Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subjects
2.2. Immunohistochemistry (IHC) for Quantification of Proteins in Human Hippocampal Area
2.3. Cell Culture and Treatments
2.4. Quantitative Polymerase Chain Reaction (qPCR) for Gene Expression Analysis
2.5. Protein Extraction and Western Blotting for Protein Expression Analysis
2.6. Chromatin Immunoprecipitation Assay (ChIP Assay) for p65 Analysis
2.7. Statistical Analysis
3. Results
3.1. Clinical and Demographic Characteristics of the Subjects Studied
3.2. GLUT4 Protein Detection in Hippocampus of Human Brain
3.3. Diabetes Decreases Neuronal GLUT4 Protein Content and Soma Area in Hippocampal CA4/Hilus Area
3.4. Obesity Increases NFKB Subunit p65 but Does Not Change Carboxymethyllysine (CML) Content in Neurons from Hippocampal CA4/Hilus Area
3.5. TNF Represses SLC2A4/GLUT4 Expression by a NFKB-Mediated Mechanism in Human Neuronal SH-SY5Y Cells
3.6. TNF Represses the Expression of Neuronal Markers in Human Neuronal SH-SY5Y Cells
3.7. Inhibition of Histone Deacetylase 3 (HDAC3) Increases SLC2A4 Expression, Abrogates TNF-Induced Re-Pression of SLC2A4 Repression and Enhances Nuclear Content of CREB in Human Neuronal SH-SY5Y Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Data Availability Statement
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
ADGs | AD-related genes |
AGEs | advanced glycation end products |
BBB | blood–brain barrier |
BAS | Biobank for Aging Study |
BMI | body mass index |
CA1 | cornu ammonis 1 area |
CA4 | cornu ammonis 4 area |
CHIP | chromatin Immunoprecipitation |
CML | carboxymethyllysine |
CNS | central nervous system |
CREB/ICER | CRE-binding proteins |
DAB | 3-3-diaminobenzidine tetrahydrochloride |
DM | diabetes mellitus |
GA | glycated albumin |
GLUT1 | glucose transporter type 1 protein |
GLUT3 | glucose transporter type 3 protein |
GLUT4 | glucose transporter type 4 protein |
GVD | granulovacuolar degeneration |
H3Kac | lysine acetylation of histone 3 |
H4Kac | lysine acetylation of histone 4 |
H3K9ac | lysine 9 acetylation of histone 3 |
HDAC3 | histone deacetylase 3 |
IHC | immunohistochemistry |
IR | insulin resistance |
MTT | tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide |
OB | obese subject |
OBDM | obese diabetic subject |
p65 | nuclear factor NF-kappa-B subunit p65 |
PB | phosphate buffer |
qPCR | quantitative polymerase chain reaction |
RAGE | advanced glycation end product receptor |
RGFP-996 | HDAC3 inhibitor |
SYP | synaptophysin protein |
SYP | synaptophysin gene (human) |
SYN1 | synapsin-1 (protein) |
SYN1 | synapsin-1 gene (human) |
Slc2a4 | solute carrier family 2 member 4 gene (mouse) |
SLC2A4 | solute carrier family 2 member 4 gene (human |
SPAS | Sao Paulo Autopsy Service |
TNF | tumor necrosis factor |
T1D | type 1 diabetes |
T2D | type 2 diabetes |
TH | tyrosine hydroxylase protein |
TH | tyrosine hydroxylase gene (human) |
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Variables | Control n = 9 | Obese n = 21 | Obese with DM n = 11 |
---|---|---|---|
Age (years), mean ± SD | 60.22 ± 9.52 | 61.95 ± 12.55 | 69.73 ± 10.54 |
BMI (kg/m2), mean ± SD | 27.21 ± 1.49 | 31.99 ± 1.38 * | 32.29 ± 1.67 * |
Male, n (%) | 3 (33.3) | 11 (52.4) | 4 (36.4) |
Ethnicity, n (%) | |||
White | 4 (44.4) | 17 (80.9) | 7 (63.6) |
Brown | 3 (33.3) | 1 (4.8) | 2 (18.2) |
Black | 2 (22.2) | 3 (14.3) | 2 (18.2) |
Socioeconomic class, n (%) | |||
High | 0 (0) | 7 (33.3) | 2 (18.2) |
Middle | 3 (33.3) | 6 (28.6) | 5 (45,5) |
Low | 6 (66.7) | 8 (38.1) | 4 (36.3) |
Education (years), mean ± SD | 5.33 ± 2.95 | 6.9 ± 3.91 | 5.45 ± 4.9 |
Dyslipidemia, n (%) | 0 (0) | 3 (14.3) | 1 (9) |
Smoking, n (%) | 4 (44.4) | 5 (23.8) | 5 (45.5) |
Alcohol use disorder, n (%) | 3 (33.3) | 1 (4.8) | 0 (0) |
Coronary arterial disease, n (%) | 1 (11.1) | 4 (19.0) | 2 (18.2) |
Hypertension, n (%) | 8 (89) | 16 (76.0) | 9 (81.8) |
Heart failure, n (%) | 0 (0) | 5 (23.8) | 3 (27.3) |
Cerebrovascular disease, n (%) | 1 (11.1) | 1 (4.8) | 4 (36.4) |
Alzheimer’s disease, n (%) | 0 (0) | 0 (0) | 1 (9) |
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Yonamine, C.Y.; Passarelli, M.; Suemoto, C.K.; Pasqualucci, C.A.; Jacob-Filho, W.; Alves, V.A.F.; Marie, S.K.N.; Correa-Giannella, M.L.; Britto, L.R.; Machado, U.F. Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation. Cells 2023, 12, 1250. https://doi.org/10.3390/cells12091250
Yonamine CY, Passarelli M, Suemoto CK, Pasqualucci CA, Jacob-Filho W, Alves VAF, Marie SKN, Correa-Giannella ML, Britto LR, Machado UF. Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation. Cells. 2023; 12(9):1250. https://doi.org/10.3390/cells12091250
Chicago/Turabian StyleYonamine, Caio Yogi, Marisa Passarelli, Claudia Kimie Suemoto, Carlos Augusto Pasqualucci, Wilson Jacob-Filho, Venâncio Avancini Ferreira Alves, Suely Kazue Nagahashi Marie, Maria Lucia Correa-Giannella, Luiz Roberto Britto, and Ubiratan Fabres Machado. 2023. "Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation" Cells 12, no. 9: 1250. https://doi.org/10.3390/cells12091250