Review

Mens Sana in Corpore Sano: Does the Glycemic Index

Have a Role to Play?
Lionel Carneiro 1,* and Corinne Leloup 2
1 Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH 43210, USA
2 Centre des Sciences du Goût et de l’alimentation, UMR CNRS 6265, INRA 1324, AgroSup,
Univ. Bourgogne Franche-Comté, F-21000 Dijon, France; corinne.leloup@u-bourgogne.fr
* Correspondence: lionel.carneiro@osumc.edu

Received: 4 September 2020; Accepted: 27 September 2020; Published: 29 September 2020

Abstract: Although diet interventions are mostly related to metabolic disorders, nowadays they are
used in a wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, to
cancer or neurological disorders and stroke, nutritional recommendations are applied to almost all
diseases. Among such disorders, metabolic disturbances and brain function and/or diseases have
recently been shown to be linked. Indeed, numerous neurological functions are often associated
with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in
various neurological conditions, such as epilepsy, stroke, or seizure recovery. In addition,
Alzheimer’s disease and Autism Spectrum Disorders are also considered to be putatively improved
by diet interventions. Glycemic index diets are a novel developed indicator expected to anticipate
the changes in blood glucose induced by specific foods and how they can affect various
physiological functions. Several results have provided indications of the efficiency of low-glycemic
index diets in weight management and insulin sensitivity, but also cognitive function, epilepsy
treatment, stroke, and neurodegenerative diseases. Overall, studies involving the glycemic index
can provide new insights into the relationship between energy homeostasis regulation and brain
function or related disorders. Therefore, in this review, we will summarize the main evidence on
glycemic index involvement in brain mechanisms of energy homeostasis regulation.

Keywords: cognition; nutrition; metabolism; neurodegeneration; ketone bodies; glycemia; nutrition

therapy

1. Introduction
Nutrition has been part of the treatment employed for diabetes and obesity for decades.
Therefore, specific food choices to help control weight and glucose homeostasis represent an
important step in the establishment of a suitable diet. To assist patients, Jenkins et al. established the
glycemic index (GI) concept in 1981 [1]. GI measures the impact of an individual food on the blood
glucose level over time when compared to the effect of glucose itself (GI = 100). The glycemic response
will thus depend on both the quantity and quality of carbohydrates (sugars, starch, or fibers) in the
food. Consequently, a low-GI food (GI ≤ 55) contains high-quality carbohydrates and will not raise
glycemia as much as a high-GI food (GI ≥ 70) for the same amount of carbohydrate. However, since
the GI does not consider the amount of carbohydrate ingested, a glucose load (GL) value was
developed. Thereby, GL represents a product of GI (quality of carbohydrate) and the quantity of
carbohydrate ingested. Low GL is considered to be below 10, while high GL is above 20 when 10 g of
glucose has a GL of 10 (Table 1).

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Nutrients 2020, 12, 2989 2 of 32

Table 1. Example of common foods with their corresponding serving size in g, glycemic index (GI) carbohydrates per serving size in g, and the resulting glucose
load (GL).

Serving Carbohydrates Per Serving Carbohydrates Per Serving Carbohydrates Per

Food GI GL Food GI GL Food GI GL
Size (g) Serving (g) Size (g) Serving (g) Size (g) Serving (g)
Tuna 100 0 0 0 Fructose 10 23 10 2 Wheat 200 45 137 62
Salmon 100 0 0 0 Blackberry 60 25 4 2 Carrot Juice 250 45 24 11
Pineapple
Sardine 100 0 0 0 Grapefruit 120 25 11 3 250 46 33 15
Juice
Mackerel 100 0 0 0 Milk, full fat 250 27 12 3 Banana 120 47 24 11
American
Crab 85 0 0 0 28 27 2 <1 Lasagna 125 47 19 9
Cheese
Eggs
50 0 1 0 Cottage 28 27 6 2 Penne 125 47 94 44
(chicken)
Chickpeas,
Beef 100 0 0 0 150 28 30 8 Butter 5 50 0 0
boiled
Chicken 140 0 6 0 Lentil 200 28 40 11 Mayonnaise 15 50 0 0
Goat 30 0 0 0 Beans, kidney 150 28 25 7 Mango 120 51 15 8
Pork 85 0 0 0 Garlic 3 30 1 <1 Tortilla 50 52 24 12
Vanilla
Lamb 85 0 1 0 4 30 3 0 Blueberry 150 53 18 7
extract
Ham 85 0 0 0 Buttermilk 245 31 12 4 Kiwi fruit 150 53 16 9
Turkey 85 0 0 0 Lime 67 32 7 <1 Date 60 54 33 21
Duck 140 0 0 0 Broccoli 80 32 4 1 Orange juice 250 55 26 14
Rabbit 85 0 0 0 Artichoke 150 32 14 4 Corn, Sweet 150 55 32 18
Cranberry
Macadamia 28 10 4 <1 Cauliflower 100 32 5 2 250 55 33 18
Juice
Pecan 28 10 4 <1 Green Bean 55 32 4 1 Honey 25 55 20 11
Almond 28 10 6 <1 Asparagus 130 32 5 2 Brown Rice 150 55 33 18
Mushrooms 75 10 4 1 Radish 100 32 7 2 Ketchup 17 55 5 3
Cabbage 80 10 5 1 Mustard 5 32 1 <1 Apricots 120 57 9 5
Peanut
55 14 5 6 Milk, skim 250 32 13 4 Potato 75 60 12 7
Butter
Peanut 28 14 6 1 Raspberries 150 32 8 3 Coca-Cola 250 60 26 16
Avocado 80 15 3 1 Ice cream 250 32 3 1 Fig (dried) 100 61 26 16
Zucchini 120 15 4 1 Pear 120 33 13 3 Beetroot 80 64 8 5
Cucumber 80 15 4 0 Apricot 120 34 9 3 Cantaloupe 120 65 6 4
Eggplant 100 15 6 2 Low Fat Milk 250 35 13 5 Sucrose 10 65 10 7
Tomato 100 15 4 1 Carrot 60 39 6 2 White rice 150 65 35 23
Nutrients 2020, 12, 2989 3 of 32

Couscous,
Celery 80 15 2 1 Plums 150 39 15 6 150 65 35 23
boiled
Lettuce 100 15 3 1 Apple 120 40 16 6 Pineapple 120 66 10 6
Spinach 100 15 4 1 Orange 120 40 11 4 Sweet potato 130 70 17 12
Onion 10 15 1 <1 Strawberry 120 40 3 1 Crepe 30 71 7 5
Hazelnuts 28 15 5 <1 Pepper 2 40 1 <1 White bread 30 71 13 10
Whole wheat
Red wine 150 15 4 <1 Apple Juice 250 40 30 12 30 71 13 13
bread
White wine 150 15 3 <1 Squash 80 41 30 8 Watermelon 120 72 6 4
Ginger 11 15 2 <1 Peach 120 42 11 5 Bagel 70 72 30 22
Yogurt, low Beans, black-
200 15 9 1 150 42 30 13 Goat milk 244 72 11 8
fat eyed
Soybean 190 16 56 9 Coconut 100 42 17 7 Rutabagas 385 72 33 24
Pistachios 28 18 8 1 Spaghetti 125 42 94 40 Popcorn 30 72 16 12
Walnut 28 20 4 1 Chocolate 28 43 16 7 Pumpkin 100 75 4 3
Cherries 100 20 16 5 Tagliatelle 125 44 90 40 Cornflakes 50 85 42 36
Lemon 60 20 5.5 1 Cranberry 110 45 8 1 Baguette 30 95 11 15
Pea 100 22 14 3 Endive 100 45 3 1 Glucose 10 100 10 10
Blue indicates low, orange indicates medium, and green indicates high GI or GL (www.glycemicindex.com) [1].
Nutrients 2020, 12, 2989 4 of 32

In fact, low-GI foods are digested and absorbed slowly compared to high-GI foods. Therefore,
low-GI foods induce a limited increase in blood glucose that lasts for an extended period. Conversely,
high-GI foods are easily digested and absorbed, and induce a rapid and high increase in blood
glucose, followed by insulin secretion that often leads to transient hypoglycemia (Figure 1) [2,3].

Figure 1. Schematic diagram of the influence of GI or GL on blood glucose (left axis) or insulin (right
axis). Low vs. medium vs. high GI or GL and their corresponding value range are indicated.

