# Impaired cerebral hemodynamics and oxygenation in type 2 diabetes: insights into insulin resistance and hyperglycemia effects

Islem Jlali, I. Touil, H. H. Amor, Sémah Tagougui

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## To cite this version:

Islem Jlali, I. Touil, H. H. Amor, Sémah Tagougui. Impaired cerebral hemodynamics and oxygenation in type 2 diabetes: insights into insulin resistance and hyperglycemia effects. Journal of Diabetes and its Complications, 2025, Journal of Diabetes and its Complications, 39 (9), pp.109102. 10.1016/j.jdiacomp.2025.109102. hal-05225366

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# Impaired cerebral hemodynamics and oxygenation in type 2 diabetes: insights into insulin resistance and hyperglycemia effects

Islem Jlali<sup>a</sup>, Imen Touil<sup>b</sup>, Hassen Haj Amor<sup>c</sup>, Sémah Tagougui<sup>a, *, e</sup>

## ARTICLE INFO

**Keywords:**

Exercise

Cerebral oxygenation

Uncomplicated type 2 diabetes

## ABSTRACT

**Aims:** Emerging evidence suggests Type 2 diabetes (T2D) may adversely affect cerebral hemodynamics and oxygenation. This study aimed to explore the impact of uncomplicated T2D on cerebral hemodynamics and oxygenation during maximal exercise.

**Methods:** In a comparative clinical trial, 30 matched pairs of subjects with obesity, stratified by T2D status, were enrolled. Hemodynamic and oxygenation parameters were assessed during incremental maximal exercise. Additionally, physical activity levels, lipid profiles, and insulin resistance markers were evaluated.

**Results:** Participants with T2D exhibited significantly impaired cerebral blood volume (total hemoglobin) and oxygenation (oxygenated hemoglobin) compared to controls, especially at exercise intensities above 80 % of VO₂peak. This impairment was independent of differences in arterial carbon dioxide partial pressure (PaCO₂) levels between the groups at peak exercise (P > 0.05, PaCO₂ 34.4 ± 3.2 vs 34.5 ± 1.3 mmHg). Moreover, individuals with T2D had a lower estimated glucose disposal rate (eGDR) compared to the control group (P = 0.02; 7.4 ± 2.4 vs 9.27 ± 0.97 mg/kg/min).

**Conclusions:** Our findings indicate that insulin resistance and hyperglycemia in T2D contribute to impaired cerebral hemodynamics and oxygenation, even before clinical signs of microangiopathy appear. These alterations could have significant implications for cognitive function and overall brain health in individuals with T2D.

**Trial registration:** PACTR202301667050563.

## 1. Introduction

Individuals with Type 2 diabetes (T2D) suffer from chronic hyperglycemia, which damages the vascular endothelium and promotes atherosclerosis, leading to various vascular complications.¹ T2D is associated with an increased risk of ischemic stroke² and the remodeling of cerebral microvascularization, evidenced by the thickening of the cerebral capillary basement membrane.³,⁴ This thickening can alter the integrity of vascular smooth muscle cells⁵ and lead to increased microvascular resistance, impacting cerebral perfusion and function. Hemodynamic and neurophysiological abnormalities can occur even before the clinical onset of complications, affecting the quality of life for individuals with T2D.⁶ Effective management strategies, including exercise, play a crucial role,⁷ but exercise tolerance is often limited in adults with T2D due to cardiac impairment, impaired muscle metabolism, and reduced cerebral perfusion and/or oxygenation during exercise.⁸,⁹

The increase in cerebral blood flow (CBF) during exercise observed in healthy individuals does not occur in those with T2D, leading to an early reduction in cerebral oxygenation and increased perceived exertion, indicating problems in brain vascular control during exercise.⁶,¹⁰ Impaired cerebral vasodilation and endothelial dysfunction in T2D can affect cerebral blood perfusion.¹¹,¹² Notably, cerebral hypoperfusion strongly correlates with insulin resistance, suggesting insulin resistance may have a deleterious effect on cerebral blood flow compared to other vascular risk factors.¹³,¹⁴

Therefore, the objective of this study was to investigate the possible effects of uncomplicated T2D and insulin resistance on cerebral oxygenation during maximal exercise. Understanding the impact of T2D on cerebral oxygenation during exercise can provide insights into the underlying mechanisms and help develop targeted interventions to improve exercise capacity and brain health in individuals with T2D.

