Rutgers study reveals that exercise activates insulin-related brain cells, potentially improving cognition and offering new strategies to prevent dementia

Study: Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes. Image Credit: oatawa/Shutterstock.com

A recent study published in Aging Cell explores the impact of exercise on the short-term regulation of insulin pathways in brain circuits.

Insulin and the brain

Insulin is a glucose-lowering hormone that targets the peripheral tissues, especially the skeletal muscle and fatty tissues. Insulin also circulates throughout the brain, wherein it can impact the function of the prefrontal cortex and hypothalamus, both of which are regions of the brain involved in memory and cognition.

Reduced insulin trafficking in the brain is associated with aging and prediabetes, which can reduce neuronal insulin signaling and/or lead to insulin resistance. In fact, insulin sensitivity is considered a key feature of Alzheimer’s disease and related dementia (ADRD).

Investigating changes in neuronal extracellular vesicles (nEVs) has the potential to provide important insights into the pathophysiology of insulin sensitivity in the brain, as nEVs originate in neurons, pass the blood-brain barrier, and can be captured from peripheral blood.

Exercise and cognition

Exercise has been shown to improve cognitive function by increasing gray matter volume or preventing its shrinkage, maintaining brain circulation, improving mitochondrial respiration, and reducing neuroinflammation. Recently, researchers reported increased brain insulin sensitivity from eight weeks of exercise training in young adults. Similarly, higher levels of brain-derived neurotrophic factor (BDNF) within the nEVs have been observed following 16 weeks of exercise.

Despite these observations, it remains unclear whether exercise affects insulin signaling proteins within nEVs or increases pro-BDNF levels in prediabetic older people.

About the study

Prediabetes is characterized by fasting blood glucose levels between 100 and 125 mg/dL, two-hour postprandial glucose levels within the range of 140 to 199 mg/dL, and/or glycosylated hemoglobin (HbA1c) levels between 5.7-6.4%. All study participants were diagnosed with prediabetes, as demonstrated by a 75 g glucose tolerance test (GTT) assessed according to the American Diabetes Association (ADA) criteria.

The current study included 21 sedentary older adults with a mean age of 60 and an average body mass index (BMI) of 33.5 kg/m2. However, none of these individuals smoked, were diagnosed with other comorbidities, or were prescribed glucose-lowering medications.

Exercise training intervention

A two-week supervised 12-session program of continuous or interval exercise was initiated, with 13 and eight participants in the two types of exercise groups, respectively. In the continuous group, each session was aimed at attaining 70% of the peak heart rate (HRpeak), compared to 90% and 50% of HRpeak for three minutes each in the interval exercise group. All exercise sessions lasted 60 minutes each, with day seven being a rest day.

The aerobic fitness and body weight were measured before and after the exercise intervention. Using a 75g oral GTT (OGTT), fasting whole-body glucose tolerance was measured as the total area under the curve (tAUC). The simple index of insulin sensitivity (SiiS) was also assessed.

Immediately before OGTT and one hour from the start, nEV levels were measured to determine nEV-associated insulin signaling protein and pro-BDNF levels. Differences in protein levels at these time points reflected the stimulation of insulin release by the OGTT.

The intensity of exercise did not change the nEV measurements. As a result, the subgroups were assessed together for the effects on the insulin pathway.

Changes in insulin signaling

Following exercise, higher peak oxygen consumption (VO2 peak), peripheral insulin sensitivity, and fat oxidation, along with reduced body weight and improved whole-body glucose tolerance, were observed.

After exercise training, pro-BDNF levels at the start of the OGTT decreased; however, no changes occurred after glucose intake. Exercise also increased the post-OGTT insulin signaling protein tAkt in parallel with a reduction in the ratio of pAkt to tAkt at the one-hour point of the test. This change in tAkt after glucose intake was higher after exercise than at baseline.

Other nEV-associated proteins like p-IRS-1-Ser473, pJNK, p-ERK-1/2, or pp38 did not show any change after exercise.

Conclusions

Two weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro-BNDF among adults with prediabetes, thereby potentially lowering ADRD risk.”

After exercise training, nEVs contained more tAkt in response to fasting or postprandial glucose intake without any change in pAkt. This observation reflects better insulin signaling in brain neurons and improved insulin sensitivity in the brain.

These findings corroborate prior work reporting that improved peripheral insulin sensitivity leads to greater glucose uptake by peripheral tissues and less in the brain. The brain may rely on fatty acids released from fatty tissues broken down in response to the increased energy expenditure without a corresponding increase in dietary intake.

Additional research is needed to clarify the effects of various forms and modes of exercise on nEV protein cargos and cognitive function. These studies have the potential to support the development of future interventions that can prevent or treat ADRD in these high-risk patients.