Cited by 302Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchMetabolism, Diabetes, and Cancer

Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes

Gupta, Amit, Bisht, Bharti, Dey, Chinmoy Sankar·2011·Neuropharmacology

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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Crossref · 10.1016/j.neuropharm.2011.01.033

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  • Two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use.

    “two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use[85, 86].”
  • When insulin is added to metformin, it potentiates insulin's effects on amyloid reduction, improves neuronal insulin resistance, and impairs glucose uptake and Alzheimer's disease-associated neuropathological characteristics by activating the insulin signaling pathway.

    “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].”
  • Insulin regulates food intake, energy homeostasis, reproduction, sympathetic activity, learning and memory, as well as neuronal proliferation, apoptosis, and synaptic transmission in the central nervous system.

    “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].”

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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
  • Health Sciences › Medicine › Physiology › 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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