Gao XY, Zhou CX, Li HM, Cheng M, Chen D, Li ZY, Feng B, Song J. Correlation between cerebral neurotransmitters levels by proton magnetic resonance spectroscopy and HbA1c in patients with type 2 diabetes. World J Diabetes 2024; 15(6): 1263-1271 [DOI: 10.4239/wjd.v15.i6.1263]
Corresponding Author of This Article
Jun Song, PhD, Department of Endocrinology, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China. songjuntj@tongji.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Observational Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xiang-Yu Gao, Chen-Xia Zhou, Hong-Mei Li, Da Chen, Zi-Yi Li, Bo Feng, Jun Song, Department of Endocrinology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
Xiang-Yu Gao, Department of Endocrinology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266000, Shandong Province, China
Min Cheng, Department of Immunization Program, Huangdao District Center for Disease Prevention and Control, Qingdao 266400, Shandong Province, China
Author contributions: Song J and Feng B designed the study and provided critical suggestions of the manuscript and should be considered as co-corresponding authors; Gao XY and Zhou CX analyzed the data, illustrated the results, and wrote the initial manuscript, these authors contributed equally to this work; Li HM and Cheng M participated in samples collection and information input; Chen D and Li ZY corrected language errors and revised the article critically for important intellectual content.
Supported bythe Academic Leaders Training Program of Pudong Health Bureau of Shanghai, No. PWRd2023-03; Clinical Research Fund of Shanghai Municipal Commission of Health, No. 202040136; National Natural Science Foundation of China, No. 82070842; and Jiangxi Health Commission Science and Technology Plan Project, No. 202212838 and No. 202212852.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Shanghai East Hospital (Approval No. 2021023).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: All datasets generated for this study were all included in the manuscript files and the raw data may be obtained from the corresponding author for appropriate justification.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jun Song, PhD, Department of Endocrinology, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China. songjuntj@tongji.edu.cn
Received: December 22, 2023 Revised: March 28, 2024 Accepted: April 24, 2024 Published online: June 15, 2024
Abstract
BACKGROUND
Cognitive dysfunction is the main manifestation of central neuropathy. Although cognitive impairments tend to be overlooked in patients with diabetes mellitus (DM), there is a growing body of evidence linking DM to cognitive dysfunction. Hyperglycemia is closely related to neurological abnormalities, while often disregarded in clinical practice. Changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities and may be closely related to blood glucose control in patients with type 2 DM (T2DM).
AIM
To evaluate the concentrations of cerebral neurotransmitters in T2DM patients exhibiting different hemoglobin A1c (HbA1c) levels.
METHODS
A total of 130 T2DM patients were enrolled at the Department of Endocrinology of Shanghai East Hospital. The participants were divided into four groups according to their HbA1c levels using the interquartile method, namely Q1 (< 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%) and Q4 (≥ 11.200%). Clinical data were collected and measured, including age, height, weight, neck/waist/hip circumferences, blood pressure, comorbidities, duration of DM, and biochemical indicators. Meanwhile, neurotransmitters in the left hippocampus and left brainstem area were detected by proton magnetic resonance spectroscopy.
RESULTS
The HbA1c level was significantly associated with urinary microalbumin (mALB), triglyceride, low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell function (HOMA-β), N-acetylaspartate/creatine (NAA/Cr), and NAA/choline (NAA/Cho). Spearman correlation analysis showed that mALB, LDL-C, HOMA-IR and NAA/Cr in the left brainstem area were positively correlated with the level of HbA1c (P < 0.05), whereas HOMA-β was negatively correlated with the HbA1c level (P < 0.05). Ordered multiple logistic regression analysis showed that NAA/Cho [Odds ratio (OR): 1.608, 95% confidence interval (95%CI): 1.004-2.578, P < 0.05], LDL-C (OR: 1.627, 95%CI: 1.119-2.370, P < 0.05), and HOMA-IR (OR: 1.107, 95%CI: 1.031-1.188, P < 0.01) were independent predictors of poor glycemic control.
CONCLUSION
The cerebral neurotransmitter concentrations in the left brainstem area in patients with T2DM are closely related to glycemic control, which may be the basis for the changes in cognitive function in diabetic patients.