<footnote><sup>a</sup> Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, F-59000 Lille, France</footnote>

<footnote><sup>b</sup> Pulmonology Department, Taher Sfar Hospital, Mahdia, Tunisia</footnote>

<footnote><sup>c</sup> Cardiovascular department, Taher Sfar Hospital, Mahdia, Tunisia</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: semah.tagougui@univ-lille.fr (S. Tagougui).</footnote>
## 2. Materials and methods

In this comparative clinical trial, we recruited 30 matched pairs subjects with obesity/overweight aged between 18 and 40. The first group with T2D (n = 15) forming the experimental group and the second group without T2D (n = 15) forming the control group. Informed consent was obtained from all volunteers prior to inclusion into the trial, which was approved by the ethics regional committee. Individuals with T2D were free from microvascular and macro-vascular complications. Retinopathy was assessed through retinal examination, nephropathy was evaluated by measuring microalbuminuria and urinary serum creatinine levels, peripheral neuropathy was determined by assessing reflexes, using a 10 g monofilament, and employing a tuning fork. Autonomic neuropathy was evaluated through various measures, including assessing neurogenic bladder function, response to standing, and assessing for signs of gastroparesis and enteropathy. Additionally, we took into consideration the patients' medical history, including any previous cardiovascular events, cerebrovascular insufficiency, and coronary insufficiency. Individuals with T2D were excluded from the study if they were treated by insulin or medication other than metformin. We include individuals with diabetes duration between 3 and 10 years. The control participants were defined as taking no medication, having no immediate family member with T2D, and being confirmed as glucose tolerant via an oral glucose tolerance test. We evaluated the physical activity level over seven consecutive days via accelerometry (GT3M ActiGraph). Participants came twice to the laboratory. On the morning of the first visit, after an overnight fast, blood samples were taken in order to measure glycated hemoglobin and glycemia. We have used estimate glucose disposal rate (eGDR) to estimate insulin resistance in our population. The eGDR (mg/kg/min) was calculated according to the following formula:

$$eGDR = 19.02 - (0.22^* \text{BMI}) - (3.26^* \text{HT}) - (0.61^* \text{HbA}_{1c})$$

(BMI = body mass index (kg/m²), HT = hypertension (yes = 1/no = 0), and HbA1c = HbA1c (%)).

During the second visit, an incremental maximal exercise to examine maximal oxygen uptake was performed on treadmill. Heart rate, oxygen saturation, cerebral perfusion and O₂ extraction were assessed in continuous.

### 2.1. Cardiopulmonary response test

Graded exercise test was carried out according to the Bruce Protocol, which is systematically structured into 7 stages. The first stage initiate at a pace of 2.7 km/h and an incline of 10% and the last at 9.6 km/h and incline of 22%. Workloads (speed and inclination) were subsequently increased each 3-min period in a simultaneous way until volitional exhaustion was reached.¹⁵

The exercise test was supervised by a cardiologist, who monitored the individual throughout the test to ensure their safety and well-being. Additionally, an electrocardiogram (Cardioline, Italy) was used to evaluate heart rate both at rest and continuously during exercise. Pulse oximetry (Oxymed, France) was utilized to monitor oxygen saturation levels. VO₂peak was measured throughout exercise (breath-by-breath system, Ergocard, Medisoft). It was determined as the highest 15-s average value during the exercise test. To eliminate any influence of different breathing habits in the outcomes, exhaled gases during exercise were assessed through a mouthpiece and wearing a nose clip to avoid nasal respiration.

### 2.2. Blood analyses

Arterial blood gas samples were collected from the radial artery at rest and at maximal exercise (immediately after the end of the test to measure pH, partial pressure of oxygen (PaO₂), partial pressure of

carbon dioxide (PaCO₂), lactate, and HCO₃⁻. Lactate was analysed by amperometry using the ABL800 FLEX machine from Radiometer, while the PCO₂ and pH levels were measured by potentiometry, also using the ABL800 FLEX machine. Additionally, arterial oxygen content (CaO₂) was calculated based on the measured PaO₂, arterial oxygen saturation (SaO₂), and the hemoglobin concentration (Hb) according to the formula CaO₂ = (SaO₂ x 1.34 x Hb) + (PaO₂ x 0.0031).

