Elsevier

The Lancet Neurology

Volume 3, Issue 3, March 2004, Pages 169-178
The Lancet Neurology

Review
Insulin and neurodegenerative disease: shared and specific mechanisms

https://doi.org/10.1016/S1474-4422(04)00681-7Get rights and content

Summary

Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.

Section snippets

Insulin and the brain

As recently as 10 years ago, the brain was described as “an insulin insensitive organ” in medical textbooks. Evidence for the presence of insulin and its receptors in the CNS has challenged that notion.3, 4 Insulin is readily transported into the CNS across the blood-brain barrier by a saturable, insulin receptor-mediated transport process.5, 6, 7, 8 The raising of the peripheral insulin concentration acutely increases the concentration in the brain and CSF, whereas prolonged peripheral

Alzheimer's disease

Early observations that many patients with AD had impaired glucose tolerance were typically attributed to low physical activity or dietary differences. Specifically, a substantial proportion of adults with AD had high insulin concentrations in response to glucose challenge and reduced insulin-mediated glucose uptake. This pattern is characteristic of insulin resistance, in which more insulin is required to accomplish some of its physiological functions. Further inquiry established that this

Peripheral insulin abnormalities

The association of AD and several syndromes related to peripheral hyperinsulinaemia and insulin resistance, such as type-2 diabetes mellitus, has been largely borne out in epidemiological work, although some inconsistency has been noted. A clear association has been shown between dementia and diabetes. However, whether an independent association exists between diabetes and either AD or vascular dementia is more controversial, and there are many methodological challenges to the assessment of

Summary

In summary, evidence indicates an association between peripheral hyperinsulinaemia, insulin resistance, type-2 diabetes mellitus and hypertension, and increased risk of AD. Several studies have also replicated findings that insulin regulates amyloid concentrations in vitro and, more importantly, in vivo in human and mouse models. Both increased and decreased insulin concentrations have been proposed to promote AD pathogenesis through differing effects on Aβ release and clearance. Although

Insulin dysregulation and neurodegenerative disease: shared and specific mechanisms

As we learn more about the multifaceted role of insulin in the brain, we will be better able to identify the shared and specific contributions of insulin dysregulation to various neurodegenerative disorders. Some general mechanisms have obvious relevance to several disorders (panel 1). The interplay between insulin abnormalities and vascular function may be a converging mechanism in AD, vascular dementia, and PD. Insulin-mediated effects on brain vasculature could cause chronic hypoperfusion

Search strategy and selection criteria

Relevant studies were identified by searches of MEDLINE with the terms “insulin”, “diabetes”, “hypertension”, and “vascular” combined with “AD”, “PD”, “HD”, “vascular dementia”, and “Lewy-body dementia”. We searched from 1960 through 2003. Articles were also found by reviewing reference lists of papers identified by the above searches. Only papers published in English were included.

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