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Insulin Sensitivity In The Brain And Periphery

Insulin Sensitivity In The Brain And Periphery

The influence of insulin activity within the brain on cognitive processes, peripheral metabolism, and eating behavior has been the subject of extensive study and is widely acknowledged in the scientific community. Researchers have observed that insulin, traditionally associated with metabolic regulation, also exerts significant effects on brain function. These effects encompass cognitive functions such as memory, mood regulation, and sensory perception, as well as metabolic processes like body fat distribution and the modulation of peripheral metabolism.

However, despite the recognition of these broad effects, there remain substantial gaps in our understanding. Specifically, the precise impact of two critical factors—age and peripheral insulin sensitivity—on brain insulin activity remains a subject of ongoing investigation and is not yet fully elucidated.

Age, as a fundamental aspect of an individual’s life course, is known to bring about various changes in the body. It is well-established that insulin sensitivity tends to decrease with advancing age, making it a key consideration when studying brain insulin activity. The question of how age interacts with brain insulin responsiveness and how this interaction affects cognitive and metabolic functions remains a complex and evolving area of research.

Peripheral insulin sensitivity, on the other hand, is a crucial factor in metabolic health. Conditions like obesity and type 2 diabetes mellitus are characterized by peripheral insulin resistance, where the body’s response to insulin is impaired. The relationship between peripheral insulin sensitivity and brain insulin activity is intricate and not yet fully understood.

In light of these uncertainties, researchers seek to uncover the precise connections between age, peripheral insulin sensitivity, and brain insulin activity. By doing so, they aim to shed light on whether changes in peripheral insulin sensitivity with age play a role in altering brain insulin responsiveness and, subsequently, how this impacts cognitive and metabolic processes. This ongoing exploration holds the potential to deepen our comprehension of how these factors interplay and may eventually lead to advancements in the fields of neuroscience, metabolism, and cognitive science.

Insulin and the Brain 

Insulin receptors are found throughout various regions of the brain, even though the uptake of glucose by neurons is mainly independent of insulin. The brain’s sensitivity to insulin plays a role in cognitive and metabolic processes, affecting memory, mood, eating behavior, body fat distribution, and peripheral metabolism. Peripheral insulin resistance is a key feature of obesity and type 2 diabetes, which tends to increase with age.

There’s a strong connection between reduced peripheral insulin sensitivity and age-related neurodegenerative conditions such as cognitive decline and Alzheimer’s disease. While the production of active insulin within the brain is a subject of debate, it’s generally believed that most brain insulin comes from pancreatic beta cells and enters the brain through the bloodstream, crossing the blood-brain barrier through specific receptors.

Studies have shown a correlation between insulin levels in the blood and cerebrospinal fluid, with lower levels observed in insulin-resistant individuals and with advancing age. Measuring brain insulin action in humans is challenging due to standard techniques like the hyperinsulinemic-euglycemic clamp affecting insulin throughout the body. However, using intranasal insulin along with functional neuroimaging, such as fMRI, allows for non-invasive quantification of brain insulin sensitivity.

This method revealed that intranasal insulin induces specific changes in regional cerebral blood flow (CBF), indicating brain insulin responsiveness. These CBF changes are influenced by factors like abdominal obesity, type 2 diabetes, and age, suggesting variations in brain insulin sensitivity. The study also suggests that interventions like pharmacological treatments, exercise, and weight loss could potentially normalize brain insulin responsiveness in those at risk of type 2 diabetes.

In this study, the relationship between age, peripheral insulin sensitivity, and brain insulin action was examined in men and women with varying body weights. Brain insulin action was defined as the change in regional CBF caused by intranasal insulin compared to a placebo spray. The study hypothesized region-specific correlations between intranasal insulin-induced CBF changes, peripheral insulin sensitivity, and age. Additionally, it explored potential connections between brain insulin action and brain volume, as both tend to decrease with age and peripheral insulin resistance.

