TABLE 2.

The roles of insulin in peripheral infection-induced CNS damage.

Pathogen or disease/host	Study design and outcome measures	Findings	Proposed direction of causality and/or mechanism	References
Sepsis/rat	Animal model: surgically induced polymicrobial sepsis model in rats. Glucose treatment, insulin treatment compared to control. Outcome measures: Blood glucose, behavioral deficits, brain activity (EEG), BBB permeability, glial activation and inflammation in the cerebrum.	1. Sepsis induced hyperglycemia. 2. Glucose treatment led to a decline in survival rate, reduced brain activity, increased BBB permeability, and enhanced microglial and astroglial activation and inflammatory responses in the cerebrum. 3. Glycemic control (insulin treatment) inhibited inflammatory responses and restored BBB integrity and brain activity to near normal.	Peripheral infection →Hyperglycemia. →Glial activation and neuroinflammation. → Cognitive dysfunction. Note: Insulin help restore brain functions by preventing BBB disruption and neuroinflammation.	Huang et al., 2020
Sepsis/mouse	Animal model: surgically induced polymicrobial sepsis model in mice. Mice with moderate hyperglycemia were compared to control (normoglycemia). Outcome measures: neuronal damages, glial activation, and cell death in the hippocampus and frontal cortex.	(A) In hyperglycemic mice (compared to normoglycemia mice), sepsis induced: 1. Higher neuronal damage in frontal cortex. 2. Microglial activation in frontal cortex and hippocampus. 3. More apoptotic cells in frontal cortex. (B) Insulin prevented the above damages	Hyperglycemia →Enhanced infection (sepsis)-induced brain damage. Note: Insulin prevents hyperglycemia-induced susceptibility to sepsis-induced brain damages	Sonneville et al., 2015
Sepsis/mouse	Animal model: surgically induced polymicrobial sepsis model in mice. Outcome measures: cognitive functions, hippocampal synaptic plasticity, and hippocampal insulin signaling in post-septic mice compared to control.	1. Post-septic mice exhibited cognitive impairment, which was accompanied by reduced synaptic plasticity and disrupted insulin signaling in the hippocampus. 2. Treatment with a GLP-1 receptor agonist (insulinotropic) or GSK3β inhibitor (insulin signaling downstream) rescued cognition.	Peripheral infection →Disruption of hippocampal insulin signaling. → Impaired synaptic plasticity and cognitive deficits.	Neves et al., 2018
Sepsis/rat	Animal model: sepsis model induced by LPS (i.p.) in rats. Insulin treatment: continuous intravenous infusion for 6h after LPS stimulation. Compared to control (saline). Outcome measures: Inflammatory cytokines and oxidative stress in the cortex, hippocampus, and hypothalamus.	In the brain regions (cortex, hippocampus, and hypothalamus): 1.Insulin alleviated sepsis-induced inflammatory response (IL-1β, IL-6, and TNF-α). 2. Insulin suppressed oxidative damage while restoring antioxidants (SOD and GSH).	Peripheral infection →Inflammation and oxidative stress in the brain. Note: Insulin treatment lowered sepsis-induced inflammation in the brain	Chen Q. et al., 2014
Systemic inflammation/mouse	Animal model: LPS (i.p.) challenge in chronic neurodegeneration model (ME7 prion infection) in mice. Treated with glucose and insulin. Outcome measures: blood glucose, cognitive performance	LPS challenge induced hypoglycemia and acute cognitive impairment in mice with brain disease (ME7 prion infection), which was mitigated by glucose and mimicked by insulin.	Peripheral infection →Metabolic imbalance in the CNS. →Cognitive impairment. Note: Brain disease (prion disease) makes the CNS more vulnerable to peripheral inflammation	Kealy et al., 2020

Relevant keywords, such as insulin and leptin, are highlighted in bold.