Diet interventions are used in physiological conditions, and are also used in sports for weight
management, to lose fat mass or gain lean mass. In addition, metabolic disorders are commonly
associated with nutritional recommendations to induce weight loss, control glucose levels, or manage
dyslipidemia [4]. Most notably, specific diets have also been used in non-metabolic conditions for
centuries. For instance, epilepsy treatment has included a ketogenic diet (KD) for almost 100 years
[5]. Interestingly, specific diets are used in cancer, cognitive improvement, neurological disorders,
and mental diseases [6–9]. Most of the diets involved are characterized by a low carbohydrate content
or low-GI food. Although GI and GL are determined for individual foods, diets based on these values
have been developed, as well as methods of evaluation of GI/GL meals [10,11]. Therefore, the diets
used in medical nutrition therapies are expected to be low-GI diets. In fact, the impact of a meal on
glycemia is likely to be a key factor in disease development. Indeed, since glucose represents the main
source of energy for our body in a healthy state, a disturbed glucose supply will alter the normal
function of cells.
The brain represents 2% of the body weight, while it is the main glucose consumer (20%) in
humans [12]. Therefore, brain control of the glucose supply is finely regulated by the brain itself.
Indeed, the brain possesses the ability to sense glucose levels and to trigger an adaptive response
when glucose levels are low. Then, the brain will stimulate food intake or glucose production by
peripheral organs. This will maintain a constant energy supply for brain activity [13]. Therefore, brain
glucose detection is a key mechanism for both brain activity control and energy homeostasis
regulation. The brain plays a central role in the maintenance of energy homeostasis of the whole
body. Moreover, nutrient sensing is one of the most regulated mechanisms and involves specific
regions such as the hypothalamus [14]. Among the nutrients sensed, glucose is the most studied and
characterized [15]. Since the GI impacts the blood glucose level, the composition of meals based on
GI is expected to involve the brain circuits of glucose sensing. Moreover, low-GI diets are also prone
Nutrients 2020, 12, 2989 5 of 32

to an increased production of ketone bodies since they are low in carbohydrates [8]. Finally, the
carbohydrate composition of a meal induces changes in gut microbiota and in signals involved in
food intake regulation and neurological disorders [16]. Overall, by involving key signals of both
metabolic regulations and neuronal functions, GI diets can improve cellular and whole-body
metabolism via brain regulation. Indeed, recent reports demonstrate a clear relationship between
brain function and energy homeostasis. For instance, Alzheimer’s disease (AD) shows metabolic
defects, including glucose uptake deficiency in the brain, insulin resistance, and even food intake
alterations [17,18]. Furthermore, neurodegeneration is also associated with metabolic impairment
and diabetes [19,20].
Although low-GI diets have been developed to help diabetic people to manage their body
weight and glycemia, numerous effects on brain function have also been described. Therefore, the
cognitive function (memory, attention, etc.) in healthy people, as well as improvements in the brain
function of patients with brain dysfunctions, have been measured in relation to diets. Autism
Spectrum Disorders (ASD), epilepsy, neurological disorders, and seizures have all been tested and
displayed interesting results.
Therefore, in this review, we aim to present the current understanding of the effect of diets and
their GI/GL on brain functions, including cognition and energy homeostasis regulation. Furthermore,
the mechanisms involved will be described. Indeed, common mechanisms in both cognition and
energy sensing can provide new insights to develop novel therapeutic approaches in diseases
associated with these functions. Finally, learning about the mechanisms involved should help us
understand the relationship between metabolism and neurological function. The results presented
here were obtained from PubMed and Web of Science research using combinations of the following
key words: brain, neurodegenerative disease, energy homeostasis, cognition, glucose load, glycemic
index, and nutrition. Such an understanding is of great importance for developing novel nutritional
approaches for disease treatment, in addition to generating new nutritional recommendations for
healthy people.

2. Effect of a Glycemic Index Diet on Brain Function

Several studies have highlighted the role of a low-GI diet in insulin sensitivity, vascular system
function, and weight management [21]. Recommendations in diabetic patients to help control their
blood glucose level represent one of the most important applications of GI/GL indexes, despite some
caveats in their interpretation. Besides this metabolic role, diets are used in neurodegenerative
disorders, cancer, and even seizures. Such diet interventions started to gather interest following the
discoveries of the influence of nutrients on brain function and notably on cognition, brain plasticity,
and synaptic function, among others [9]. More recently, studies on the effects of specific diets on brain
function gave rise to new evidence on the importance of nutrition in alterations and thus
improvements. Low-GI diets have been used to ameliorate cognitive function, but also improve
several pathological symptoms observed in specific neurological disorders, from dementia and
depression, to ASD and AD (Table 2) [7].
Nutrients 2020, 12, 2989 6 of 32

Table 2. Example of various diets’ composition for macronutrients with some examples of common foods associated with them. The low-GI diet highlighted in green is
taken as a reference for a healthy diet.

Low High
Regular Modified
GL Keto Diet MCT Diet Japanese Diet Mediterranean Diet Low GI Diet Western Diet High GI Diet GL
Diet Keto Diet
Diet Diet
Carbohydrates 45% 45–55% 5–10% 15% 5–10% 45–55% 50–60% 15–20% 50% 45% 55%
30% MCTs
Fat 35% 20–35% 70–75% 55% 30% LCFA 20–35% 25–35% 60% 35% 35% 30%
10–15% others
Proteins 20% 10–35% 20–25% 30% 20–25% 10–35% 5–25% 20–25% 15% 30% 15%
Kcal 2200 2200 2200 2200 2200 ~80% of regular 2200 2200 ~120% of regular 2200 2200
Fresh food, Low carbs food, High Keto diet with Keto diet Fish, Fruits, Olive oil, fruits, vegetables Low GI foods Junk foods, processed High GI food,
low high
low Fat, fish, meat, eggs, increased enriched in MCT seasonal food, and legumes, low amount of enriched, high food with added low non
Food GL GL
processed vegetables, fruits, nuts, amount of rich food such as green tea, soy, rice meat and fish, moderate non digestible sugar, saturated fats, digestible
foods foods
food berries… carbs coconut oil (brown)… wine fibers… high GI food… fibers
The low-GI diet highlighted in green is taken as a reference for a healthy diet.
Nutrients 2020, 12, 2989 7 of 32

Indeed, since glucose represents the main energy source for the brain, glucose level control
appears critical for maintaining normal brain activity. Furthermore, neurological disorders are often
associated with changes in neuronal activity, which can be targeted by modifying the availability of
energetic substrates [22]. Nevertheless, diets can also be used in healthy people in a non-metabolic
context. Indeed, different attempts to find out how to improve health through diet have been tested
for decades in terms of physical activity, memory, and attention [23].

Effect of the Glycemic Index on Cognitive Function in Healthy People

Normal life requires a balanced diet with adapted macro- and micronutrients to maintain
optimal cellular functions. Among other factors, cognition is likely to be altered by diet due to the
high energy needs of the brain. Furthermore, the poor feeding habits of modern societies can very
much alter normal cognitive function in healthy people. Therefore, a healthy diet can benefit healthy
people and unhealthy populations. Aging, for instance, is often accompanied by cognitive decline.
Therefore, determining the effects of dietary habits on cognition could be important for delaying
aging-related declines. In this regard, the study of cognition in healthy elderly populations has tried
to determine the role of GI/GL.
A recent study revealed that a low-GL diet contributes to maintaining a better cognitive function
in the elderly. This result, along with others, support the role of GI/GL during the aging process
(Table 3) [24–26]. Furthermore, these studies show either a decreased risk of dementia or AD
occurrence. These observations confirm a negative effect of Western diets on cognition, which has
been previously documented [27–29]. However, the study of Garber et al. indicates that only people
with poor glucose regulation display a positive effect of GL [30]. High fat associated with high GI has
been shown to induce insulin resistance, while the same fat content with a low GI improved insulin
sensitivity [31]. Therefore, here, it is possible that the effects observed are due to insulin sensitivity
improvement. Indeed, insulin is known to participate in cognitive function [32]. Furthermore, the
improvement of glucose homeostasis could improve the energy supply to the brain and thus
cognitive function.
Overall, the results presented do not completely address a role in healthy people since the effects
observed are those on low glycemic control people. In support of that, previous analyses performed
in younger populations over the past years have failed to give a precise answer on the effect of GI/GL
on cognition in healthy people. In fact, a meta-analysis and study conducted by Philipou et al.
revealed discrepancies in the results obtained on the role of GI/GL in cognition in healthy persons
[33,34]. Such observations make it difficult to draw a conclusion on the relationship between GI/GL
and cognition in healthy people (Table 3).
Younger populations of schoolchildren could also be targeted by diet adjustments to improve
learning and memory functions. Indeed, different studies on adolescents have described a positive
relationship between the GI/GL of breakfast meals and cognition through improving learning, but
also attention, stress, and even mood [35–40]. Here, schoolchildren were divided into low- or high-
GI breakfasts or no breakfast at all. Then, cognitive tasks were used to test the ability of the diets to
inhibit cognitive interference (Stroop test [41]), memory tasks, focus, learning and mood, hunger and
thirst, and fatigue in adolescents.
It was previously shown that adolescents who consume breakfast exhibit improved cognitive
function compared to those who do not consume breakfast [42]. The higher glucose supply was then
expected to help maintain the better performance displayed in the cognitive tests. This result confirms
previous results discussed in the elderly. Nonetheless, introducing low- and high-GI breakfast
groups to a breakfast omission group provides a more precise picture on the putative mechanism
involved. Thereby, both low- and high-GI breakfasts show improved adolescent cognition compared
to the group without breakfast. Such a result supports the need of an energy supply for brain
function. Moreover, low-GI breakfasts are more effective in these improvements than high GI
breakfasts. This greater improvement related to low-GI breakfasts is also associated with lower
glycemic and insulinemic responses. In fact, a high-GI breakfast group presented the lowest reaction
time during the Stroop test. However, this increase in reaction was to the detriment of accuracy,
Nutrients 2020, 12, 2989 8 of 32

