Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation

Abstract

Diabetes mellitus (DM) is an important risk factor for dementia, which is a common neurodegenerative disorder. DM is known to activate inflammation, oxidative stress, and advanced glycation end products (AGEs) generation, all capable of inducing neuronal dysfunctions, thus participating in the neurodegeneration progress. In that process, disturbed neuronal glucose supply plays a key role, which in hippocampal neurons is controlled by the insulin-sensitive glucose transporter type 4 (GLUT4). We investigated the expression of GLUT4, nuclear factor NF-kappa B subunit p65 [NFKB (p65)], carboxymethyllysine and synapsin1 (immunohistochemistry), and soma area in human postmortem hippocampal samples from control, obese, and obese+DM subjects (41 subjects). Moreover, in human SH-SY5Y neurons, tumor necrosis factor (TNF) and glycated albumin (GA) effects were investigated in GLUT4, synapsin-1 (SYN1), tyrosine hydroxylase (TH), synaptophysin (SYP) proteins, and respective genes; NFKB binding activity in the SLC2A4 promoter; effects of increased histone acetylation grade by histone deacetylase 3 (HDAC3) inhibition. Hippocampal neurons (CA4 area) of obese+DM subjects displayed reduced GLUT4 expression and neuronal soma area, associated with increased expression of NFKB (p65). Challenges with TNF and GA decreased the SLC2A4/GLUT4 expression in SH-SY5Y neurons. TNF decreased SYN1, TH, and SYP mRNAs and respective proteins, and increased NFKB binding activity in the SLC2A4 promoter. Inhibition of HDAC3 increased the SLC2A4 expression and the total neuronal content of CRE-binding proteins (CREB/ICER), and also counterbalanced the repressor effect of TNF upon these parameters. This study revealed reduced postmortem human hippocampal GLUT4 content and neuronal soma area accompanied by increased proinflammatory activity in the brains of DM subjects. In isolated human neurons, inflammatory activation by TNF reduced not only the SLC2A4/GLUT4 expression but also the expression of some genes related to neuronal function (SYN1, TH, SYP). These effects may be related to epigenetic regulations (H3Kac and H4Kac status) since they can be counterbalanced by inhibiting HDAC3. These results uncover the improvement in GLUT4 expression and/or the inhibition of HDAC3 as promising therapeutic targets to fight DM-related neurodegeneration.

Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia

“…These data ascribe the hippocampal GLUT4 protein the same functional role it plays in the classic insulin-sensitive tissues [40], placing the transporter as a key player in the hippocampal metabolic glucose utilization. Additionally, we and others have already described GLUT4 in hippocampal neurons of the human brain, where it seems to play an important role under pathological conditions, as further discussed [74][75][76].…”

“…This observation indicates that inflammation is an important mechanism for neurodegeneration during the health-T2D transition. Additionally, no alterations in the immunoreactivity for carboxymethyllysine (a marker of AGE activity) was observed in hippocampal CA4 neurons from obese or obese diabetic subjects [76].…”

“…Hippocampal neurons of the cornu ammonis 4 area (CA4 area) from obese + T2D subjects displayed reduced GLUT4 expression and neuronal soma area, associated with an increased expression of NFKB-p65 (a marker of inflammatory activity). Interestingly, increased inflammatory activity (NFKB-p65 expression) was also observed in the CA4 area from obese subjects without T2D, although decreased GLUT4 expression and reduced neuronal soma area have not been detected in these subjects yet [76]. This observation indicates that inflammation is an important mechanism for neurodegeneration during the health-T2D transition.…”

“…Recently, we have investigated the GLUT4 expression and possible AD-related mechanisms in postmortem brains from obese and obese + T2D subjects [76]. Hippocampal neurons of the cornu ammonis 4 area (CA4 area) from obese + T2D subjects displayed reduced GLUT4 expression and neuronal soma area, associated with an increased expression of NFKB-p65 (a marker of inflammatory activity).…”

Tirzepatide prevents neurodegeneration through multiple molecular pathways

“…Moreover, hyperglycemia by modulating the expression of glucose transporters induces neuronal insulin resistance [ 60 ]. In the brains of AD patients, a significant reduction in the expression of GLUT1, GLUT3, and GLUT4 was observed, impacting neuronal activity [ 61 ], progressive neuronal loss, and neurodegeneration [ 58 , 62 ]. Intriguingly, in our study, we observed that TIR treatment prevented the HG induced mRNA and protein downregulation of GLUT3 along with GLUT1, GLUT4, and SORBS1, a protein that takes part in diabetes pathogenesis [ 31 ], and regulates GLUT4 translocation [ 32 ] affecting neuronal insulin resistance [ 63 ].…”