### 2.3. Prefrontal cortex hemodynamics and oxygenation

Throughout exercise, continuous noninvasive measurements of cerebral oxygenation/deoxygenation status were measured with near-infrared spectroscopy (NIRS) (PortaMon; Artinis Medical Systems, Gelderland, the Netherlands) at 10 Hz. Upon export, data were down-sampled to 1 Hz. The PortaMon was placed on the left-side prefrontal cortex between Fp1 and F3 according to the modified international electroencephalography 10-20 system,¹⁶ secured using a Velcro strap, and covered with a cloth bandage to exclude ambient light. The NIRS monitor emits two wavelengths (780 and 850 nm) which across micro vessels during exercise. Using the Beer-Lambert law and normalization to values from the baseline period, we determined changes of relative concentrations of oxygenated (O₂Hb) and total hemoglobin (THb). Changes in THb reflect changes in composite of local blood volume and microvascular hematocrit.

### 2.4. Statistical analysis

Statistical analyses were performed using Statistica for Windows software (version 10, StatSoft, Inc., Tulsa). Results were reported as mean ± SD. After checking normality with the Shapiro-Wilk test, anthropometric data, physical activity level and VO₂peak were compared between groups using the t-student independent test. For blood analysis before and after exercise, a two-way ANOVA with repeated measures [group (type 2 diabetes, Control) × time (before exercise, after exercise)] was performed. To study the evolution of NIRS measurements during exercise, a two-way ANOVA with repeated measures [group (type 2 diabetes, Control) × time (rest, 20 % VO₂peak, 40 % VO₂peak, 60 % VO₂peak, 80 % VO₂peak, at peak exercise)] was also performed. If significant main effects or interactions were observed, Bonferroni post hoc comparisons were applied.

Pairwise correlations between NIRS measurement and HbA1c was tested using Pearson's correlation coefficient (ρ) in the T2D group.

## 3. Results

According to the matching procedure, demographic and anthropometric data did not differ between the two groups. We also took care to closely match physical activity level, given its possible effect on cerebral oxygenation (Table 1).

Remarkably, VO₂peak was impaired in individuals with T2D despite comparable heart rates at maximal exercise and comparable physical activity level.

### 3.1. Prefrontal cortex hemodynamic and oxygenation

During the maximal exercise, THb augmented significantly in both groups. Although the levels of THb as well as the slope of THb augmentation were higher in control group notably at exercise intensities >80% of VO₂peak (Fig. 1).

O₂Hb increase throughout exercise was different between individuals with T2D and their respective control individuals, especially at exercise intensities >80% of VO₂peak (Fig. 1).
<table><caption>**Table 1**
Participant characteristics.</caption><thead><tr><th></th><th>Type 2 diabetes</th><th>Control</th><th>P values</th></tr></thead><tbody><tr><td><strong>Anthropometric and demographic data</strong></td><td></td><td></td><td></td></tr><tr><td>Total (male/female) (n)</td><td>15 (10/5)</td><td>15 (10/5)</td><td>NS</td></tr><tr><td>Age (year)</td><td>39.5 ± 1.7</td><td>35.8 ± 5.4</td><td>NS</td></tr><tr><td>Weight (kg)</td><td>91 ± 13.8</td><td>92 ± 16.0</td><td>NS</td></tr><tr><td>BMI (kg·m<sup>-2</sup>)</td><td>31.6 ± 3.3</td><td>31.3 ± 4.4</td><td>NS</td></tr><tr><td>Participants with BMI (25–30) (n)</td><td>5</td><td>5</td><td>NS</td></tr><tr><td>Participants with BMI (30-25) (n)</td><td>10</td><td>10</td><td>NS</td></tr><tr><td>HbA<sub>1c</sub> (%)</td><td>8.3 ± 1.2**</td><td>5.3 ± 0.2</td><td>P < 0.001</td></tr><tr><td>Diabetes duration (yr)</td><td>6.14 ± 3.08</td><td>NA</td><td>NA</td></tr><tr><td>Smokers (n)</td><td>2</td><td>2</td><td>NS</td></tr><tr><td>Non smokers (n)</td><td>13</td><td>13</td><td>NS</td></tr><tr><td><strong>Fasting metabolic data</strong></td><td></td><td></td><td></td></tr><tr><td>Blood glucose (mmol.L<sup>-1</sup>)</td><td>11.7 ± 3.0**</td><td>5.0 ± 0.6</td><td>P < 0.001</td></tr><tr><td>eGDR (mg·kg<sup>-1</sup>·min<sup>-1</sup>)</td><td>7.4 ± 2.4*</td><td>9.2 ± 0.9</td><td>P = 0.02</td></tr><tr><td>HGB (g·dL<sup>-1</sup>)</td><td>13.27 ± 1.5</td><td>14.4 ± 0.9</td><td>NS</td></tr><tr><td>Capillary blood glucose (mg/dL)</td><td>170 ± 30</td><td>110 ± 40</td><td>P < 0.05</td></tr><tr><td><strong>Physical activity (accelerometry)</strong></td><td></td><td></td><td></td></tr><tr><td>Average MVPA (min·day<sup>-1</sup>)</td><td>42.7 ± 8.9</td><td>41.5 ± 18.0</td><td>NS</td></tr><tr><td>Sedentary time (h·day<sup>-1</sup>)</td><td>7.1 ± 1.7</td><td>7.6 ± 1.6</td><td>NS</td></tr><tr><td><strong>Maximal oxygen consumption</strong></td><td></td><td></td><td></td></tr><tr><td>VO<sub>2peak</sub> (mL·min<sup>-1</sup>·kg<sup>-1</sup>)</td><td>37.8 ± 4.8*</td><td>44.8 ± 5.7</td><td>P < 0.05</td></tr><tr><td><strong>Usual daily nutrient intake</strong></td><td></td><td></td><td></td></tr><tr><td>Total caloric (TC) intake (kcal)</td><td>2193.4 ± 348.5</td><td>2263 ± 583.2</td><td>NS</td></tr><tr><td>Protein (% of TC)</td><td>15.4 ± 2.1</td><td>15.4 ± 1.7</td><td>NS</td></tr><tr><td>Fat (% of TC)</td><td>27.1 ± 6.3</td><td>29.1 ± 5.6</td><td>NS</td></tr><tr><td>Carbohydrate (% of TC)</td><td>48.3 ± 4.2</td><td>50.9 ± 5.0</td><td>NS</td></tr></tbody></table>