which was significantly better in the low-GI group. Furthermore, this gain of accuracy was better
maintained across the morning [38]. Finally, low-GI breakfast children display better results in
cognitive tests assessing their working memory, as well as attention (Table 3).
All of these studies support the role of glucose in cognition improvement since both low- and
high-GI breakfasts are beneficial compared to no breakfast. However, since a low-GI breakfast gives
better results than a high-GI breakfast, the role of a high circulating glucose level in such an
improvement is disputed [43]. Indeed, since a low-GI meal induces a lower increase in blood glucose
compared to a high-GI meal, a high glucose level cannot be the main or only contributor [38]. In a
previous study, a breakfast with low GI and high GL gave better results in terms of cognitive
improvement than a low-GI/low-GL breakfast [37]. This result indicates that the energy intake is as
important as the origin, which in this study, mainly came from carbohydrates. Therefore, high- or
low-GL diets differ by the amount of carbohydrate. However, low-GI/low-GL and low-GI/high-GL
diets contain the same amount of total energy (twice that of low-GL diets). Furthermore, high GL
induces a more important increase in the glucose level than high GI. Interestingly, the cortisol level
was higher in the high-GI group, suggesting that low GI could protect against the stress response
(cognitive tests in the study). Finally, the authors also reported that adolescents fed the high-GL meal
felt more confident, less sluggish, and less hungry or thirsty before the tests. The low-GI fed group,
on the other hand, were happier, more alert and less nervous and thirsty before the tests. Previous
research supports the findings of Micha et al., showing improved alertness and decreased fatigue
following a low-GI/high-GL breakfast [44]. However, even so, cognitive test results are not affected
by GL, since the observed effects were similar in all groups. This observation confirms the results
mentioned above indicating that a high glucose level is not the main vehicle of cognition
amelioration. Moreover, the glucose increase measured could suggest stimulation of the
hypothalamic–pituitary–adrenal axis. In turn, this activation would result in the increased cortisol
level measured. This loop would then serve as an anticipatory response to a stress [37]. Consequently,
this decreased stress will contribute to the improved results obtained during the cognitive tests.
Interestingly, a low blood glucose level after a fast alters the hypothalamic–pituitary–adrenal axis
[45]. Low GI could then be responsible for lowering the cortisol level by inducing a lower blood
glucose level. During a learning and memory task, this effect could represent an advantage for both
memorizing and recalling (Table 3).
Nutrients 2020, 12, 2989 9 of 32

Table 3. Summary of human studies on diet effects on cognitive function in different neurological conditions.

Group Diet Method Results Limitation Ref

Correlation between GI and Improved cognition in blood Different diets, background, food habits,
Cognitive Healthy
No specific diet cognitive score both assessed glucose regulation defect medical history [26–28,32]
Elderly
via questionnaire people Questionnaire assessment of cognition only
Low GI breakfast vs High GI Cognitive test for learning Schoolchildren tested only during the
Low GI improves cognition
breakfast vs no breakfast and memory, accuracy and morning for the GI breakfast.
Schoolchildren and accuracy and decrease [37–43,46]
Low GI/low GL vs low GI/high GL vs speed score, stress, hunger No effect measured after lunch or on a long
stress
high GI/low GL vs high GI/high GL and thirst assessment time period.
Correlation between the GI
Only study, group compared to elderly
Adults No specific diet of the diet and cognitive No effect [47]
No adults group with high GI diet
score
Pediatric patients, number of 50% decrease in the number
Epilepsy KD, modified KD, low GI [8,48]
seizure of seizure
Decreased risk of stroke with
Vegetarian diets, Mediterranean diet vegetarian diets
Stroke Stroke occurrence [49–55]
High GI/GL diet Poor outcome following
stroke with High GI/GL
High GI associated with
Observational studies,
High GI Diet, accumulation of Aβ
Post mortem brain analysis, No interventional studies, no controlled
Alzheimer’s disease Low GI, healthy diet, KD, MCT diet, Healthy diet decrease Aβ, [56–59]
memory test diet, no longitudinal studies, no mechanistic
Mediterranean diet improves memory and
studies, only hypothesis
verbal communication
Parkinson’s disease Japanese diet PD rate Low PD rate [60,61]
High GI increase ASD
Autism Spectrum Animal studies, social
High GI or low GI diet phenotype while low GI [62–65]
Disorder behavior analysis
improve social behavior
Depression and Rate of disease in a Increased depression and
High GI/GL [66]
Anxiety population anxiety rate
Nutrients 2020, 12, 2989 10 of 32

According to studies in both adolescent and older populations, the glucose level and the source
of carbohydrates are important in cognition, memory, and mood. However, healthy young
populations display a strong effect, while the elderly only present a positive effect of a low-GI diet in
groups with poor glucose regulation. It is possible that aging alters the sensitivity to GI/GL.
Moreover, elderly studies have been conducted via questionnaires. This means that there could have
been a large variety of meals, as well as nutritional habits, within the group studied. This could have
influenced the results observed. Finally, it is worth noting that the elderly are cognitively healthy,
but can display other medical histories and medications that could alter the real impact of diet on
cognition. A longitudinal study should help determine how a specific dietary habit followed for a
long time period will impact cognition in healthy populations. Additionally, the selection of healthy
participants could help determine the effect on the development of age-related diseases, including
cognitive deficits. To date, there is no study on the impact of a GI diet on cognition, mood, or memory
in an adult population exhibiting healthy conditions. Furthermore, the role of the glucose supply in
brain activity is supported by the demonstration of blood glucose level variation, depending on a
mental task and emotion in younger adults (≈25 years) [46]. More recently, younger adults (18–23
years old) and older adults (65 to 85 years old) were tested for memory recognition after a glucose or
placebo injection. Only the older group showed an improvement in cognition. However, as
previously mentioned, this population displays poor glucose control [67]. Overall, it is suggested that
the glucose supply is still critical for maintaining a normal brain function, as shown by a decreased
blood glucose level during high brain activity [46,68]. In addition, a higher cognitive decline in people
with poor blood glucose control or insulin resistance was previously observed [47] (Table 3).
It is worth noting that Philippou et al. failed to draw a conclusion on the consensual effect of GI
on cognition in their review [33]. Nevertheless, in regard of the key role of the blood glucose level in
cognition, GI values can still be important. In fact, in previous studies, the task or parameter analyzed
(recognition, learning, memory, mood, accuracy, etc.) and the population studied (different ages,
ethnicities, and health conditions) could have affected the results, making comparisons difficult.
Finally, the meal composition and time of the experiment (morning vs. noon vs. evening) are also
important parameters that change between studies. Despite all of these issues, the review by
Philippou et al. helps us make assumptions about possible mechanisms by which GI affects cognition.
First, it is suggested that the blood glucose concentration, rather than the amount provided,
influences memory enhancement. Therefore, since high GI induces a transient increase in blood
glucose, while a low GI leads to a more sustained increase, although lower, a low GI is more likely to
induce long-term effects [43,69,70]. In support of that, it has been described that the GI enhancement
of cognition appears in the post prandial phase following a meal [43,69,70]. Another putative
mechanism involves insulin that is affected by GI and plays a role in cognition. Indeed, insulin
resistance alters this role in cognition regulation [71], while low GI improves the insulin sensitivity
and should thus improve cognition [72]. Cortisol is another hormone involved in cognitive function
modulation via the above-mentioned hypothalamic–pituitary–adrenal axis stimulation induced by a
lower blood glucose level due to low-GI food [37]. Consequently, low GI is associated with a decrease
in the stress response, triggering improved results in cognitive tasks (Table 3).
Altogether, it is difficult to conclude a clear effect of GI on cognition. Nevertheless, the
schoolchildren studies gave the most solid results. Indeed, the results are interesting since GI and
nutritional approaches could be important in childhood and during learning processes. Therefore,
efforts need to be made to better understand the impact of nutrition on cognition. This knowledge
would be useful for setting up new nutritional recommendations for children. Finally, the studies
presented so far do not address in depth the mechanisms involved in cognition and the role of GI/GL.
However, pathological studies have allowed the effects of diet on brain function to be tested with
more attention.