Core Tip: Diabetic neuropathy is one of the most common chronic complications, and its pathogenesis has not been fully clarified until now, especially the central neuropathy. Cognitive dysfunction is the main manifestation of central neuropathy, although cognitive impairments tend to be neglected in diabetes, there is factually increasing evidence linking diabetes mellitus (DM) to cognitive dysfunction. Several studies indicated that the changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities. Here, we described the relationship between cerebral neurotransmitters concentrations that were measured using proton magnetic resonance spectroscopy and hemoglobin A1c levels in patients with type 2 DM.
Citation: Gao XY, Zhou CX, Li HM, Cheng M, Chen D, Li ZY, Feng B, Song J. Correlation between cerebral neurotransmitters levels by proton magnetic resonance spectroscopy and HbA1c in patients with type 2 diabetes. World J Diabetes 2024; 15(6): 1263-1271
Diabetes mellitus (DM) can lead to a variety of chronic complications, especially in patients with a long disease duration and poor glycemic control. Complications may affect the heart and vascular system, kidneys, nervous system, retinas, and feet, leading to a serious burden on public health and the economy[1]. Distal symmetric peripheral polyneuropathy is the most common type of diabetic neuropathy[2,3], by contrast, central neuropathy is often disregarded. Few studies to date have focused on central neuropathy in patients with DM, and the changes that occur in morphologic and functional neurology-related substances are unclear, thus there is a need to develop a diagnostic technique for further explore central neuropathy in diabetic patients. Cognitive dysfunction is the main manifestation of central neuropathy, although cognitive impairments tend to be neglected in patients with DM, there is factually increasing evidence linking DM to cognitive dysfunction. This association was first reported half a century ago[4]. Several studies have indicated that changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities[5-7]. However, few studies have focused on the changes in cerebral neurotransmitter levels in diabetic patients.
Proton magnetic resonance spectroscopy (1H-MRS) is a powerful tool that is used to identify neurometabolic substrates and neurotransmitters in the human brain. 1H-MRS has the advantages of being noninvasive, having high spatial resolution, and accurately localizing cerebral functional regions. Additionally, it can detect energy metabolism, reveal biochemical changes, and quantitatively analyze compounds in living tissues[8,9]. Neurotransmitters such as N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) are primarily monitored. NAA is a marker of neurons and axons, which concentration reflect the number and function of neurons[10]. Cho is mainly distributed in glial cells, and it participates in cell membrane composition and myelin formation[11]. Cr is involved in energy metabolism, and is often used as a reference resonance against which the NAA or Cho or both can be compared due to its relatively constant throughout the normal brain tissue and in different pathological conditions[12,13]. In the present study, we used 1H-MRS to investigate the possible association of various neurotransmitters with cerebral metabolic changes in T2DM patients with different levels of HbA1c.
MATERIALS AND METHODS
Study subjects’ recruitment
A total of 130 inpatients with T2DM, including 75 males and 55 females, in Department of Endocrinology, Shanghai East Hospital were recruited. The mean age was (60.98 ± 13.13) years and the duration of diabetes was (10.00 ± 8.80) years. All participants met the 1999 World Health Organization criteria for T2DM diagnosis. Exclusion criteria include: Neuropsychiatric disorders, acute infection, thyroid dysfunction, severe heart failure, cardiac function (NYHA) > level III, severe hepatic dysfunction, chronic renal failure or other serious medical conditions. And patients were divided into four groups according to HbA1c levels by interquartile method: Q1 (< 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%), and Q4 (≥ 11.200%). This study was approved by the Ethics Committee of Shanghai East Hospital, and all subjects signed informed consent in accordance with the Declaration of Helsinki. The study was registered in the Chinese clinical trial registry (ChiCTR-2100047148).
Clinical variables detection
The patients’ basic clinical data were collected, including age, sex, height, weight, body mass index, neck/waist/hip circumferences, duration of DM, systolic blood pressure, diastolic blood pressure, and clinical complications. Fasting blood samples and early morning urine samples were collected from each individual and used to detect a series of biochemical metrics, including HbA1c, urinary microalbumin (mALB), total cholesterol, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, fasting blood glucose, fasting insulin, besides, homeostasis model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-β) were also calculated.
