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Hippocampal insulin resistance and cognitive dysfunction

Key Points

  • Clinical studies suggest that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive decline and dementia, and have found evidence that insulin resistance (IR) occurs in the brain of patients with T2DM and Alzheimer disease (AD).

  • Structural and functional deficits in synaptic plasticity, as well as impairments in a variety of behavioural tests of learning and memory, are observed in the hippocampus in rodent models of T2DM.

  • Evidence for hippocampal IR has also been observed in rodent models of AD.

  • Data from these experimental studies suggest that hippocampal IR is an important mechanistic mediator of the synaptic plasticity and cognitive deficits in T2DM and AD.

  • Several pathological features of T2DM and AD may contribute to the development of hippocampal IR, including increases in oxidative stress and in the amount of pro-inflammatory cytokines and amyloid-β peptides, as well as hypothalamic–pituitary–adrenal axis dysfunction.

  • Importantly, both lifestyle (diet and exercise) and pharmacological interventions that are known to alleviate peripheral IR effectively restore hippocampal neuroplasticity in rodent models of T2DM and AD, and this effect may be due to restoration of insulin signalling in the hippocampus.


Clinical studies suggest a link between type 2 diabetes mellitus (T2DM) and insulin resistance (IR) and cognitive dysfunction, but there are significant gaps in our knowledge of the mechanisms underlying this relationship. Animal models of IR help to bridge these gaps and point to hippocampal IR as a potential mediator of cognitive dysfunction in T2DM, as well as in Alzheimer disease (AD). This Review highlights these observations and discusses intervention studies which suggest that the restoration of insulin activity in the hippocampus may be an effective strategy to alleviate the cognitive decline associated with T2DM and AD.

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Figure 1: White matter structure is altered in individuals with T2DM.
Figure 2: Complex relationships between insulin signalling in the brain and elsewhere in the body in health and disease.
Figure 3: Insulin receptor signalling in the hippocampus.


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The authors thank V. Macht for assistance with the figures. The work of G.J.B. is supported by a Vidi grant from The Netherlands Organisation for Health Research and Development (ZonMw; grant 91711384), and a clinical established investigator grant from The Netherlands Heart Foundation (grant 2010 T073). The work of L.P.R. is supported by the US Department of Veterans Affairs (grants I21 BX002085 and IO1 BX001804) and the University of South Carolina Research Foundation.

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Correspondence to Lawrence P. Reagan.

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Competing interests

L.P.R. serves as a consultant for I.R.I.S. (Servier) and has received research support for studies involving animal models of depression. G.J.B. consults for and receives research support from Boehringer Ingelheim, consults for Takeda Pharmaceuticals and has received speaker's fees from Eli Lily. Financial compensation for these services is transferred to the University Medical Center Utrecht and not to G.J.B. personally.

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Insulin resistance

(IR). A state in which an increase in release of insulin from the pancreas is required to maintain normal plasma glucose levels. In the CNS, IR may be characterized by the decreased ability of insulin to promote structural and functional plasticity.


The condition in which an individual has a body mass index of >30 kg per m2, which is normally the result of an increase in fat mass.

Lacunar infarcts

Strokes that, in most cases, are caused by the occlusion of a small perforating artery, visible on MRI as a round or ovoid, subcortical, fluid-filled cavity (with a signal similar to that of cerebrospinal fluid) of 3–15 mm in diameter.

White matter hyperintensities

Signal abnormalities observed on MRI, consisting of white matter that is hyperintense on T2-weighted images (such as fluid-attenuated inversion recovery images) and is without cavitation (it has a signal different to that of cerebrospinal fluid). White matter hyperintensities, presumed to be of vascular origin, reflect tissue abnormalities that range from slight disentanglement of the white matter structure to varying degrees of myelin and axonal loss.

Amyloid plaques

Extracellular deposits of amyloid-β surrounded by dystrophic neurites, reactive astrocytes and microglia. These plaques are a core pathological hallmark of Alzheimer disease.

Neurofibrillary tangles

Intracellular aggregates composed of a hyperphosphorylated form of the microtubule-associated protein tau. These aggregates are a core pathological hallmark of Alzheimer disease.

Pittsburgh compound B

(PiB). A positive emission tomography (PET) tracer that is well retained in amyloid-containing areas of the brain.


A hormone that is synthesized and released by adipocytes in direct proportion to body fat mass. Like insulin, leptin is proposed to facilitate neuroplasticity in the hippocampus.

Peroxisome proliferator-activated receptor-γ

(PPARγ). A nuclear receptor that regulates the expression of genes which control glucose metabolism and homeostasis, among other functions.

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Biessels, G., Reagan, L. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16, 660–671 (2015).

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