3. Low-GI Diet and Neurological Dysfunctions

The previous studies are somewhat confusing and difficult to interpret, in addition to providing
very little insight on the mechanisms involved. Interestingly, brain dysfunction research generates
Nutrients 2020, 12, 2989 11 of 32

more information on the nutritional impact on brain function. Indeed, nutrition therapies used in
brain dysfunctions have presented promising results in improvement of the pathology. Therefore,
several reports on epilepsy, seizure, ASD, AD, and others have studied brain function after diet
interventions. It should be noted that these studies have also permitted hypotheses on the
mechanisms involved to be drawn. Therefore, such research could provide greater insights on the
mechanisms in play in neurological diseases and metabolic regulation.

3.1. Epilepsy
Epilepsy has been associated with a ketogenic diet (KD) intervention for a long time [5]. KD is a
low-carbohydrate and high-fat diet. Additionally, because of its side effects (ketoacidosis,
hyperlipidemia, and hypoglycemia), other diets have been tested more recently (Table 2). Most of
these diets are modified KDs with more carbohydrates, including a low-GI diet [73]. Overall, these
diets have been shown to decrease the number of seizures in pediatric patients by at least 50% [74]
(Table 3). Several attempts to elucidate the mechanisms in play have led to different hypotheses
involving ketone bodies, mitochondria, or gene regulation. In these diets, the decrease in
carbohydrates is compensated for by a higher amount of fat, which induces a shift in nutrient
utilization in favor of lipid oxidation. This high rate of lipid oxidation in turn generates ketone bodies
[8,75]. Ketogenesis usually occurs in the liver during fasting periods, but also in type 1 diabetes (due
to a defect of glucose utilization because of the absence of insulin) or obesity. Neurological disorders
have been associated with decreased glucose utilization. In this condition, the brain becomes
dependent on ketone bodies for energy supply [12]. Ketone bodies are used as an alternative source
of acetyl-coA, which is paralleled by a consumption of oxaloacetate. This stimulates the Krebs cycle
and increases α-ketoglutarate. In turn, α-ketoglutarate forms high amounts of glutamate by
consuming aspartate, whose level is then lowered. Finally, the glutamate produced is decarboxylated
by the glutamic acid decarboxylase to produce the inhibitory neurotransmitter GABA (γ-
aminobutyric acid) [76]. Interestingly, GABA is described as an anti-seizure substance, and drug
agonists targeting it are used in epilepsy [48,77–80]. Among these molecules, benzodiazepines
enhance GABA’s action [81]. In support of this mechanism, children treated with low-carbohydrate
diets (low GI) present high levels of GABA in their cerebrospinal fluid [82].
Another hypothesized mechanism of ketone bodies is that they directly enter mitochondria and
the tricarboxylic acid cycle (TCA) to be oxidized. In turn, the stimulated oxidative metabolism
inhibits phosphofructokinase 1 and glycolysis. This direct metabolization of ketone bodies decreases
the ATP produced in glycolysis that will open the ATP sensitive potassium channels (K-ATP) and
decrease neuronal activity [83]. In support of that, a genetic model of drosophila exhibiting seizure-
like activity upon mechanical stimulation showed a reduced number of seizures when given ketone
bodies. Moreover, blocking the KATP channels or adding a GABA antagonist has been shown to
partially reverse the effect of ketone bodies [84]. This partial effect suggests that other mechanisms
are also involved. For instance, other studies indicate a blockade of vesicular glutamate transporter
(VGLUT) transfer to the synapse by ketone bodies. Such a blockade will decrease the excitatory
glutamate neurotransmitters and thus neuronal activity [85,86].
Mitochondria have also been linked to the anti-seizure effect of KD. Here, ketone bodies increase
mitochondrial respiration and NADH oxidation, inhibit reactive oxygen species (ROS) production,
and enhance ATP production [87]. All of these should prevent the mitochondrial permeability
transition (mPT), which ultimately leads to cell death [88]. In support of that, mice with recurrent
epileptic seizures show an increased threshold of mPT. This anti-mPT effect depends on cyclophilin
D modulation (part of the mPT). Furthermore, learning and memory and long-term potentiation are
decreased in these mice, suggesting a role in cognition [89]. However, this theory is contradictory to
previous activity decreasing ATP production. Therefore, more research is needed to completely
determine the role of ketone bodies in ATP production. Nevertheless, mitochondrial activity has been
linked to neuronal function and diseases, while KD is known to improve mitochondrial activity [90].
Therefore, KD induces decreased mitochondrial ROS production compared to a normal chow, via
changes in the gene expression of the oxidative pathway. Another possibility is that the increased
Nutrients 2020, 12, 2989 12 of 32

NAD/NADH ratio induced by ketone bodies dampens ROS production [91]. Ketone bodies also
improve the consumption of O2 within the respiratory chain. By doing so, KD decreases the rate of
ROS production by the mitochondria. Since seizure is associated with oxidative stress, KD or
modified KD could diminish the seizure occurrence in epileptic patients [92]. Moreover, besides
having a direct effect on ROS production, KD also stimulates the antioxidant protein catalase, whose
expression is stimulated by the activated peroxisome proliferator activated receptor γ2 (PPARγ2)
transcription factor [92]. Here, PPAR activation occurs after histone hyper-acetylation following the
inhibition of histone deacetylases (epigenetic regulation) [93,94]. In turn, PPAR upregulates
antioxidant genes and downregulates pro-inflammatory genes (NFKappaB, cyclooxygenase 2, and
iNOS) [95]. Histone deacetylase inhibitors are used as anti-inflammatory and anti-epileptogenic
molecules [96]. Interestingly, ketone bodies are shown to inhibit histone deacetylase, although the
precise mechanism still needs to be determined [97].
Finally, Rahman et al. hypothesized that ketone body neuroprotection could rely on the G-
protein coupled receptor GPR109 recently identified, which is activated by ketone bodies and found
in the brain. Moreover, mice fed a KD or infused with ketone bodies showed a decrease of ischemic
infarcts dependent on GPR109. Furthermore, the authors demonstrated that the activation of GPR109
by ketone bodies occurs in infiltrated monocytes and macrophages. In turn, these cells produce
prostaglandins and induce an anti-inflammatory response that reduces seizures [98,99]. Finally, the
anti-inflammatory role of ketone bodies inhibits NLRP3 inflammasome assembly through the
blockade of K+ efflux. However, the precise mechanism remains to be elucidated [100].

