Insulin Resistance: Understanding the Cognitive Implications

Dear Editor,

This article focuses on insulin resistance (IR) as a potential risk factor for impairing cognitive performance, which could progress into a major neurocognitive disorder later.

Some well-studied risk factors increase the likelihood of developing IR. Visceral adiposity, often contributed by lifestyle factors such as severe stress, sedentary behavior, poor dietary habits, low-quality sleep, smoking, and alcohol consumption, is a strong predictor of IR. ¹ Genetic predisposition to IR can be due to various reasons, including mutation in the InSR genes, which encode for the insulin receptors and resistance due to the release of autoantibodies against insulin. Also, it can be due to impaired tyrosine kinase activity.

Insulin plays a pertinent role in maintaining the glucose levels in the brain. The inability of insulin to bind to the insulin receptors due to the downregulation of the receptors or disruption of the signaling pathways can expose the cells to oxidative stress, thereby hastening the dysfunction at the cellular level. ² In recent studies, the term “type 3 diabetes” has been introduced to describe the potential relationship between Alzheimer’s disease (AD) and IR. High IR contributes to the neuropathological changes in AD, including Aβ accumulation, tau hyperphosphorylation, neurotoxicity, neuroinflammation, and oxidative damage resulting from altered insulin signaling. ³

As per the Longitudinal Ageing Study in India (LASI), which is a nationwide study, the estimated prevalence of dementia in adults aged 60 years and above in India is 7.4% and is projected to increase at least three times by 2050. ⁴

We analyzed the data of 1,007 participants aged 45 years and above recruited by the Tata Longitudinal Study of Ageing (TLSA), a community-based longitudinal cohort study approved by the Institutional Ethics Committee. Of these 1,007 participants, 569 (56.5%) had IR and 438 were healthy. The participants underwent various clinical and cognitive assessments and detailed blood investigations. The cognitive performance was evaluated using Addenbrooke’s Cognitive Examination (ACE III), and IR was measured using the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) formula. ⁵ Using a cross-sectional approach, this study analyzed the available baseline data from the TLSA cohort to investigate the relationship between IR and cognition.

In our study cohort, the estimated general prevalence of insulin resistance was 56.5%. The average age of participants was 62.82 ± 9.54 years, as shown in Table 1. Among the participants, 49.1% were females and 50.9% were males, with an average education of 14.74 ± 4.26 years.

Table 1.

Sociodemographic Characteristics of the Study Population.

Sociodemographic Characteristics	Insulin Resistance	Non-insulin Resistance	p Value
Age (in years)	60 (54, 67)	63 (56, 70)	.001
Gender
Male, n (%)	276 (48.5%)	232 (53%)	.16
Female, n (%)	293 (51.5%)	206 (47%)
Education (in years)	15 (12, 17)	15 (14, 17)	.006

Continuous variables are reported as median (interquartile range), and categorical variables are expressed as n (%).

A Mann–Whitney U test was performed to compare the ACE scores of participants with and without IR. As shown in Table 2, the results revealed that participants without IR scored significantly higher in ACE total, ACE attention, and ACE visuospatial tasks than their healthy counterparts. The results revealed that participants without IR scored significantly higher in ACE total, ACE attention, and ACE visuospatial tasks than their healthy counterparts.

Table 2.

Comparison Between Cognitive Variables and IR Status.

Cognitive Variables	Insulin Resistance	Non-insulin Resistance	p Value
ACE III (total)	90.5 ± 7.52	91.3 ± 7.34	.040*
Attention	16.6 ± 1.64	16.9 ± 1.48	.008*
Memory	23.3 ± 3.01	23.4 ± 2.91	.548
Fluency	11.4 ± 2.16	11.5 ± 2.13	.301
Visuospatial	14.3 ± 1.90	14.5 ± 1.85	.007*
Language	24.7 ± 1.80	24.7 ± 1.82	.973

*indicates significance at p < .05.

ACE, Addenbrooke’s Cognitive Examination.

The generalized regression model (GLM) was utilized to analyze the relationship between cognitive variables and IR status. Further, GLM analysis was performed after adjusting for confounding variables such as age, years of education, and C-reactive protein (CRP), which showed significant differences in the Mann–Whitney U test. Age was considered a covariate since it is inversely correlated with glucose tolerance. Similarly, participants with more years of education may perform better in ACE cognitive tests than those with fewer years of education. In addition, CRP was also included as a covariate since it is a significant predictor of inflammation in IR. ⁶

Based on the GLM analysis, it was observed that individuals with IR had performed significantly poorer in the ACE attention (B = −0.271, 95% CI = (−0.468, −0.073), p < .05) and ACE visuospatial (B = −0.258, 95% CI = (−0.494, −0.022), p < .05) tests. On further analysis after controlling for the confounding variables such as age, years of education, and inflammatory marker (high sensitivity CRP), results showed that ACE attention (B = −0.396, 95% CI = (−0.396, −0.008), p < .05) scores were lower in participants with IR. However, there was no significant difference in the visuospatial test scores after adjusting for the confounding variables.

In this regard, our study results suggest that higher insulin resistance can exacerbate attention-related issues. Previous studies have revealed that type 2 diabetes mellitus (T2DM), which IR characterizes, can lead to diminished attention. For instance, a study by Palta et al. demonstrated that individuals with T2DM scored significantly lower on attention tests than those without T2DM. ⁷ These findings highlight the potential impact of IR on attention. A study by Kern et al. found that insulin infusion helped improve attention in participants with low insulin levels. ⁸

The role of IR in attention is being actively explored. According to recent research, it has been observed that the prefrontal cortex (PFC) appears to be sensitive to changes concerning altered central and peripheral insulin levels. Given that PFC plays a vital role in attention, its sensitivity to insulin levels may explain why individuals with higher IR tend to perform poorly in attention-related tasks. ⁹

Over the past few years, the incidence of IR has increased rapidly; consequently, it is essential to consider IR as a significant risk factor for cognitive decline.

Although it may not be possible to manage all the causes, especially genetic factors contributing to IR, addressing the issue and adopting a healthier lifestyle is feasible, thereby impeding its advancement into metabolic diseases or cognitive dysfunction. There are no specific symptoms associated with IR. However, regular evaluation of blood sugar levels, HbA1C levels, and associated lipid levels can aid in the prompt identification of IR at an early stage. Therefore, we can prevent or delay cognitive decline by adopting a proactive approach toward managing IR with a lifestyle-based interventional approach focusing on nutrition, adequate physical activity, and appropriate management of metabolic risk factors.