Prediabetes and the Mind: Unraveling Cognitive and Mental Health Risks

Prediabetes is a clinical precursor not only to diabetes but also to emerging cognitive impairment and neuropsychiatric symptoms. In a cohort of Indian patients with T2DM and prediabetes (n=1061), 46% reported depressive symptoms and 44.3% experienced anxiety. (1) Globally, prediabetes has been associated with a greater incidence of depressive symptoms and poor mental health outcomes. (2) In India, diabetes distress affects 1 out of 3 individuals with T2D, highlighting the urgent need for routine psychological screening and support as part of comprehensive diabetes care. (3)

Prediabetes & Neurovascular Dysfunction- Overlapping Interactions of Metabolic Injury & Inflammation: The neurological burden of prediabetes stems from overlapping metabolic and vascular injury. Maastricht Study (n=2,228) showed that prediabetic individuals had a 61% higher risk of lacunar infarcts (OR 1.61), greater white matter hyperintensity volume (β = 0.07 log-mL), and reduced white matter volume (β = –4.0 mL) compared to those with normal glucose levels. (4) These structural brain abnormalities indicate early neurodegeneration and impaired cerebral perfusion, driven by insulin resistance, elevated cortisol, inflammation, and oxidative stress that disrupt neurovascular integrity and affect cognitive and emotional regulation before overt diabetes develops. (2) Elevated perceived stress, sedentary urban lifestyles, poor dietary habits, and stress-induced hormonal and immune changes are key risks for brain health in Indian prediabetes. (5)

Psychosocial and Cognitive Health Guidelines in Prediabetes

The American Diabetes Association (2025) highlights that psychosocial concerns in type 2 diabetes, including diabetes distress, depression, anxiety, and cognitive impairment, are strongly linked to increased A1C, blood pressure, vascular complications, psychosocial burden, and mortality. Depression and cognitive impairment particularly exacerbate glycemic control and cardiovascular risks, while anxiety further elevates blood pressure and dyslipidemia. (6)

The Australian Position Statement (2020) on prediabetes management emphasizes the need for comprehensive psychosocial support, highlighting that individuals with prediabetes face a higher risk of depression and anxiety, potentially accelerating the progression to T2D. It recommends integrating emotional health assessments and behavioral interventions, particularly for those experiencing significant distress or psychiatric disorders. A multidisciplinary approach involving psychologists or social workers is advised to provide sustained emotional support and facilitate behavior change strategies. (7)

Evidence for Metformin in Cognitive Protection

Beyond glycemic control, metformin has demonstrated promising neuroprotective and cognitive-enhancing effects. A systematic meta-analysis showed that metformin use was associated with a 45% lower odds of cognitive impairment (OR 0.55; 95% CI: 0.38–0.78) and a 24% reduced risk of dementia incidence (HR 0.76; 95% CI: 0.39–0.88) in patients with T2D. (8)

Findings from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) further showed that T2D patients with mild cognitive impairment who were treated with metformin exhibited better cognitive performance, preserved hippocampal volume and cortical thickness, and a significantly improved CSF biomarker profile, characterized by higher amyloid-β and lower tau/phospho-tau levels, indicating reduced neurodegeneration and disease burden. (9)

Mechanistically, metformin acts via AMPK activation, reducing neuroinflammation, inhibiting microglial proliferation, and lowering pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6. (10)

Another Indian review by Gupta et al. (2025) emphasizes that metformin crosses the blood-brain barrier and enhances synaptic plasticity and mitochondrial function, making it a strong candidate for neuroprotection in Indian T2D populations. (11)

Take-Home Message

• Prediabetes is linked to early cognitive and emotional dysfunction due to overlapping metabolic and neurovascular injury.
• Indian studies reveal high levels of stress, depression, and anxiety among individuals with prediabetes, highlighting the need for mental health screening.
• Addressing psychosocial distress in prediabetes and diabetes is vital to prevent disease progression and mitigate cardiovascular risks.
• Metformin shows neuroprotective benefits beyond glucose control, including reduced dementia risk and improved neurovascular integrity and function.

References:

1.Tripathi, P., Sharma, B., Kadam, N. et al. Improvement in symptoms of anxiety and depression in individuals with type 2 diabetes: retrospective analysis of an intensive lifestyle modification program. BMC Psychiatry 24, 714 (2024). https://doi.org/10.1186/s12888-024-06130-2

2. Zhou, Jin, and Xiaojiao Yang. “Association between depression and the prevalence and prognosis of prediabetes: Data from National Health and Nutrition Examination Survey (NHANES) 2013-2018.” PloS one vol. 20,1 e0304303. 13 Jan. 2025, doi:10.1371/journal.pone.0304303

3. Sinha, Ratnesh et al. “Prevalence of diabetes distress among type 2 diabetes mellitus patients in India: a systematic review and meta-analysis.” Health psychology and behavioral medicine vol. 12,1 2324091. 5 Mar. 2024, doi:10.1080/21642850.2024.2324091

4. van Agtmaal, Marnix J M et al. “Prediabetes Is Associated With Structural Brain Abnormalities: The Maastricht Study.” Diabetes care vol. 41,12 (2018): 2535-2543. doi:10.2337/dc18-1132

5. Mishra, Amit et al. “Higher Perceived Stress and Poor Glycemic Changes in Prediabetics and Diabetics Among Indian Population.” Journal of medicine and life vol. 13,2 (2020): 132-137. doi:10.25122/jml-2019-0055

6. American Diabetes Association Professional Practice Committee; 5. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S86–S127.

7. Bell, Kirstine et al. “A position statement on screening and management of prediabetes in adults in primary care in Australia.” Diabetes research and clinical practice vol. 164 (2020): 108188. doi:10.1016/j.diabres.2020.108188

8. Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellmanq SM, Aromataris E. Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2018;65(4):1225-1236. doi:10.3233/JAD-180263

9. Pomilio, Carlos et al. “Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study.” GeroScience vol. 44,3 (2022): 1791-1805. doi:10.1007/s11357-022-00568-6

10. Kruczkowska W, Gałęziewska J, Buczek P, Płuciennik E, Kciuk M, Śliwińska A. Overview of Metformin and Neurodegeneration: A Comprehensive Review. Pharmaceuticals (Basel). 2025;18(4):486. Published 2025 Mar 28. doi:10.3390/ph18040486

11. Gupta, P., Dutta, S., Jash, R. et al. Metformin: Beyond Diabetes Management to Neuroprotection and Cognitive Enhancement. Curr. Pharmacol. Rep. 11, 17 (2025). https://doi.org/10.1007/s40495-025-00395-1