Note: Data are mean ± SD or number of patients.

At *p* < 0.05 Values are significantly different from those in control group.

At **p* < 0.05 Values are significantly different from those in control group MVPA: moderate vigorous physical activity.

BMI, body max index; HGB, hemoglobin; eGDR, estimated glucose disposal rate.

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Recordings made by NIRS from the prefrontal cortex. Change in ΔO₂HB (a), Change in ΔTHb (b), Values are mean ± SD.</figcaption></figure>

## 3.2. Factors that may alter prefrontal cortex hemodynamics and oxygenation

Both at rest and at maximum exercise, there were no intergroup difference in PaO₂ and PaCO₂. Lactate increased and pH decreased during exercise without any difference between groups (Table 2). Individuals with T2D who had altered exercise capacity showed lower eGDR than control group (P = 0.02; 7.4 ± 2.4 vs 9.27 ± 0.97 mg/kg/min) (Table 1).

<table><caption>**Table 2**
Circulatory and metabolic data at rest and at maximal exercise in both groups.</caption><thead><tr><th rowspan="2"></th><th colspan="2">Type 2 diabetes</th><th colspan="2">CONTROL</th><th rowspan="2">ANOVA</th></tr><tr><th>Before exercise</th><th>At maximal exercise</th><th>Before exercise</th><th>At maximal exercise</th></tr></thead><tbody><tr><td>HR (bpm)</td><td>87.26 ± 6.8</td><td>158.2 ± 21.6†</td><td>77.4 ± 10.4</td><td>166.14 ± 0.77†</td><td>Groupe: NS<br>Exercice: p < 0.01<br>Interaction: NS</td></tr><tr><td>SaO₂ (%)</td><td>97.4 ± 0.91</td><td>94.3 ± 4.9†</td><td>97.14 ± 0.77</td><td>95.85 ± 1.35†</td><td>Groupe: NS<br>Exercice: p < 0.01<br>Interaction: NS</td></tr><tr><td>PH</td><td>7.4 ± 0.02</td><td>7.37 ± 0.05</td><td>7.4 ± 0.04</td><td>7.36 ± 0.05</td><td>Groupe: NS<br>Exercice: p < 0.01<br>Interaction: NS</td></tr><tr><td>PaO₂ (mmHg)</td><td>98.2 ± 12.9</td><td>105.08 ± 11.05</td><td>106.3 ± 11.5</td><td>106.3 ± 11.8</td><td>Groupe: NS<br>Exercice: NS<br>Interaction: NS</td></tr><tr><td>Lactate (mmol·L<sup>-1</sup>)</td><td>2.73 ± 0.8</td><td>5.4 ± 2.0†</td><td>1.69 ± 0.43</td><td>4.7 ± 2.7†</td><td>Groupe: NS<br>Exercice: p < 0.01<br>Interaction: NS</td></tr><tr><td>PCO₂ (mmHg)</td><td>36.7 ± 2.6</td><td>34.4 ± 3.2</td><td>36.7 ± 3.1</td><td>34.5 ± 1.3</td><td>Groupe: NS<br>Exercice: p < 0.01<br>Interaction: NS</td></tr><tr><td>HCO₃- (mEq/L)</td><td>23.89 ± 2.24</td><td>20.4 ± 3.5</td><td>22.6 ± 2.4</td><td>19.7 ± 2.24</td><td>Groupe: NS<br>Exercice: p < 0.01<br>Interaction: NS</td></tr><tr><td>CaO₂ (mL·dL<sup>-1</sup>)</td><td>17.8 ± 1.9</td><td>17.3 ± 1.8</td><td>19.3 ± 1.2</td><td>19.1 ± 1.3</td><td>Groupe: NS<br>Exercice: p < 0.01<br>Interaction: NS</td></tr></tbody></table>