Neurotransmitters measurement
In this study, we utilized a 1.5T superconducting magnetic resonance imaging system (Eclipse; Marconi Medical System/Philips Medical Systems, Best, the Netherlands) and point-resolved spectroscopy for monomer hydrogen protons. The dimensions for MRS in both the left hippocampus and left brainstem area were set at 20 mm × 20 mm × 20 mm. During the scanning process, the head was kept still to prevent artifacts from head movement, and the collection time for the hippocampus and brainstem region was 228 seconds. The data analysis software of the Eclipse system was used to obtain the following neurotransmitter ratios in various brain tissues with Cr as a reference: NAA/Cr, Cho/Cr and NAA/Cho.
Statistical analysis
Quantitative data were presented as mean ± SD or median (P25, P75), and categorical data were summarized using frequencies as well as percentages of participants. Mann-Whitney U-test or chi-square test was used for non-parametric data to compare the differences in variables between different subgroups. Spearman correlation analysis was used to assess the relationship between neurotransmitters with HbA1c. Furthermore, ordinal regression analysis was used to analyze the independent predictors after adjusting for possible confounding factors. P values < 0.05 were considered as statistically significant. All analyses were performed using SPSS Version 26.0 (IBM Corp., Armonk, NY, United States).
RESULTS
Clinical and biochemical features of T2DM patients by quartiles of HbA1c
Patients were categorized into four groups according to quartiles of the HbA1c level: Q1 (< 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%), and Q4 (≥ 11.200%). The clinical characteristics were shown in Table 1. We found that patients with the higher HbA1c levels had lower TG (P < 0.05) and HOMA-β (P < 0.01) but higher mALB, LDL-C and HOMA-IR (P < 0.05).
Table 1 Clinical characteristics of study participates by quartiles of hemoglobin A1c.
Variables
HbA1c quartiles
P value
Q1 (< 7.875), n = 32
Q2 (7.875-9.050), n = 33
Q3 (9.050-11.200), n = 32
Q4 (≥ 11.200), n = 33
Age (yr)
63.5 ± 13.3
60.9 ± 9.7
59.5 ± 16.1
60.2 ± 13.0
0.640
Sex (male/female)
18/14 (56.3/43.8)
16/17 (48.5/51.5)
20/12 (62.5/37.5)
21/12 (63.6/36.4)
0.582
Diabetes duration (yr)
6.5 (3.0, 17.5)
10 (6.5, 15.0)
8.0 (1.3, 19.8)
5.0 (1.0, 12.0)
0.173
Height (cm)
165.6 ± 8.1
164.2 ± 8.8
166.8 ± 9.0
167.4 ± 6.6
0.392
Weight (cm)
71.5 ± 11.5
70.9 ± 11.4
73.8 ± 18.3
71.4 ± 8.7
0.803
BMI (kg/m2)
26.1 ± 3.7
26.2 ± 3.3
26.2 ± 4.5
25.4 ± 2.5
0.772
Neck line (cm)
39.1 ± 3.5
38.2 ± 3.8
38.3 ± 4.0
38.4 ± 2.4
0.731
Waist line (cm)
97.3 ± 8.9
95.0 ± 10.2
94.5 ± 11.1
94.7 ± 8.5
0.646
Hip line (cm)
103.5 ± 8.3
102.1 ± 8.8
100.3 ± 9.7
100.9 ± 8.7
0.492
WHR
0.94 ± 0.05
0.93 ± 0.04
0.94 ± 0.05
0.94 ± 0.04
0.698
SBP (mmHg)
132.8 ± 21.2
139.1 ± 17.5
132.6 ± 20.3
134.3 ± 16.2
0.474
DBP (mmHg)
77.2 ± 9.0
80.0 ± 8.2
78.3 ± 9.0
80.3 ± 8.0
0.415
mALB (g/L)
11.0 (11.0, 41.5)
11.0 (10.5, 50.0)
32.5 (12.0, 123.5)
20.0 (12.5, 53.5)
0.031
TC (mmol/L)
4.46 ± 1.01
4.70 ± 1.11
4.81 ± 1.29
5.00 ± 1.35
0.321
TG (mmol/L)
1.54 (1.04, 2.32)
2.17 (1.10, 2.93)
1.81 (1.37, 3.83)
1.37 (0.84, 2.28)
0.044
HDL-C (mmol/L)
1.25 ± 0.37
1.11 ± 0.32
1.10 ± 0.31
1.14 ± 0.31
0.274
LDL-C (mmol/L)
2.83 ± 1.10
3.02 ± 1.02
2.89 ± 0.88
3.51 ± 1.15
0.037
HOMA-IR
3.09 (1.69, 4.48)
4.59 (3.07, 7.12)
6.05 (4.34, 10.41)
6.06 (3.62, 8.14)
< 0.001
HOMA-β
80.15 (35.79, 131.06)
38.55 (21.90, 73.18)
53.04 (22.48, 96.73)
21.70 (10.86, 45.92)
0.001
Complicated with hypertension (%)
17 (53.1)
21 (63.6)
17 (53.1)
18 (54.5)
0.796
Complicated with CHD (%)
20 (62.5)
18 (54.5)
23 (71.9)
18 (54.5)
0.429
Neurotransmitters detected by 1H-MRS
As showed in Table 2, there were statistically significant differences in NAA/Cr and NAA/Cho in the left brainstem area between these groups (P < 0.05). Specifically, higher quartiles of HbA1c were associated with higher NAA/Cr and NAA/Cho. However, there were no significant differences in the neurotransmitters levels of the left hippocampus. And the significant differences among the four groups are presented in more detail in Figure 1.
