Insulin Resistance and Cognitive Impairment

Craft, Suzanne

doi:10.1001/archneur.62.7.1043-a

Cited by 31 publications

(11 citation statements)

References 17 publications

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“…The insulin resistance syndrome is associated with reduced brain insulin levels and sensitivity in age-related memory impairment and AD (5,27–29). Brain insulin plays an important role as a neuromodulator in cognition (4,5), energy homeostasis, food intake, sympathetic activity, neuron-astrocyte signaling, synapse formation, and neuronal survival (7,30).…”

Section: Discussionmentioning

confidence: 99%

Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

et al. 2014

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Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.

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Section: Discussionmentioning

confidence: 99%

Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

et al. 2014

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“…However, only within the past several years has this field greatly expanded due to input from both human and experimental animal studies that produced new information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive impairment [7, 8, 22, 83, 88-90]. Concerns over the role of peripheral insulin resistance as a mediator of cognitive impairment and sporadic AD have been ratcheted up by globalization of the obesity epidemic [1, 84].…”

Section: Mechanisms Of Brain Insulin/igf Resistance In Neurodegeneratmentioning

confidence: 99%

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease

Monte

2012

CAR

386

219

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Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

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“…Correspondingly, epidemiologic, clinical, and experimental data indicate that peripheral insulin resistance associated with obesity, Type 2 diabetes mellitus (T2DM), metabolic syndrome (dyslipidemic states), and non-alcoholic steatohepatitis (NASH), can all mediate brain insulin/IGF resistance, and thereby contribute to the pathogenesis of mild cognitive impairment (MCI), dementia, or AD (3, 4, 22–29). More recently, human and experimental animal studies have provided new information about the causes and effects of brain insulin resistance and deficiency, particularly in relation to cognitive impairment (5, 6, 19, 30–33). The near globalization of the obesity epidemic is sounding alarms that now draw all of our attentions (23, 34).…”

Section: Systemic Disease Factors Contributing To Brain Insulin/igmentioning

confidence: 99%

Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease

Monte¹

2012

Front Biosci

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Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential.

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Insulin Resistance and Cognitive Impairment

Cited by 31 publications

References 17 publications

Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease

Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease

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