Vignesh Subramanian ’24

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by dysfunctions relating to hyperglycemia, the state of high glucose levels in the bloodstream. Such excessive blood sugar is typically the combinatory result of inadequate secretion of insulin (a hormone that directs cells and the liver to take up glucose for energy and long-term storage, respectively), uncontrolled secretion of glucagon (an antagonistic hormone that triggers the release of stored glucose), and insulin resistance. Diminished insulin levels and poor cellular diffusion of blood glucose have previously been implicated as contributors to declines in cognitive performance and forms of dementia. However, these studies’ reliance on evidence devoid of broad-based examination of patients’ lifespan neurological changes has created difficulty in decoupling the effects of typical brain aging from T2DM-mediated neurodegenerative damage over time. To examine the relationship between the two, researchers led by Dr. Mujica-Parodi of Stony Brook University worked to characterize the neurocognitive effects longitudinally displayed by T2DM patients.

The researchers first obtained a large cohort of human subjects from the UK Biobank, matching T2DM patients and healthy controls pairwise by age and other personal characteristics. Cross-sectional neuroimaging and cognitive data on these subjects was submitted to a series of statistical correlation measures to determine the extent to which T2DM- and aging-related degenerative pathways overlapped in their display of changes in five cognitive domains. Finally, meta-analyses of studies on similar cognitive measures for T2DM patients and that compiled MRI, FDG-PET, and other neuroimaging data on their brain structure and function were conducted to both substantiate previous findings and examine the correlation between disease chronicity and cognitive performance.

The researchers found that T2DM patients indeed demonstrated deficits in cognitive performance independent of natural age-related decline, which were accompanied by atrophy of gray matter in brain regions critical to learning, working memory, and decision-making (occurring approximately 26% ± 14% faster than seen with normal aging). While these patterns of T2DM-mediated atrophy strongly overlapped with age-related pathways of natural degeneration, the former definitively exacerbated neurocognitive symptoms beyond levels displayed by control subjects, which became more severe with increased disease duration. Later examination of T2DM patients undergoing treatment with metformin, the most commonly prescribed anti-diabetic medication, showed it did not significantly improve long-developed cognitive and atrophic effects. This underwhelmingly studied, wide-ranging contribution to neurodegeneration by glucose toxicity and neuronal insulin resistance ultimately indicates that new diagnostic modalities need be developed to catch the acceleration of structural brain damage by diabetes earlier in prognosis. 

Works Cited:

[1] B. Antal, et al., Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses. eLife 11, e73138 (2022). doi: 10.7554/eLife.73138.

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:Type_2_Diabetes_Mellitus.jpg