3.2. Stroke
Vegetarian diets (low GI and GL) have been described to lower the risk of stroke [101,102] (Table
3). Therefore, a relationship between GI/GL and stroke likely exists. On the other hand, a high-
fructose diet that should have a high GI worsened post ischemic brain injury in rats [103]. In this
study, the authors highlighted an important effect in the hippocampus with increased inflammation
while neuronal plasticity was decreased, in parallel with neuronal loss. These changes lowered the
neuronal performances during ischemic recovery compared to normal chow fed mice. These results
support a role of the diet during the recovery period following a stroke. Here, the glucose level is also
at play during the acute stage of a stroke and the recovery period. Therefore, diabetes is a risk factor
for stroke [49,50]. The oxidative stress associated with hyperglycemia is expected to be the
mechanism involved in the poor outcome following a stroke. This suggests that better glucose level
control could help decrease the risk of stroke [104]. Diet intervention studies have provided
interesting results in this regard. Therefore, a high-GL diet is associated with a poor outcome in
patients with acute ischemic stroke [105]. Recently, Song et al. found that, in diabetic patients, this
poor outcome does not depend on diabetes, but only on the diet’s effect on glycemic variation.
Furthermore, the authors suggested that chronic hyperglycemia is the main anticipated cause.
Chronic hyperglycemia induced by a high-GL diet was previously shown to induce a poor outcome
after a stroke [106,107]. One possible explanation for this is the cerebral hypo-perfusion or edema
associated with hyperglycemia, which leads to poor recovery from stroke [51,52]. Moreover, stroke
is often linked to cytotoxicity, whose association with hyperglycemia dampens the recovery [53]. In
addition, mitochondrial dysfunction due to lactate production from glucose metabolism has also
been suggested. Here, lactate acidifies the intracellular environment and triggers mitochondrial
dysfunction [108]. A rapid increase in blood glucose also leads to oxidative stress and endothelial
dysfunction observed in diabetes [109]. Furthermore, high increases followed by periods of low levels
are more deleterious than a continuous rise. Interestingly, high GI/GL increases glucose transiently,
and thus has a negative effect on stroke outcome. Indeed, a dysfunctional endothelium has been
described as a negative factor for acute ischemic stroke outcome [110]. Moreover, high-GI/GL diets
induce insulin resistance [31] that will increase serum levels of fibrinogen and the von Willebrand
factor (endothelial function), thus increasing the risk of stroke [111,112]. Therefore, high GI/GL
should induce hypercoagulability and an increased risk of thrombosis. This phenotype is paralleled
by an increase in small vessel diseases that could impair stroke outcome [113]. Finally, in a cohort of
Nutrients 2020, 12, 2989 13 of 32

Chinese women followed for 10 years, a positive association between GI and the risk of stroke was
observed, supporting the previous hypothesis [114]. Furthermore, the low-GI Mediterranean diet is
associated with a reduction in the risk of stroke [115]. Finally, Lim et al. studied the role of diets in
stroke recovery and cognition impairments. In their study, the authors described that glycemic
variability with hyperglycemic episodes is detrimental to cognitive function recovery. Therefore, a
diet avoiding amplitude oscillations for glycemia is more suitable for both vascular and cognitive
function recovery after a stroke [116].
Overall, evidence indicates that high glucose increases induced by diet impact both the risk and
outcome of stroke. The mechanisms in play are related to mitochondria and inflammation, as well as
hypercoagulation. Moreover, chronic and rapid hyperglycemia following a meal is deleterious for
both the risk and outcome. Therefore, a low-GI diet that induces a sustained elevation in blood
glucose should be beneficial for recovery after a stroke, and decreases the risk of occurrence by
improving cardiovascular function.

3.3. Alzheimer’s Disease (AD)

Diets are widely use in AD to help delay or slow the development of the disease [54,55].
Additionally, the relationship between AD and metabolic disorders (insulin resistance) means that
this disease is considered as type III diabetes [117]. Therefore, nutritional approaches to studying AD
have provided insights into the brain function in the pathology related to diet changes. Recently, it
was reported that a high-GI diet increases the accumulation of amyloid β (Aβ) in brains of the elderly,
which is a marker of AD, as well as a risk factor for the onset of the disease. In addition, these
individuals showed a cognitive decline, and PET scan imaging demonstrated an increased
association between Aβ accumulation and a high-GI diet [118] (Table 3). This interaction being
independent of all other factors (age, sex, and education) indicates that high GI is highly involved in
Aβ accumulation in aging populations and represents an increased risk factor for AD. In support of
a key role of diet in AD onset, high-fat diet (HFD)-induced insulin resistance increases brain Aβ
accumulation. However, mice deleted for IRS2 (insulin signaling) become insulin resistant, but do
not accumulate Aβ, unless fed an HFD. Others have also shown that Aβ accumulation is
accompanied by pTau aggregation (characteristic of AD) in an insulin-resistant AD mice model.
Finally, oxidative stress and inflammation have been described in this mice model [119].
Overall, these results indicate that the Aβ burden is related to the diet, confirming that
nutritional adjustments could help prevent AD onset and slow its progression [120]. In support of
this, a recent review describes that a healthy diet can decrease the risk of AD by lowering oxidative
stress and dampening Aβ accumulation [56]. Moreover, this review discusses the anti-inflammatory
effect of a healthy diet. In AD, inflammation is caused by Aβ accumulation that stimulates the
recruitment of microglia and astrocytes parallel to interferon gamma (IFNγ), interleukin 1β (IL1β),
and tumor necrosis factor α (TNF α) secretion [57,121].
AD is characterized by a decreased glucose uptake and utilization by brain cells. However, the
brains of AD individuals can still use ketone bodies [58,122]. Therefore, KD could be used in AD to
slow progress of the disease or to delay the cognitive deficit. A medium-chain triglyceride diet (MCT
diet) is a diet less restrictive in carbohydrates, but still ketogenic, and is used in AD [58]. The low
content of carbohydrates forces the organism to use lipid oxidation as the energy source, which also
produces ketone bodies. Therefore, such diets have a low impact on glycemia, making them low-GI
diets. Brain energy metabolism and glucose uptake decreases are accompanied by mitochondrial
dysfunction in AD [58]. Brain cells increased the utilization of ketone bodies during brain energetic
deficiency, leading to a new “neuroketotherapeutic” strategy to compensate for the lack of glucose
as an energy source [58]. Besides this energetic role, ketone bodies are also involved in
neurotransmission and a reduction in oxidative stress and inflammation relevant to AD. Ketone
bodies involve the mitochondria and their functional changes. As AD is associated with
mitochondrial dysfunctions [123], ketone bodies could thus improve the disease phenotype. KD has
also been shown to increase the number of mitochondria in the hippocampus, which could contribute
to the improvement of AD [124]. Furthermore, since ketone bodies produce fewer ROS than glucose,
Nutrients 2020, 12, 2989 14 of 32

they can participate in a decrease in the oxidative stress in AD [59,125]. This decrease in ROS
production could be induced by stimulating the expression of uncoupling proteins (UCP), as shown
previously [126,127]. Another possible mechanism is that reducing glutamate transport and
improving GABA activity decreases the excitability of neurons and thus ROS production (see Section
3.1). In addition, KD was shown to upregulate antioxidant proteins (MnSOD, Glutathione, and Nrf2)
[58]. Finally, KD inhibition of histone deacetylase can allow the expression of proteins improving
cellular homeostasis and function (brain-derived neurotrophic factor (BDNF)), and in turn cognitive
deficit in AD patients [128–132]. In support of the benefit of KD diets, mice models of AD also show
decreased Aβ accumulation in the brain when fed a KD [58], while in humans, a medium-chain
triglyceride (MCT) diet has been shown to result in an encouraging improved memory or at least the
stabilization of cognitive function in AD individuals [58]. The direct effect of a KD in humans has
been summarized by Taylor et al., who present an improvement of almost all the memory and verbal
communication tests in AD patients under a KD [58] (Table 3).
Altogether, these results support an improvement of AD pathology by decreasing the
carbohydrate supply and thus lowering the GI of the meals. The benefits depend on ketone bodies
that help maintain neuronal activity, decrease oxidative stress, and stimulate gene regulation.
However, a KD displays important side effects. Therefore, more research should be conducted to
help better understand the mechanisms at play, and eventually develop a therapeutic approach
targeting these mechanisms. Moreover, other low-GI diets could have similar beneficial effects to
KDs, and thus must be tested. Overall, although there is solid evidence for ketone body involvement,
the diets used in AD have several other effects that could be involved. Therefore, conducting more
research to understand the role of low GI on the AD phenotype could help develop a diet adapted to
the disease.
For instance, the Mediterranean diet (MD) is also protective against cognitive decline in AD [55].
MD is characterized by: a high intake of vegetables, legumes, fruits and cereals, and extra virgin oil
(unsaturated fatty acids); low intake of saturated fats and meat; a moderate intake of fish; and a low
to moderate intake of dairy products and wine during meals [133,134]. MD is low in carbohydrates,
while high in fibers, and so can be classified as a low-GI diet (Table 2). MD is known to have
numerous health benefits in cardiovascular or metabolic diseases, and also in cognition (lower
decline) and in reducing the risk of dementia or AD [135,136]. Furthermore, people with mild
cognitive impairment fed an MD show a decreased risk of AD onset, and improved memory, delayed
recall, and global cognitive function [133]. Different studies suggest antioxidant, anti-inflammatory,
or cognitive function enhancement, depending on the nutrient components. For instance, olive oil, as
a main source of fats enriched in omega-3 and phenolic acid, is considered to be a main factor [133].
Olive oil decreases the glycemic response to a high-GI meal [137]. As such, olive oil helps lower the
GI of a meal, and thus decreases the glycemic increase induced by a meal that could participate in
the effects observed. In addition, since the carbohydrate content of MD is low or non-digestible,
ketogenesis is expected and repeats the action described above. Accordingly, a modified
Mediterranean–ketogenic diet has been described to be associated with changes in AD biomarkers in
cerebro spinal fluid (CSF), suggesting that ketone bodies could be involved [138]. In addition, the
observed changes in the brain could result from gut microbiota alterations, suggesting that nutrient
digestion and/or absorption are important steps in AD onset and cognition. These results reinforce
the relationship between nutrition, metabolism, and AD and cognitive function. Microbiota have
been shown to interact with brain function through the metabolism of dietary fibers in certain bacteria
that produce propionate or butyrate (short chain fatty acids (SCFA)). In turn, these SCFA exert brain
effects via histone deacetylase, transcription factors, or antioxidant regulations. All of these effects
will then provide neuroprotection and therefore protect against neurodegenerative disorders [139].
On the other hand, Western diets containing processed food and carbohydrates decrease the number
of bacteria producing SCFA. By doing so, these diets have deleterious effects on brain and cognition.
Interestingly, highly processed food will most likely have a high GI, while dietary fibers are low-GI
carbohydrates, indicating that low-GI foods are protective against neurodegenerative diseases.
Nutrients 2020, 12, 2989 15 of 32

