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Review
. 2023 Dec;29(12):1029-1044.
doi: 10.1016/j.molmed.2023.09.005. Epub 2023 Oct 10.

Diabetes: a tipping point in neurodegenerative diseases

Affiliations
Review

Diabetes: a tipping point in neurodegenerative diseases

Jose A Santiago et al. Trends Mol Med. 2023 Dec.

Abstract

Diabetes is associated with an increased risk and progression of Alzheimer's (AD) and Parkinson's (PD) diseases. Conversely, diabetes may confer neuroprotection against amyotrophic lateral sclerosis (ALS). It has been posited that perturbations in glucose and insulin regulation, cholesterol metabolism, and mitochondrial bioenergetics defects may underlie the molecular underpinnings of diabetes effects on the brain. Nevertheless, the precise molecular mechanisms remain elusive. Here, we discuss the evidence from molecular, epidemiological, and clinical studies investigating the impact of diabetes on neurodegeneration and highlight shared dysregulated pathways between these complex comorbidities. We also discuss promising antidiabetic drugs, molecular diagnostics currently in clinical trials, and outstanding questions and challenges for future pursuit.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; diabetes; insulin resistance.

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Conflict of interest statement

Declaration of interests J.A.S. is the founder of NeuroHub Analytics LLC. J.A.P. will test biomarkers in the LixiPark study RC31/16-8912 (NCT03439943)(viii). J.A.P. and J.A.S. are the inventors on Patent US 9,970,056 B2, Methods and Kits for Diagnosing, Prognosing and Monitoring Parkinson's Disease. M.K., M.L., and D.V. declare no competing interests.

Figures

Figure 1 (Key Figure).
Figure 1 (Key Figure).. Diabetes: a tipping point in neurodegeneration.
T2DM has many detrimental effects on brain structure and function. T2DM is associated with smaller brain volumes, brain atrophy, decreased blood flow, vascular lesions, disruption of the blood brain barrier, mitochondrial dysfunction, brain insulin resistance, depression, and cognitive impairment. Increasing evidence indicates that T2DM is a risk factor for AD and PD. Metabolic abnormalities associated with T2DM and the metabolic syndrome including insulin resistance, hyperglycemia, hyperlipidemia, and inflammation are implicated in the pathogenesis of neurodegenerative diseases. Intriguingly, these same metabolic abnormalities including T2DM, hyperglycemia, and hyperlipidemia are associated with a decreased risk of ALS in elderly individuals. Emerging research suggests that perturbations in glucose metabolism, insulin signaling, and bioenergetics defects could underlie the relationship between T2DM and neurodegenerative diseases. Several biomarkers, including progranulin (PRGN), triggering receptor on myeloid cells 2 (TREM2), tau, neurofilament light chain (NfL), cerebrospinal fluid (CSF) α-synuclein (SNCA), CSF tau, dopamine binding transporter (DAT), insulin signaling proteins (IR, IRS1, IRS2, IGF1, IRS1pS616, IRS-1 pS636/639, IRS1pS312, PI3K-AKT) are implicated in T2DM and neurodegeneration and may be useful for therapeutic development. Targeting the insulin pathway with antidiabetic drugs and the glycolysis pathway have elicited neuroprotection in several studies. To date, no disease modifying therapy is available for AD, PD, and ALS. Lifestyle modifications including diet and physical activity may help mitigate symptoms and possibly confer neuroprotection. This figure was created using BioRender (https://biorender.com/).

References

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