At †p < 0.05 Values are significantly different from those at rest.

Abbreviations: HR, heart rate; PaO₂, the partial pressure of O₂; PCO₂, The partial pressure of carbon dioxide; HCO₃⁻, ion bicarbonate; CaO₂, arterial O₂ content.

Interestingly, in T2D group the HbA₁c correlated negatively with THb at 100 % of VO₂peak (P < 0.05, r = -0.5).

## 4. Discussion

This study sheds light on the potential impact of insulin resistance and hyperglycemia on hemodynamics and cerebral oxygenation in the prefrontal cortex, even in the absence of clinical manifestations of micro-angiopathy in individuals with T2D. We suggest that these metabolic abnormalities may have early effects on cerebral vascular function and oxygen supply to the brain.

### 4.1. Prefrontal cortex blood volume during exercise

We noted a significant increase in prefrontal cortex blood volume in individuals with and without T2D. This result is rationally explained by
the elevation of PaCO₂ during exercise, resulting in cerebral vasodilation and increased regional blood volume.¹⁷ Of particular interest, we found the increase in cerebral blood volume as reflected by THb was significantly blunted in individuals with T2D compared to the control group, despite these individuals being free from clinical microvascular complications. It is well known that there is a dynamic relationship between cerebral blood volume and cerebral blood flow, defined as the volume of blood flowing through a mass of brain over a period of time.¹⁸,¹⁹ Given the coupling between cerebral blood volume and cerebral blood flow has been the target of numerous studies,²⁰,²¹ the notable impairment in cerebral blood volume among individuals with T2D revealed in our study may reflect an impairment in cerebral blood flow. These findings align with those reported by Kim et al.⁶ in individuals with uncomplicated T2D but with comorbid hypertension, which may contribute to the remodeling of systemic resistance arteries and reduced peripheral vascular conductance.²² It is worth noting that cerebral blood flow plays a crucial role in ensuring adequate oxygen and substrate delivery to the brain, and its regulation involves various mechanisms, including the partial pressure of arterial carbon dioxide (PaCO₂).²³

Interestingly, our study showed similar levels of PaCO₂ in both groups during exercise (at peak exercise, *P* > 0.05, PaCO₂ 34.4 ± 3.2 vs 34.5 ± 1.3 mmHg). However, previous research has demonstrated impaired vasodilatory capacity in individuals with T2D, affecting both systemic and cerebral vasculature. This impairment is reflected in altered cerebral CO₂ responsiveness²⁴ and reduced flow-mediated dilation due to decreased nitric oxide bioavailability.²⁵ Additionally, insulin resistance, which is elevated in T2D, can also influence cerebral blood flow.¹⁴ Indeed, individuals with insulin resistance but without T2D exhibited a significant impairment in cortical blood flow.²⁶ Hoscheidt et al. suggest that insulin resistance may influence both macrovessels and microvessels, potentially contributing to an uncoupling of arterial blood flow from regional cortical microperfusion. This uncoupling provides novel evidence that a mismatch of blood flow supply and demand may occur in discrete brain regions among individuals with elevated insulin resistance.¹³ While the underlying mechanisms for insulin resistance-related decreased cerebral perfusion are unknown, studies conducted in obese rats provide evidence that excessive generation of reactive oxygen species and uncoupling of the enzyme nitric oxide synthase attenuate bioavailability of nitric oxide (NO) and vasodilation in response to insulin levels.²⁷ A decrease in NO bioavailability in obesity and insulin resistance has also been attributed to decreased activity of the phosphatidylinositol 3-kinase²⁸ pathway and increases in caveolin-1,²⁸ potentially increasing the risk for vascular disease through the disruption of mechanisms involved in normal arterial function.