The gut–brain axis and nutrition have also been shown to participate in the pathophysiology of
Autism Spectrum Disorder (ASD) [140]. Moreover, Parkinson’s disease (PD) is improved by a KD.
Altogether, nutrition and GI could have an impact on other neurological conditions.

3.4. Others: Dementia, Depression, Mental Health, etc.

Metabolism is often associated with pathological brain conditions. Therefore, the AD and PD
risk increases with malnutrition and insulin resistance, while diet control is protective (138).
Furthermore, insulin has been shown to increase dopamine transporter mRNA levels in the
substantia nigra [141]. Therefore, it is assumed that a high-GI/GL diet could prevent PD by inducing
high insulin secretion [142] (Table 3). However, the study suggesting a role for insulin is
controversial, since high GI induces insulin resistance, while low GI improves insulin sensitivity [31].
Nonetheless, whilst the population studied presented a lower rate of PD while consuming high-GI
food such as rice, it is likely that other dietary factors could be involved. Indeed, the Japanese diet is
considered a healthy diet contributing to the expanded life expectancy observed in Japan. Therefore,
cardiovascular-related death and neurodegenerative disease rates are amongst the lowest in the
world [143]. The Japanese diet is characterized by raw ingredients used in meal preparation. The diet
is low in fat and calories because most of the foods used are vegetables, fish, meat, and rice, providing
an excellent nutritional balance. This diet is low in red and processed meats, whole milk, refined
grains, sweet drinks or alcohol, candy, and sweets, but enriched in fruits, vegetables, stevia
sweeteners, and whole grains and fish products (Table 2). Overall, the Japanese diet is expected to be
low GI (stevia has a GI/GL = 0) [142]. Therefore, the observed decrease in PD in the study of Murakami
et al. could be due to an improved insulin sensitivity, rather than increased insulin levels. It was also
described that a high-fat (high-GI) diet is responsible for a decreased number of dopaminergic
neurons in the substantia nigra due to a reduced PPAR and inflammation. Therefore, a low-fat diet
such as the Japanese diet could prevent these PPAR and dopaminergic neuron decreases and protect
against PD [144]. The MD is also associated with a decreased risk of PD. Here, the microbiota changes
induced by the diet are interesting since they are related to dietary fibers (lowering the GI) as a
carbohydrate source in the diet. In addition, it strengthens the importance of the gut–brain axis in
brain function and disease. Dietary fibers are known to stimulate the production of SCFA that could
be part of the mechanism of protection against PD in the MD. Indeed, SCFA can improve insulin
sensitivity, reduce inflammation, and stimulate brain-derived neurotrophic factor (BDNF)
production, helping to protect against PD. Another possible mechanism occurs through the
antioxidant-rich content of the MD. It should be noted that some of the antioxidant products in the
diet can also stimulate SCFA production, reinforcing the role of these molecules in brain function and
pathology [145]. In support of that, the SCFA concentration in the feces of PD patients is decreased
compared to control individuals [146]. However, Shin et al. also observed an increase of plasma SCFA
correlated with the PD severity [147]. This result suggests putative SCFA leakage from the intestinal
lumen into the bloodstream. Nevertheless, further studies are needed to clearly address the impact
of SCFA on PD, and more generally, the impact of diets.
Depression and anxiety are other brain diseases that exhibit a relationship with energy
homeostasis [60,61]. Furthermore, depression has been studied in relation to GI/GL [148]. Although
the results are inconsistent, it seems that high-GI/GL diets increase the risk of depression, as well as
aggravate the score of the disease [148] (Table 3). Rodent studies showed that HFD impaired 5-HT
neurotransmission, which increases anxiety behavior. The same group also reported decreased
anxiety following Connexin 43 downregulation or phosphorylation, or treatment with metformin
(activator of AMPK) [149–151]. In this context, metformin triggers a decrease in circulating branch
chain amino acids (BCAA) that in turn contribute to the anxiolytic and antidepressant effect. BCAA
have been previously linked to glutamate transport between intracellular to extracellular medium
[152]. It was also observed that a metformin decrease of BCAA is due to the inhibition of ketone-
derived BCAA production [153], suggesting that ketone bodies could be involved in depression and
anxiety. Interestingly, in addition to ketones, anxiety and depression have been associated with
oxidative stress, inflammation, and gut–brain communication [66,154]. Moreover, drugs have been
Nutrients 2020, 12, 2989 16 of 32

developed to target glutamate signaling and its recycling in the synapse [155]. Therefore, it is likely
that diet interventions could involve similar processes to those described above.
Autism Spectrum Disorder (ASD) is a neurological condition associated with behavioral and
social interaction defects and that shows energy homeostasis dysregulation [156]. In fact, type 2
diabetes and obesity during pregnancy are risk factors for ASD in offspring [156,157]. Chronic
inflammation observed in metabolic disorders and immune system activation that occurs during
pregnancy appear to be key in the risk of ASD [158–160]. It is noteworthy that chronic inflammation
can be decreased by a low-GI diet in obese subjects [161]. On the other hand, a high-GI diet increases
advanced glycation end products (AGEs) that are involved in inflammation during obesity and
diabetes. Indeed, the AGE activation of specific receptors results in C Reactive Protein (CRP)
production and oxidative stress [162,163]. In support of this possible mechanism, Currais et al.
demonstrated that mice offspring from high-GI-fed parents displayed increased brain inflammation,
reduced neurogenesis, and characteristic ASD behaviors [164]. Dietary strategies have triggered
improvement of the ASD phenotype after birth. For instance, KD given to a mice model of ASD
improved the social behavior and decreased repetitive behaviors [165]. In another attempt, gluten-
free foods decreased the inflammatory grade and improved the ASD phenotype. However, only
some of the subjects showed improvement, while others failed to observe a benefit [166,167]. These
studies, which used different diets, suggest that a specific nutrient or compound could be at play.
Furthermore, inflammation is involved in the onset of the disease; however, other brain energetic
alterations could also be present, but remain to be determined. Therefore, more research on both the
understanding of ASD brain alterations and diet interventions to determine the role of specific
nutrients or metabolic products needs to be conducted.
Microbiota are also associated with ASD behaviors [62,140,168]. Even if the role of gut
microbiota is poorly understood, amino acid metabolism and inflammation are possible mechanisms
participating in the phenotype observed. A low-GI diet induces changes in microbiota that are
associated with ASD improvement. Therefore, the participation of a product with low-GI
carbohydrates could be important. Finally, the ASD mice model shows decreased blood levels of
methionine, also described in humans [63–65]. Interestingly, a high-GI diet also decreases the
methionine levels [164]. Methionine is a precursor for DNA methylation and gene regulation [169].
In comparison, a low-GI diet maintains higher levels of methionine, suggesting that diet could
improve ASD through epigenetic regulations. In line with the role of microbiota and low GI,
sulforaphane, produced from low-GI vegetables (cauliflower and broccoli), has been identified as a
putative treatment in ASD. Indeed, sulforaphane given to autistic children improved their behavioral
phenotype. Moreover, although the mechanism of action is not known, sulforaphane has been
described to modulate oxidative stress, methylation, or apoptosis, and to be a potent neuroprotective
molecule [170–174]. Overall, the identification of this molecule supports a beneficial role of a low-GI
diet in ASD. It is noteworthy that, similar to other neurological conditions, ASD improvement
through the diet is linked to oxidative stress, gene regulation, and inflammation. Moreover, a
sulforaphane extract from vegetables is a promising molecule for the treatment of ASD. Further, other
molecules produced or present in low-GI foods could also exist and participate in the beneficial
effects, and would thus be useful in other neurological diseases (Table 3).
Intriguingly, oxidative stress, inflammation, ketone bodies, the gut–brain axis, microbiota,
glutamate metabolism, and neurogenesis are all involved in the neurological conditions described.
All of them can also be affected by the diet and especially the carbohydrate content and source.
Therefore, low-GI diets are likely to improve neurological disorders, but may also be of interest in
physiological conditions, since they help improve cognition and neuronal activity. A more
generalized use of a low-GI/GL diet could help prevent or delay the onset of neurological disorders,
while it could also help during the growing up period and in learning performances in childhood.
Although most of the mechanisms described appear to be common to the diseases described and
are linked to diet intervention changes, no exact mechanisms and molecules involved in these
beneficial effects have been precisely identified. Nevertheless, a lot of common pathways indicate a
role of ketone bodies and SCFA. Therefore, more studies to determine diet involvement in the
Nutrients 2020, 12, 2989 17 of 32

