Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes.
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.
Department of Integrative Biology & Physiology, University of California, Los Angeles, CA, USA.
Rahul
R
Agrawal
Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA.
Yumei
Y
Zhuang
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA; Department of Nutrition, University of California, Davis, CA, USA.
Bethany P
BP
Cummings
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA; Department of Nutrition, University of California, Davis, CA, USA.
Kimber L
KL
Stanhope
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA; Department of Nutrition, University of California, Davis, CA, USA.
James L
JL
Graham
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA; Department of Nutrition, University of California, Davis, CA, USA.
Peter J
PJ
Havel
Department of Integrative Biology & Physiology, University of California, Los Angeles, CA, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA. Electronic address: fgomezpi@mednet.ucla.edu.
Fernando
F
Gomez-Pinilla
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D007333:Insulin Resistance; D000069450:Liraglutide; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009765:Obesity / Q000150:complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000378:metabolism
D000447:Aldehydes; D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D011972:Receptor, Insulin; C027576:4-hydroxy-2-nonenal
Dietary energy restriction; Energy homeostasis; Insulin signaling; Liraglutide; Plasticity; Type-2 diabetes