The prefrontal cortex plays a major role in executive functions. Although the individual's inability to adequately increase cortical blood flow in response to short bouts of exercise might not result in immediate clinical symptoms, this limitation could become problematic over the long term with sustained strenuous exercise programs.

## 4.2. Prefrontal cortex oxygenation during exercise

Furthermore, in addition to changes in cerebral blood volume, the levels of cerebral oxyhemoglobin (O₂Hb) also increase during exercise. This increase is dependent on neuronal oxygen extraction and regional cerebral blood flow. However, our findings indicate that individuals with T2D exhibited lower increments in O₂Hb, particularly at exercise intensities exceeding 80 % of VO₂peak. This observation is consistent with the study by Akira et al., who explained altered changes in O₂Hb in cardiac patients by the presence of cerebral hypoperfusion during incremental exercise and reduced PaCO₂ at peak exercise.²⁹ Interestingly, in our study, there were no differences in PaCO₂ between the groups. Therefore, we propose that the lower levels of O₂Hb in individuals with T2D may be attributed to mitochondrial dysfunction. Animal studies have further investigated this phenomenon and reported that brain mitochondria from sucrose-treated T2D mice exhibit decreased

respiratory control ratio, membrane potential, and ATP/ADP ratio compared to nondiabetic mice. This observed brain mitochondrial dysfunction in T2D may be attributed to higher reactive oxygen species production in combination with greater susceptibility to oxidative damage.³⁰

While this study offers valuable insights into the impact of hyperglycemia and insulin resistance on cerebral hemodynamics, several limitations should be acknowledged. Firstly, the relatively small sample size may limit the generalizability of the findings to broader populations. Additionally, excluding individuals with microvascular and macrovascular complications associated with T2D may restrict a comprehensive understanding of the effects of these complications on cerebral hemodynamics. Despite rigorous matching of demographic and anthropometric variables between groups, the potential influence of unaccounted factors cannot be entirely ruled out.

Nevertheless, this study boasts several strengths that enhance the validity and significance of its findings. The careful matching of demographic, anthropometric, and physical activity levels between the T2D and control groups ensures robust comparisons, minimizing potential confounding variables. Furthermore, the utilization of near-infrared spectroscopy measurements provides valuable insights into prefrontal cortex hemodynamics and oxygenation during incremental maximal exercise. This non-invasive approach allows for continuous monitoring of cerebral oxygenation status, contributing to a comprehensive understanding of cerebrovascular responses to physiological stressors in individuals with and without T2D.

Our findings provide valuable insights into the complex interplay between insulin resistance, hyperglycemia, cerebral blood flow, and oxygenation in individuals with T2D. We suggest that disturbances in cerebral oxygenation and metabolism in T2D may provoke central fatigue or hinder the central nervous system's ability to fully recruit the muscles involved in exercise. These observations have important implications for understanding the pathophysiology of insulin resistance and hyperglycemia and their potential contributions to cognitive dysfunction and neurovascular disorders. Further research is needed to elucidate the underlying mechanisms and identify potential therapeutic targets to mitigate the adverse effects of these metabolic abnormalities on cerebral vascular function and brain health.

### CRediT authorship contribution statement

**Islem Jlali:** Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing.
**Imen Touil:** Writing – review & editing.
**Hassen Haj Amor:** Writing – review & editing.
**Sémah Tagougui:** Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

### Author contribution

1) ST and IJ contributed to the conception and design of the study. ST and IJ coordinated the study and acquired the data. ST et IJ analysed the data. ST and IJ interpreted the data. 2) IJ drafted the manuscript. ST, IT and H critically revised the manuscript for important intellectual content. 3) All authors approved the final version of this manuscript.

### Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence
the work reported in this paper.

## Acknowledgements

The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. We are thankful to all the participants who dedicated their time and effort to complete this study. We would like to equally acknowledge the contributions of the diabetes nurses at Taher Sfar Hospital.

## Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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