Figure 1 Cerebral neurotransmitters concentrations measured using proton magnetic resonance spectroscopy with different levels of hemoglobin A1c in patients with type 2 diabetes mellitus.
A: N-acetylaspartate/creatine (NAA/Cr, left hippocampus); B: Choline (Cho)/Cr (left hippocampus); C: NAA/Cho (left hippocampus); D: NAA/Cr (left brainstem area); E: Cho/Cr (left brainstem area); F: NAA/Cho (left brainstem area). Q1: Hemoglobin A1c (HbA1c) < 7.875%; Q2: HbA1c 7.875%-9.050%; Q3: HbA1c 9.050%-11.200%; Q4: HbA1c ≥ 11.200%. NAA: N-acetylaspartate; Cr: Creatine; Cho: Choline.
Table 2 Neurotransmitter levels of participates by quartiles of hemoglobin A1c.
Neurotransmitters
HbA1c quartiles
P value
Q1 (< 7.875), n = 32
Q2 (7.875-9.050), n = 33
Q3 (9.050-11.200), n = 32
Q4 (≥ 11.200), n = 33
NAA/Cr (left hippocampus)
1.43 (0.55, 2.58)
0.74 (0.36, 1.72)
1.02 (0.80, 1.99)
1.60 (0.78, 3.10)
0.082
Cho/Cr (left hippocampus)
0.75 (0.42, 1.32)
0.96 (0.51, 1.63)
1.10 (0.29, 2.28)
1.36 (0.68, 2.27)
0.277
NAA/Cho (left hippocampus)
1.27 (0.62, 4.48)
1.02 (0.42, 1.61)
0.83 (0.44, 2.88)
0.95 (0.47, 1.81)
0.529
NAA/Cr (left brainstem area)
0.84 (0.33, 1.58)
1.17 (0.63, 2.11)
0.92 (0.30, 1.94)
1.72 (1.04, 3.48)
0.024
Cho/Cr (left brainstem area)
1.13 (0.62, 2.04)
1.55 (0.76, 3.44)
1.54 (1.28, 2.82)
1.74 (0.70, 2.49)
0.299
NAA/Cho (left brainstem area)
0.91 (0.32, 1.64)
0.71 (0.47, 1.06)
0.69 (0.31, 1.11)
1.41 (0.82, 2.05)
0.013
Correlations of neurotransmitters with HbA1c
Spearman correlation analysis was conducted to identify the potential clinical characteristics and neurotransmitters that might be related with HbA1c. As shown in Table 3, mALB, LDL-C, HOMA-IR, and NAA/Cr in left brainstem area were significantly positively correlated with the HbA1c level (P < 0.05), whereas HOMA-β was negatively correlated with the HbA1c level.
Table 3 Correlation between variables and hemoglobin A1c by Spearman correlation analysis.
