function*, alterations also seen in children and adolescents with Metabolic Syndrome or obesity and glycaemic disorders [45, 46]. The GC, the disease duration and cerebrovascular complications are considered risk factors that influence the magnitude of the cognitive decline [12]. *Learning* and *memory* deficits are the cognitive abnormalities that most clearly differentiate patients with T2DM from

Kodl and Seaquist, established that the cognitive domains that are negatively affected in adults with T2DM are *memory\* (verbal memory, visual retention, working memory, immediate recall, delayed recall), psychomotor speed\*, executive function\*, processing speed, complex motor function, verbal fluency, attention* and it seems to be related with the development of diabetes. According to the authors, the domains marked by asterisks have strong supporting data [34]. Additionally, Sweat et al., in a study carried out in 162 adolescents (aged 19.53 ± 1.53 years), found that obese adolescents showed slower *processing speed* maintaining equivalent *executive functioning* compared with their healthy siblings [46]. Whereas, a recent systematic review performed Barkin et al., showed a consistent inverse association between obesity and *executive function* in children and adolescents, emphasising that in future research is necessary to use a standardised method of *executive function* measurement in order to establish causality with

obesity and develop new and more effective intervention strategies [47].

there is scarce scientific data for optimal management of children with T2DM [6, 43].

[6, 7].

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T1DM patients [7].

Hippocampal atrophy is one of the neuroanatomical characteristics that differs between people with T1DM and T2DM, both have reduced grey matter density and white matter lesions. Nevertheless, cortical atrophy is more pronounced in T2DM, possibly because the subjects are older on average. Moreover, the hippocampus is more affected in T2DM, is unclear why, because this area is susceptible to acute metabolic change, which is more prominent in T1DM. This suggests that age, sex, the associated comorbidities and the presence of macrovascular disease or insulin resistance might be important risk factors for hippocampal atrophy (**Figure 2**). T2DM subjects perform worse than healthy control on learning and memory tests, unlike those with T1DM, who rarely have deficits in these domains [7]. However, the results are inconclusive, because other studies have found deficits in *learning* and *memory* in T1DM patients, but Kodl and Seaquist confirmed that there is no strong evidence to suggest this [34].