Study Methods 

The study involved an extensive dataset collected from a diverse group of 110 participants, consisting of 54 women and 56 men. The participants exhibited a wide range of body mass index (BMI) values, spanning from 18 to 49 kg/m², showcasing the inclusion of individuals with varying body compositions. Furthermore, the age of the participants at the time of data collection encompassed a broad spectrum, ranging from 21 to 74 years, demonstrating a comprehensive representation of different age groups.

It’s worth noting that these measurements and data collection activities were carried out over a span of several years, commencing in 2013 and extending up to 2019. This extended timeframe allows for a more comprehensive assessment of potential changes or trends over the years, providing valuable insights into the relationships between age, BMI, and insulin action in the brain.

This diverse and longitudinally collected dataset forms the foundation for the subsequent analyses, enabling researchers to explore the intricate connections between these variables and gain a deeper understanding of the complexities of brain insulin responsiveness in individuals of varying ages and BMI levels.

They employed intranasal administration of insulin and functional magnetic resonance imaging (fMRI) within a randomized, placebo-controlled within-subject design. To evaluate brain insulin action, cerebral blood flow was measured before and after the application of nasal spray. Peripheral insulin sensitivity was assessed using a five-point oral glucose tolerance test. The researchers employed linear regression analysis to explore the connections between age, peripheral insulin sensitivity, and brain insulin action in predefined regions of interest, specifically focusing on insulin-sensitive brain regions.

Before participating, all participants provided written informed consent, and the studies received approval from the local ethics committee of the medical faculty at the University of Tübingen. Participants also consented to the use of their data in combined studies.


Significant negative associations were observed in the study between age and insulin action in the hippocampus (β = -0.215; p = 0.017) and the caudate nucleus (β = -0.184; p = 0.047). Additionally, there was a negative association between peripheral insulin sensitivity and insulin action in the amygdala (β = -0.190; p = 0.023). Notably, an interaction effect was found in the insular cortex between age and peripheral insulin sensitivity (β = -0.219; p = 0.005).

Furthermore, it was noted that women exhibited the most pronounced negative association between age and hippocampal insulin action, while men displayed the strongest associations between peripheral insulin sensitivity and age in brain regions associated with reward processing.

Final Thoughts 

The brain serves as a key target for insulin, affecting various metabolic and behavioral functions. Changes in brain insulin signaling impact diverse cell types, including neurons and glial cells, as well as brain circuits such as dopamine signaling and the blood-brain barrier. This suggests that brain insulin resistance could be a common feature across metabolic, psychiatric, and neurodegenerative disorders.

In this study, researchers assessed brain insulin action by analyzing cerebral blood flow (CBF) responses to intranasal insulin in both young and elderly participants. Their findings indicated a connection between brain insulin responsiveness, peripheral insulin sensitivity, and age. This underscores the importance of using region-specific markers to evaluate brain insulin sensitivity, which may vary between genders.

Age was linked to reduced insulin action in limbic brain regions, particularly the hippocampus and caudate nucleus, as seen in prior research. The study also noted diminished insulin responsiveness in the striatum, specifically the caudate nucleus, as individuals aged. 

The study also highlighted gender differences in brain insulin action, potentially influenced by estrogen levels. Estrogen plays a role in women’s cognitive function, food intake, and weight control, with declining levels post-menopause associated with an increased risk of neurodegenerative disorders. 

However, the impact of estrogen on brain insulin action in humans remains uncertain. The study underscored the importance of investigating brain insulin signaling in both men and women to comprehensively understand its role in metabolic, psychiatric, and neurodegenerative conditions.

The study revealed a region-specific connection among brain insulin responsiveness, age, and peripheral insulin sensitivity. These findings emphasize the importance of examining brain insulin action in both male and female individuals. Moreover, they provide additional support for the idea that brain insulin sensitivity could serve as a potential bridge between overall metabolism and neurocognitive functions.

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