Variables
r
P value
Age (yr)
-0.063
0.474
Sex (male/female)
-0.082
0.351
Diabetes duration (yr)
-0.150
0.090
Height (cm)
0.113
0.201
Weight (cm)
0.057
0.518
BMI (kg/m2)
-0.046
0.605
Neck line (cm)
-0.087
0.327
Waist line (cm)
-0.091
0.303
Hip line (cm)
-0.135
0.126
WHR
0.011
0.897
SBP (mmHg)
0.028
0.753
DBP (mmHg)
0.093
0.294
mALB (g/L)
0.215
0.014
TC (mmol/L)
0.154
0.081
TG (mmol/L)
-0.036
0.686
HDL-C (mmol/L)
-0.096
0.275
LDL-C (mmol/L)
0.216
0.014
HOMA-IR
0.345
< 0.001
HOMA-β
-0.316
< 0.001
Complicated with hypertension (%)
-0.015
0.868
Complicated with CHD (%)
-0.016
0.860
NAA/Cr (left hippocampus)
0.090
0.310
Cho/Cr (left hippocampus)
0.168
0.056
NAA/Cho (left hippocampus)
-0.061
0.502
NAA/Cr (left brainstem area)
0.257
0.007
Cho/Cr (left brainstem area)
0.128
0.182
NAA/Cho (left brainstem area)
0.166
0.081
Independent factors associated with HbA1c
Next, we conducted an ordinal regression analysis to further investigate the independent factors associated with HbA1c. Indicators with statistical significance in the correlation analysis and all neurotransmitters metrics were incorporated into the regression analysis model. As Table 4 showed, after adjustment for mALB, HOMA-β, and NAA/Cr (left brainstem area), Cho/Cr (left brainstem area) and the ratio of neurotransmitters in the left hippocampus, we found that LDL-C [Odds ratio (OR): 1.627, 95% confidence interval (95%CI): 1.119-2.370, P = 0.011], HOMA-IR (OR: 1.107, 95%CI: 1.031-1.188, P = 0.005), and NAA/Cho (left brainstem area) (OR: 1.608, 95%CI: 1.004-2.578, P = 0.048) were independently associated with HbA1c.
Table 4 Independent factors related to hemoglobin A1c by ordinal logistic regression analysis.
Factors
OR (95%CI)
P value
mALB (g/L)
1.000 (0.999-1.001)
0.896
LDL-C (mmol/L)
1.627 (1.119-2.370)
0.011
HOMA-IR
1.107 (1.031-1.188)
0.005
HOMA-β
1.000 (1.000-1.001)
0.675
NAA/Cr (left hippocampus)
0.998 (0.971-1.025)
0.907
Cho/Cr (left hippocampus)
0.997 (0.882-1.127)
0.963
NAA/Cho (left hippocampus)
0.907 (0.795-1.035)
0.145
NAA/Cr (left brainstem area)
1.006 (0.894-1.133)
0.915
Cho/Cr (left brainstem area)
1.000 (0.901-1.108)
0.997
NAA/Cho (left brainstem area)
1.608 (1.004-2.578)
0.048
DISCUSSION
In the present study, we evaluated the relationship between cerebral neurotransmitter concentrations measured using 1H-MRS and the HbA1c levels in patients with T2DM. Diabetic neuropathy is one of the most common chronic complications of DM, and its pathogenesis (especially that of central neuropathy) has not been fully clarified until now. Additionally, research on the changes of brain function that occur in diabetic patients remains insufficient. As an important neurological complication of diabetes, cognitive dysfunction may be observed very early in the disease course but is often neglected in clinical practice. In fact, the incidence of cognitive impairment in patients with T2DM ranges from 10.8% to 17.5%[14], indicating that hyperglycemia is closely related to neurological abnormalities. Moreover, cognitive impairment is difficult to be accurately defined, and scales such as the Mini-Mental State Examination and the Montreal Cognitive Assessment are often used to quantify scores in daily clinical practice[15]. However, cerebral metabolic molecular detection is not widely available, possibly because of measurement constraints. At present, with the deepening understanding of cognitive impairment among the public and the popularization of 1H-MRS, increasing numbers of studies are suggesting that changes in brain neurotransmitter levels might be involved in the pathological process of cognitive impairment[7,16,17]. 1H-MRS is widely used to investigate neuropsychiatric diseases with the advantages of noninvasiveness and high accuracy[14]. The main neurotransmitters evaluated mainly include NAA, Cho, Cr, myo-inositol (mI), the combination of glutamate and glutamine, lactate, and gamma-aminobutyric acid (GABA), etc.