production of these molecules should be conducted to determine precise diet recommendations.

Considering this, neurological disorders are likely to be successfully targeted by nutritional therapies.

4. Glycemic Index and Brain Regulation of Energy Homeostasis

GI/GL values predict the impact of food on the metabolic response, such as blood glucose and
insulin levels. Therefore, a high GI/GL will induce a rapid and high increase in blood glucose and
insulin, while a low GI/GL will induce a slow and limited increase of blood glucose that slightly
affects insulin levels. Due to these effects, diets based on low-GI foods have been developed to help
control weight and prevent cardiometabolic disorders [21,175]. However, studies to address GI/GL’s
effect on weight loss or glucose management in diabetic people have given rise to contradictory
results. Among other reasons, the differences can likely be attributed to a range in GI values for the
same food making food choices based on such criteria more difficult. In addition, GI only considers
the carbohydrate content of food, while lipids, proteins, and vitamins can also influence the metabolic
impact of the food [176].
The brain consumes a large part of glucose from the body for its activity and needs a constant
supply [12]. Therefore, according to the “selfish brain” theory, the brain competes with the body for
glucose. Because of this, the brain sends a message to increase glucose availability when its activity
increases. Furthermore, the brain is overly sensitive to glucose availability, and responsive to changes
in the glucose supply [13]. Such sensitivity makes the brain a key regulator, not only for its needs,
but also for maintaining a constant glucose level in the blood [15]. Blood and brain parenchyma
glucose levels are linked through transport across the blood–brain barrier via GLUT1 [177]. While
hyperglycemia decreases GLUT1 expression, a drop in blood glucose will stimulate GLUT1
expression [178]. However, the brain glucose level does not change in association with the blood
concentration [179]. Therefore, micro-dialysis experiments have revealed a brain to blood glucose
ratio of about 0.5. Furthermore, this ratio decreases when blood glucose increases [180]. This
observation could be the result of a decreased GLUT1 expression that limits glucose uptake by the
brain. Altogether, these results indicate a tightly regulated glucose supply to the brain to prevent
both hypo- and hyperglycemia from reaching the brain.
Physiological conditions involve complex inter-organ communication to keep body weight and
energy homeostasis in a balanced state. The brain plays a crucial role by integrating information on
the body’s energy status and adapting food intake and energy expenditure via signals sent to
peripheral organs [181]. Furthermore, specific areas of the brain are involved in the sensing of
glucose, as well as hormone concentration changes (insulin, ghrelin, leptin, etc.) [182]. In this regard,
GI/GL is expected to act in the brain control of energy homeostasis. However, little is known about
the impact of high or low GI/GL on those mechanisms. Nevertheless, due to changes in blood insulin
and glucose levels, changes in brain responses are likely to occur. Whether these changes are due to
direct (glucose or insulin level) or indirect (hormonal, nutrient, or cytokine level changes due to the
meal) effects on the brain control of metabolism should be determined. Moreover, the relationship
between GI and metabolic disorders remains unclear, despite several studies having been conducted
[183–187]. Intriguingly, the mechanisms involved in cognition or neurological disorders have been
described in brain energy homeostasis regulation. Therefore, ROS signaling, mitochondrial activity,
the gut–brain axis and SCFA, ketone bodies, astrocyte–neuron communication, glutamate
metabolism, and gene regulation and neurogenesis or plasticity have been involved in brain
metabolic regulations.
Nevertheless, so far, only a few studies have tried to determine the impact of GI/GL on the brain
control of metabolism. However, nutrition can affect the body weight, insulin sensitivity, adiposity,
and other metabolic parameters. Therefore, we will discuss results suggesting a GI/GL impact on the
brain control of energy homeostasis.

GI/GL and Brain Glucose Detection

Within the brain, specific regions are dedicated to the sensing of signals involved in energy
homeostasis regulation. The hypothalamus is the first area to sense these peripheral signals on the
Nutrients 2020, 12, 2989 18 of 32

energy status of the body. Within the different nuclei forming the hypothalamus, various neuronal
populations have been well described [14]. Furthermore, glucose sensing and the regulatory response
to the periphery have been well characterized in the hypothalamus [15]. This precise sensing of blood
glucose is possible due to the blood–brain barrier permeability being weaker in this area of the brain.
Due to this, the impact of foods on the blood glucose level is directly integrated by the hypothalamus
to restore euglycemia. In this regard, GI/GL should involve a hypothalamic activation of neuronal
circuits of glucose and energy homeostasis regulations. Low-GI food leads to a controlled increase in
the blood glucose level that is progressively returned to euglycemia. In this case, insulin release is
only limited, and the glucose level is decreased due to tissue utilization. On the other hand, high
GI/GL results in a high increase of glucose levels in the first phase. Such a rise in blood glucose
stimulates brain hyperglycemia detection. In turn, high glucose excited (HGE) neurons are activated,
leading to the release of neurotransmitters (GABA in VMN and NTS or anorexigenic neuropeptides
POMC/CART in the ARC) [188]. In a second phase, this should lead to a decreased blood glucose
level that involves the same area, but stimulates other neurons called glucose-inhibited neurons. The
activation of these neurons occurs when glucose levels decrease. Following their stimulation, the
brain will send adaptive signals to stimulate food intake and glucose production [189]. The brain
sensing a high glucose level will induce a peripheral response through inducing insulin release by
the pancreas [190]. This response contributes to the rapid decrease of the glucose level and the
hypoglycemia induced. Following this second phase, hypoglycemia detection is activated and
involves the brain in contributing to stimulating the food intake by activating orexigenic neurons.
Interestingly, the redox balance is involved in both hyper- and hypoglycemia sensing. Therefore,
hyperglycemia induces mitochondrial ROS production in the hypothalamus. The inhibition of this
ROS production inhibits the insulin secretion normally observed due to a lack of nervous activation
[191]. In addition, changes in the morphology of mitochondria are required to finely regulate this
ROS signaling [192]. During obesity and diabetes, a hypersensitivity to glucose is observed. This
hypersensitivity is characterized by insulin secretion by the pancreas after detection of a glucose level
lower than the usual level. This hypersensitivity is linked to dysfunctions of mitochondrial
respiration activity. Consequently, ROS levels are higher than in the non-obese group. Finally, an
antioxidant treatment to decrease the ROS level in the hypothalamus restores the normal glucose
sensing function, demonstrating the importance of redox balance [193,194]. Dysfunctions of
mitochondrial dynamics and ROS signaling have also been shown during metabolic unbalance [195].
Hypoglycemia detection also depends on ROS signaling. Here, ROS are produced during normal
hypoglycemic counter-regulation. However, after recurrent hypoglycemic episodes, there is no ROS
production [196]. These results support a key role of mitochondria and the redox balance in the
hypothalamic regulation of energy homeostasis, as also shown in other studies [197–201]. In addition,
lipids, insulin, and ghrelin signaling in the hypothalamus also participate in ROS signaling.
Therefore, according to the mechanisms putatively involved in a low- vs. high-GI diet, and its impact
on ROS production (see Section 3), it is likely that the hypothalamic regulation of metabolism will be
affected by the GI of a food or diet. For instance, a high-GI diet could mimic a recurrent increase in
ROS and therefore disrupt the mechanism of hypoglycemia counter-regulation. Additionally,
recurrent increases in glucose and insulin could participate in the development of insulin resistance
in the brain, as has been observed for a high-GI diet in peripheral tissues [31]. On the other hand, a
low-GI diet would produce ketone bodies that are inhibitors of ROS production by interfering with
the mitochondrial respiration, as described above [90–92,202–208]. Interestingly, ketone bodies have
recently been shown to be involved in metabolic disorders and the brain control of energy
homeostasis, notably by affecting the food intake [202–208]. Discrepancies in results could be due to
various parameters, including the origin of ketone bodies. Indeed, a high-fat diet is associated with
hyperketonemia induced by an increase in fat metabolism from the diet, while fasting ketone bodies
are produced from lipid stores in the body. Therefore, the results observed can be altered by other
signals, such as fatty acids, hyperglycemia, hyperinsulinemia, and leptin, among others, during the
consumption of a high-fat diet. A high-GI diet probably falls into this situation since it is high in
carbohydrate and high-GI foods. A low-GI diet, however, will induce ketone body production from
Nutrients 2020, 12, 2989 19 of 32

