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Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Pharmacological treatments presently available can slow down the progression of symptoms but can not cure the disease. Currently there is widening recognition that AD is closely associated with impaired insulin signaling and glucose metabolism in brain, suggesting it to be a brain-specific form of diabetes and so also termed as "type 3 diabetes". Hence investigating the role of pharmacological agents that could ameliorate neuronal insulin resistance merit attention in AD therapeutics, however the therapeutics for pathophysiological condition like neuronal insulin resistance itself is largely unknown. In the present study we have determined the effect of metformin on neuronal insulin resistance and AD-associated characteristics in an in vitro model of "type 3 diabetes" by differentiating neuronal cell line Neuro-2a under prolonged presence of insulin. We observed that prolonged hyperinsulinemic conditions in addition to generating insulin resistance also led to development of hallmark AD-associated neuropathological changes. Treatment with metformin sensitized the impaired insulin actions and also prevented appearance of molecular and pathological characteristics observed in AD. The results thus demonstrate possible therapeutic efficacy of peripheral insulin-sensitizer drug metformin in AD by its ability to sensitize neuronal insulin resistance. These findings also provide direct evidences linking hyperinsulinemia and AD and suggest a unique opportunity for prevention and treatment of "type 3 diabetes".
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“The increasing evidence for insulin resistance and glucose metabolism playing an important role in dementia led to the investigation of metformin in AD treatment, where it was found to reduce neuronal insulin resistance and improve glucose uptake via activation of AMPK, IR, and PI3/Akt signaling, and attenuate production of Aβ.”
From BACE1: More than just a β‐secretase (2022) · cites this paper as [175]
In the citing paper
“two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use[85, 86].”
From Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial (2016) · cites this paper as [85]
In the citing paper
“However, when insulin is added to metformin, it potentiates insulin’s effects on amyloid reduction, improves neuronal insulin resistance, and impairs glucose uptake and AD-associated neuropathological characteristics by activating the insulin signaling pathway [129].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [129]
In the citing paper
“Insulin has been shown to regulate a wide range of processes in the central nervous system such as food intake, energy homeostasis, reproduction, sympathetic activity, learning and memory [129], as well as neuronal proliferation, apoptosis, and synaptic transmission [130].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [129]
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AMP-activated protein kinase in neurodegenerative disorders
Chauhan, P., Jaiswal, S. K., Gupta, R., & Jha, N. K. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-44173-8.00019-x
НЕЙРОПРОТЕКТОРНЫЕ ФУНКЦИИ МЕТФОРМИНА (ОБЗОР ЛИТЕРАТУРЫ)
Гридасова, Е. И., Плешкова, В. С., Чичкан, А. С., & Смирнова, П. Н. (2026) · Military and tactical medicine Emergency medicine · doi:10.55359/2782-3296.2026.81.44.009
Metadata
- Authors
- Gupta, A., Bisht, B., & Dey, C. S.
- Affiliations
- National Institute of Pharmaceutical Education and Research (IN)
- Corresponding author
- Dey, Chinmoy Sankar
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 60
- Issue
- 6
- Pages
- 910-920
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2001599368
- Cited by
- 302
- References
- 61
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 29 · 2023: 15 · 2022: 26 · 2021: 25 · 2020: 25 · 2019: 19 · 2018: 27 · 2017: 20 · 2016: 22 · 2015: 16 · 2014: 23 · 2013: 16 · 2012: 15
- FWCI
- 12.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Science and Technology, Ministry of Science and Technology, India
- Council of Scientific and Industrial Research, India
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metformin, Alzheimer's disease, type 3 diabetes, hyperinsulinemia, insulin signaling, N2a cells, insulin-sensitizing drugs, brain glucose metabolism
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Cholinesterases, Diabetes Mellitus, Experimental, Glucose, Hyperinsulinism, Hypoglycemic Agents, Insulin Resistance, Metformin, Neurons, Peptide Fragments, Amyloid beta-Peptides, Phosphatidylinositol 3-Kinases, Mice
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