Cr values, which encompass Cr, Cr phosphate and lower levels of GABA, serve as an indicator of energy metabolism. Cr acts as a reserve form of high-energy phosphates and a buffer for ATP and ADP[18]. Studies have shown that the concentration of Cr is relatively constant under different metabolic conditions in the brain, including pathological conditions[12,13]. In the present study, Cr was also used as an internal reference to examine changes in the concentration of other metabolites. NAA mainly exists in neurons. In normal brain tissue measured by 1H-MRS, NAA exhibits the highest peak and mainly exists in mature neurons and neurites such as axons, serving as a marker for neurons. Thus, its content reflects the functional status and integrity of neurons. Recent studies have suggested that declining NAA levels in gray matter reflect death or injury of neurons and changes in the neurometabolic status, whereas declining NAA levels in white matter reflect loss or injury of axons[19,20]. Cho values encompass glycerol Cho phosphate, Cho phosphate, and phosphatidylcholine, which are involved in the synthesis and breakdown of cell membranes[11]. These neuromediators tend to be involved in the physiological activities of brain functions such as memory function and cognitive function, but how changes in the concentrations in different nerve tissues and sites relate to pathophysiological changes in diabetic patients still remains poorly understood.
Since specific cerebral regions such as the hippocampus, frontal cortex, basal ganglia and brainstem play critical roles in learning and memory, previous studies have mostly examined the levels of neurotransmitters in these areas[21-23]. Previous findings have demonstrated that the NAA concentration is reduced in the hippocampus of diabetic patients, suggesting the presence of neuronal damage and cognitive dysfunction[24-26]. One such study showed that the NAA concentration was decreased in the visual cortex along with an increase of HbA1c level, and that NAA/Cr and NAA/Cho decreased as diabetic retinopathy progressed, although these decreases were not statistically significant[27]. Researchers in Netherlands also reported that no alterations in NAA and Cho were observed in the cerebral white matter (centrum semiovale) of patients with T2DM, and they considered that these neurotransmitters should not be regarded as predictors of cognitive impairment in diabetic patients[28]. Our previous studies also showed that cognitive dysfunction and obstructive sleep apnea hypopnea syndrome in diabetic patients were associated with changes in neurotransmitter contents[29,30]. The results of the present study differ from previous findings in that no significant differences in the neurotransmitters within the hippocampus were observed between subgroups, while NAA/Cr and NAA/Cho in the left brainstem area were elevated with the increase of HbA1c level in T2DM patients. It should be noted that previous studies primarily focused on different cerebral regions, focusing much less on the brain, which may offer unique insights. Additionally, most previous studies focused on the differences in neurotransmitter levels between patients with or without DM, whereas all the participants in our study had T2DM, and they were grouped according to their HbA1c level to detect the changes in neurotransmitters with different HbA1c levels. Of course, the absence of a normal control group for comparison is a limitation of the present study. Additionally, the underlying mechanism causing brain damage in patients with diabetes requires further investigation.
In addition to cerebral neurotransmitters, the present results also indicated that T2DM patients with the higher HbA1c quartiles had lower HOMA-β and higher HOMA-IR. Furthermore, after adjustment for confounding factors via ordinal regression analysis, LDL-C, HOMA-IR and NAA/Cho (left brainstem area) were independently associated with HbA1c and acted as positive predictors of poor glycemic control.
CONCLUSION
The cerebral neurotransmitter levels in the left brainstem area of T2DM patients are closely related to blood glucose control. Thus, their measurement serves as a sensitive method for early monitoring of cerebral function changes in diabetic patients, which maybe play a vital indicative role in prevention of cognitive impairment in diabetic patients in the future. Moreover, further prospective studies involving more participants of various age groups and a healthy control population as well as randomized controlled trials are necessary to validate our findings and gain a more comprehensive understanding of the associations explored in the present work.
ACKNOWLEDGEMENTS
The authors would like to thank the members of the Medical Imaging Department, East Hospital, Tongji University School of Medicine for their technical support. And we also thank Angela Morben for editing the English text of a draft of this manuscript.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Dabla PK, India; Horowitz M, Australia S-Editor: Chen YL L-Editor: A P-Editor: Xu ZH
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