the fatty acids produced from adipose tissue. Moreover, in addition to ketone bodies produced in the
liver, in this condition, astrocyte ketogenesis will also be stimulated [209,210]. Indeed, it is possible
that the signal exhibited by ketone bodies produced by astrocytes locally would be different from
that displayed by hepatic ketone bodies that would affect the whole body.
Ketone bodies could also be involved in metabolism through the acetylation or methylation of
genes, thus modulating their transcription, as described before [93–95]. Indeed, such gene regulation
has previously been linked to the brain control of energy homeostasis [211–214]. Of particular
interest, these processes have been shown to be involved in neurogenesis, brain plasticity, and
neuronal function. Therefore, low-GI diet-produced ketone bodies should lead to changes in these
mechanisms and modify the neural regulation of metabolism. Since ketone bodies are associated with
fat metabolism, they would rather signal a lack of energy that would stimulate food intake or increase
the glucose supply. However, this assumption remains to be tested, since others have described an
inhibition of food intake by ketone bodies. Nevertheless, epigenetic mechanisms stimulated by low
GI should help control the energetic balance, while high GI should lower ketone body production
and thus block their signal. However, further studies are needed to completely understand the role
of ketone bodies in the brain regulation of energy homeostasis.
Interestingly, ketone bodies are involved in changes in ATP production. Such a role has been
described in neurological disorders. Either ketone bodies, by inhibiting glycolysis, decrease the ATP
production, or by forming substrates for the mitochondrial respiration, maintain ATP production.
Such hypotheses remain to be tested. Nevertheless, ATP levels would be responsible for the
regulation of KATP channel closure [83–86]. Such a role of ATP production would then regulate the
depolarization of glucose excited (GE) neurons that are KATP-dependent channels [215].
Astrocyte ketogenesis also supports a role for glial cells in energy homeostasis. First, astrocytes
provide energy to neurons to maintain normal activity. Furthermore, astrocytes play a role as a sensor
of the metabolic status, and signal this information to the neurons [216,217]. Therefore, astrocyte–
neuron communication is key in the regulation of energetic signal transport and sensing by neurons.
Indeed, studies have described the role of astrocytes in the detection of leptin, glucose, fatty acids,
and amino acids and their involvement in the metabolic balance [218–223]. The role of astrocytes in
glutamate recycling is also associated with the lactate supply to neurons for neurotransmitter action
[222]. In addition, disrupting the communication between astrocytes by blocking the Connexin 43
protein that participates in the astroglial network in the hypothalamus inhibits the glucose sensing
response. This result supports indispensable transport through astrocytes for normal glucose
detection [224]. The astrocyte-neuron lactate shuttle theory (ANLS) hypothesizes that astrocytes
metabolize glucose taken up from the bloodstream, and then convert it into lactate in glycolysis. The
lactate produced is then transferred to neurons, where it can be oxidized. Therefore, lactate serves as
a signaling molecule for the blood glucose level. Accordingly, lactate infusion to the brain mimics the
response obtained with glucose [225]. Overall, glucose changes associated with ANLS and glutamate
recycling represent targets for a GI diet producing ketone bodies following similar mechanisms
described in neuronal disorders. However, such a hypothesis has not been tested in the context of
brain nutrient sensing.
Finally, the gut–brain axis is also involved in the brain regulation of energy homeostasis. In
addition, the diet composition and GI alter the gut function via microbiota that have an effect on
neurological disorders [226–228]. Here, the same molecules identified in neurological conditions are
also known to affect brain circuits of metabolic control. Indeed, dietary fibers are expected to provide
resistance to the onset of metabolic disorders, as well as the discussed effect on neurological disorders
and cognition. Dietary fibers are found in low-GI food such as vegetables [16]. Therefore, the action
of GI on microbiota will affect the brain control of energy homeostasis via SCFA. Here, SCFA have
been described to have a satiating effect [37,229]. More recently, microbiota changes have been shown
to activate POMC neurons (anorexigenic), reinforcing the role of the gut–brain axis in food intake
control [230]. Other works indicate that leptin sensitivity inhibition and pro-glucagon and BDNF
decreases induced by microbiota changes could participate in obesity [231]. Interestingly, leptin
sensitivity and BDNF are linked to AD, strongly suggesting that microbiota could be key elements in
Nutrients 2020, 12, 2989 20 of 32

the relationship between brain disorders and metabolism. Therefore, meal composition and the GI of
foods and meals represent an interesting target in the elucidation of this relationship, but also in
preventing, delaying, and treating the diseases.

5. Conclusions and Perspectives

GI/GL values have given rise to new diets to help people with metabolic diseases control their
body weight and glucose homeostasis. Encouraging results on weight management and insulin
sensitivity improvement have been observed. In addition, more historical diets, such as ketogenic or
modified ketogenic diets, the Mediterranean diet, and the Japanese diet, which are likely to have a
low GI, are associated with a healthy lifestyle. In addition to their metabolic improvement properties,
these diets also exhibit positive effects on neuronal diseases. Therefore, people following these types
of diets present a decreased risk of developing brain diseases while aging. Furthermore, these diets
have also been used for decades to treat epilepsy, for example. However, even though it is known
that these nutritional interventions improve wellbeing, little is known on the mechanisms involved.
Interestingly, despite the primary role in metabolic control, the most important progress in the
understanding of the brain impact of a low-GI diet has come from neurological condition studies.
Nevertheless, it is worth noting that the mechanisms identified or hypothesized from these studies
have been described in the context of the brain control of energy homeostasis. Among these
mechanisms, the redox balance, mitochondrial function, ATP production, insulin sensitivity, gene
regulation, astrocyte-neuron lactate shuttle, and neurotransmitter regulation are all involved (Figure
2).

Figure 2. Schematic representation of the different mechanisms putatively involved in the beneficial
effect of a low-GI diet on neurological disorders (left panel), paralleled with known mechanisms
involved in the brain control of energy homeostasis (right panel).

Therefore, these mechanisms appear to be key in brain function, and an alteration of them could
lead to neurological dysfunctions. These dysfunctions would then lead to neurological disorders or
defects in brain regulatory mechanisms such as energy homeostasis. Therefore, the inability of the
brain to precisely modulate energy needs for its own needs will trigger neurological dysfunctions.
However, a better understanding of these mechanisms is still needed to completely understand
both neurological disorders and metabolic disorders. Moreover, improved knowledge could help to
decipher the increasingly evident relationship between neuronal disorders and the metabolic
balance.
Finally, a better understanding of the mechanisms involved in diets could help develop and
improve nutritional recommendations for improving the health of people with these diseases. In
addition, the diet could be a good target for preventing the development of both metabolic and
neuronal disorders. Moreover, deciphering how these mechanisms involve diets could result from
such studies and thus also improve cognitive function in healthy people.
Nutrients 2020, 12, 2989 21 of 32

Author Contributions: writing—original draft preparation, L.C. and C.L.; writing—review and editing, L.C.
and C.L. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding

Conflicts of Interest: The authors declare no conflict of interest.

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