Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes

Abstract

The rising prevalence of type-2 diabetes is becoming a pressing issue based on emerging reports that T2DM can also adversely impact mental health. We have utilized the UCD-T2DM rat model in which the onset of T2DM develops spontaneously across time and can serve to understand the pathophysiology of diabetes in humans. An increased insulin resistance index and plasma glucose levels manifested the onset of T2DM. There was a decrease in hippocampal insulin receptor signaling in the hippocampus, which correlated with peripheral insulin resistance index along the course of diabetes onset (r=-0.56, p<0.01). T2DM increased the hippocampal levels of 4-hydroxynonenal (4-HNE; a marker of lipid peroxidation) in inverse proportion to the changes in the mitochondrial regulator PGC-1α. Disrupted energy homeostasis was further manifested by a concurrent reduction in energy metabolic markers, including TFAM, SIRT1, and AMPK phosphorylation. In addition, T2DM influenced brain plasticity as evidenced by a significant reduction of BDNF-TrkB signaling. These results suggest that the pathology of T2DM in the brain involves a progressive and coordinated disruption of insulin signaling, and energy homeostasis, with profound consequences for brain function and plasticity. All the described consequences of T2DM were attenuated by treatment with the glucagon-like peptide-1 receptor agonist, liraglutide. Similar results to those of liraglutide were obtained by exposing T2DM rats to a food energy restricted diet, which suggest that normalization of brain energy metabolism is a crucial factor to counteract central insulin sensitivity and synaptic plasticity associated with T2DM.

Keywords: Dietary energy restriction; Energy homeostasis; Insulin signaling; Liraglutide; Plasticity; Type-2 diabetes.

Fig. 1

(A) Phosphorylation of insulin receptor (InR) and (B) IRS-1 in control (CON), pre-diabetic (Pre-db), 2 weeks-diabetic (2 wks-db), 3 months-diabetic (3 mos-db) and 6 months-diabetic (6 mos-db) groups. (C) Negative correlation between insulin resistance index (HOMA-R) and InR phosphorylation. ^#P<0.05, ^##P<0.01 Vs CON; ^**P<0.01 Vs Pre-db; ANOVA (one-way) followed by Bonferroni’s multiple comparison post-hoc test.

Fig. 2

(A) Phosphorylation of AMPK, (B) protein expression of SIRT1, (C) PGC-1α, (D) levels of 4HNE, (E) Negative correlation between PGC-1α expression and 4HNE and (F) TFAM in control (CON), pre-diabetic (Pre-db), 2 weeks-diabetic (2 wks-db), 3 months-diabetic (3 mos-db) and 6 months-diabetic (6 mos-db) groups. ^#P<0.05, ^##P<0.01 Vs CON; ^*P<0.05, ^**P<0.01 Vs Pre-db; ANOVA (one-way) followed by Bonferroni’s multiple comparison post-hoc test.

Fig. 3

(A) BDNF levels, (B) phosphorylation levels of TrkB and (C) Positive correlation between BDNF and PGC-1α expression in control (CON), Pre-diabetic (Pre-db), 2 weeks-diabetic (2 wks-db), 3 months-diabetic (3 mos-db) and 6 months-diabetic (6 mos-db) groups. ^##P<0.01 Vs CON; ^*P<0.05, ^**P<0.01 Vs Pre-db; ANOVA (one-way) followed by Bonferroni’s multiple comparison post-hoc test.

Fig. 4

(A) Phosphorylation of insulin receptor (InR) and (B) IRS-1 in vehicle (VEH), energy restricted (RES) diet and liraglutide (LIR) treated groups. ^##P<0.01 Vs VEH; ANOVA (one-way) followed by Bonferroni’s multiple comparison post-hoc test.

Fig. 5

(A) Phosphorylation of AMPK, (B) protein expression of SIRT1, (C) PGC-1α, (D) TFAM and (E) levels of 4HNE in vehicle (VEH), energy restricted (RES) diet and liraglutide (LIR) treated groups. ^#P<0.05, ^##P<0.01 Vs VEH; ANOVA (one-way) followed by Bonferroni’s multiple comparison post-hoc test.

Fig. 6

(A) BDNF levels and (B) Phosphorylation levels of TrkB in vehicle (VEH), energy restricted (RES) diet and liraglutide (LIR) treated groups. ^##P<0.01 Vs VEH; ANOVA (one-way) followed by Bonferroni’s multiple comparison post-hoc test.

Fig. 7

Proposed mechanism by which type-2 diabetes (T2DM) can affect the brain and leads to insulin resistance with subsequent effects on synaptic plasticity and mental health. It also suggests a mechanistic pathway by which insulin signaling and BDNF signaling can act on metabolic pathways that regulate brain plasticity and function. T2DM leads to the disruption of insulin and BDNF receptor signaling, thereby affecting the co-transcriptional regulator PGC-1α signaling. Impairment in PGC-1α function decreases mitochondrial biogenesis by suppressing mitochondrial DNA transcription, and mitochondrial proliferation through mitochondrial transcription factor A (TFAM). Reactive oxygen species (ROS), a byproduct of mitochondrial electron transport chain, leads to generation of 4-hydroxynonenal (4HNE) via lipid peroxidation. In turn, 4HNE disrupts mitochondrial function and overall neuronal functions. The treatment with liraglutide (LIR), a glucagon-like peptide-1 (GLP-1) agonist, prevents the detrimental influence of T2DM on synaptic plasticity by enhancing insulin receptor signaling in brain, and possibly by reducing oxidative stress (ROS). Dietary energy restriction (RES) mainly increases mitochondrial biogenesis, thereby helping to preserve brain plasticity and mental health under diabetic condition. Overall, these events are important to understand how T2DM influences brain functions and synaptic plasticity. The insulin and mitochondrial interventions appear crucial for the maintenance of neuronal function and promote mental health.