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Review
. 2023 Jul 14;24(14):11450.
doi: 10.3390/ijms241411450.

Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials

Keren Esther Kristina Mantik  1   2 , Sujin Kim  1 , Bonsang Gu  1   2 , Sohee Moon  1 , Hyo-Bum Kwak  2   3 , Dong-Ho Park  2   3 , Ju-Hee Kang  1   2
Affiliations
Review

Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials

Keren Esther Kristina Mantik et al. Int J Mol Sci. .

Abstract

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.

Keywords: anti-diabetics; clinical trial; dementia; drug repositioning; insulin; insulin-like growth factor 1.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Current proposed mechanisms of anti-diabetic drugs, including (A) insulin, (B) insulin secretagogues, (C) insulin sensitizers, and (D) SGLT-2 inhibitors and amylin analogues as DMT for dementia. * GLP-1 receptor agonists, ** Sulfonylurea, # SGLT-2 inhibitors, ## Amylin analogs, solid red line: current proposed mechanism, dashed red line: further studies needed.
Figure 2
Figure 2
Current status of clinical trial phases in repositioning anti-diabetic drugs for dementia treatment.
Figure 3
Figure 3
Targeted conditions and diseases in clinical trials repositioning anti-diabetic drugs for dementia treatment.
Figure 4
Figure 4
Classification of drug modes of action in clinical trials repositioning anti-diabetic drugs for dementia treatment.
See this image and copyright information in PMC

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