Lawrence P. Reagan, Ph.D.
Professor & Vice Chair
Department of Pharmacology, Physiology and Neuroscience
University of South Carolina School of Medicine
Columbia, SC



Diabetes and obesity as chronic metabolic stressors

In addition to peripheral complications, it is becoming increasingly clear that the complications of type 2 diabetes (T2DM) and insulin resistance (IR) extend to the central nervous system (CNS) and include deficits in cognitive function. A major obstacle in the identification of the mechanistic basis for neuroplasticity deficits in T2DM and IR is that metabolic disorders are characterized by a variety of endocrine and metabolic changes, all of which may act independently, as well as in additive or synergistic ways, to promote cognitive dysfunction. However, IR appears to be a keystone mechanism through which peripheral endocrine changes lead to deficits in the structural and functional integrity of brain regions like the hippocampus. In this regard, we have previously demonstrated that induction of hypothalamic-specific IR elicits an obesity phenotype that is characterized by metabolic and endocrine changes including peripheral IR, as well as deficits in hippocampal synaptic plasticity. Mechanistically, this peripheral IR may be elicited by pro-inflammatory cytokines and reactive oxygen species, both of which are characteristic of T2DM. However, it is likely that there is a bi-directional relationship between these factors and peripheral IR, which further complicates the identification of the fundamental factors responsible for hippocampal neuroplasticity deficits in metabolic disorders. Another unanswered question is the functional relationship between peripheral IR and CNS IR in cognitive dysfunction in T2DM. While peripheral endocrine and metabolic abnormalities associated with T2DM are likely to directly impact hippocampal structure and function, we have recently demonstrated that hippocampal-specific insulin resistance, independent of peripheral IR, also elicits deficits in hippocampal synaptic plasticity. In this regard, rats with hippocampal-specific IR exhibit impairments in stimulus-evoked LTP that are accompanied by decreases in the expression and phosphorylation state of hippocampal glutamate receptor subunits. Additionally, rats with hippocampal-specific IR exhibit deficits in spatial learning and memory. Our ongoing studies indicate that hippocampal-specific IR also induces deficits in morphological plasticity, including decreases in neurogenesis in the dentate gyrus, as well as synaptic re-organization and dendritic atrophy of CA1 pyramidal neurons. Such observations support the concept that CNS insulin activity acts independently of peripheral insulin to facilitate hippocampal synaptic plasticity. Additionally, these findings illustrate that hippocampal IR, alone and in combination with peripheral IR, are responsible for the neurological complications observed in patients with metabolic disorders and in age-related dementia, including impairments in cognitive function.

Wednesday, May 8th, 2019
3:00 - 4:00 pm
School of Medicine, Room 132A