Abstract
The study will pilot-test a 3-month supervised exercise program to improve plasma brain-derived neurotrophic
factor (BDNF) levels and domains of cognition that are mostly affected in type 2 diabetes mellitus (T2DM),
including memory, processing speed, and executive function, overall and according to genotypes of the BDNF
Val66Met variant. T2DM impairs the brain, leading to cognitive dysfunction, which carries substantial lifetime
consequences. This highlights an urgent need to find effective therapeutic strategies to improve cognitive
function among those with T2DM. Aerobic exercise enhances cognitive function among healthy subjects
through increased release of BDNF. BDNF supports survival of existing neurons and promotes growth
of new neurons and synapses. Emerging evidence suggests that reduced BDNF levels may exacerbate
cognitive dysfunction associated with T2DM. Compared to drug delivery of BDNF, aerobic exercise is a low-
cost, safe, and easily accessible path to increasing endogenous BDNF levels. In persons with T2DM, integrity
of the blood-brain barrier (BBB) is impaired. Although a growing body of evidence supports the protective role
of regular exercise in BBB integrity, very little is known about how resting peripheral BDNF levels may change
in response to regular aerobic exercise training after adjusting for BBB permeability among individuals with
T2DM. One critical genetic variant that affects cognition in human is the BDNF Val66Met variant. The Met
allele interferes with the activity-dependent secretion of mature BDNF among Met carriers. Despite the strong
evidence suggesting aerobic exercise has a beneficial effect on cognitive function, significant variability in
individual response to exercise training in cognitive outcomes has been reported among Val/Val vs. Met
carriers. However, the evidence on how the BDNF Val66Met variant influences cognitive outcomes following
an aerobic exercise intervention among individuals with T2DM is currently lacking. A total of 84 participants
with T2DM will be randomized 2:1 to receive aerobic exercise intervention (n=56) or attention control (n=28) for
3 months. The study will evaluate the feasibility of the intervention. The study will also evaluate preliminary
effectiveness of the supervised exercise program on cognitive function and plasma BDNF levels after
controlling BBB permeability. An exploratory aim is to explore the influence of the BDNF Val66Met
polymorphism on cognitive outcomes and plasma BDNF levels in response to aerobic exercise intervention.
The purpose of this study is well aligned with the National Institute of Nursing Research (NINR) mission to
develop personalized interventions that address mechanisms underlying symptoms of illness through symptom
science research. Based on the findings of this proposed study, our long-term goal is to develop a
personalized exercise program for high-risk individuals susceptible to cognitive dysfunction based on their
genomic profiles.
