Insulin Resistance, Cognitive Impairment and Neurodegeneration: Roles of Nitrosamine Exposure, Diet and Lifestyles

Monte, Suzanne de la; Tong, Ming; Wands, Jack R.

doi:10.5772/17682

Cited by 3 publications

(4 citation statements)

References 183 publications

(216 reference statements)

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“…Besides the direct consequences of brain metabolic dysfunction, insulin resistance reinforces the neurodegeneration cascade in exacerbating amyloid accumulation, neuronal loss, and synaptic disconnection 7 . Altogether, the aggregate data support the hypothesis that Alzheimer's is a metabolic disorder in which brain insulin deficiency and resistance are at the core, and therefore shares molecular, biochemical, and pathophysiological features with diseases such as Type I and Type II diabetes mellitus 4, 6, 33, 44, 45 . Consequently a role for insulin therapy is justified in correcting the metabolic dysfunction.…”

Section: Introductionsupporting

confidence: 70%

“…The consistent findings were that, among individuals who had brain insulin resistance associated with MCI, early AD, or Type 2 diabetes mellitus, significant improvements in cognition, memory, attention and metabolic function occurred within a few months of treatment in the clinical trials 26, 41, 62, 63 . Mechanistically, in addition to the stimulatory effects on energy metabolism, insulin increases amyloid clearance from the brain 64 and it supports neuronal cytoskeletal and cholinergic functions 6, 9, 11 . Furthermore, enhanced insulin signaling inhibits the activity of kinases that promote tau hyperphosphorylation, and activates pathways that mediate synapse formation and neuronal plasticity 65 .…”

Section: Intranasal Insulin Therapymentioning

confidence: 99%

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Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

Monte¹

2013

Expert Opinion on Drug Delivery

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Introduction Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also minimize potentially hazardous off-target effects. Areas covered This review covers the role of intra-nasal insulin therapy for cognitive impairment and neurodegeneration, particularly Alzheimer's disease. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The author provides evidence that brain insulin resistance is an important and early abnormality in Alzheimer's disease, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy. Expert Opinion Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival, and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy, and specificity of intranasal insulin therapy.

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Section: Introductionsupporting

confidence: 70%

Section: Intranasal Insulin Therapymentioning

confidence: 99%

Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

Monte¹

2013

Expert Opinion on Drug Delivery

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“…12,[30][31][32][33][34] The molecular and biochemical consequences of insulin resistance in the brain are caused due to impairments in the insulin signalling pathway that compromises neuronal survival, energy production, gene expression, plasticity and white matter integrity. 33,35,36 The brain undergoes a starvation state due to deficit in glucose uptake and utilization, thus causing oxidative stress, impairments in homeostasis and increased cell death. Impairments in insulin signalling results in neurodegeneration due to increased activity of kinases that aberrantly phosphorylates tau, generation of reactive oxygen species that damages proteins, nucleic acids and lipids, leads to accumulation of amyloid beta monomers and plaques, causes mitochondrial dysfunction and increase signalling through pro-inflammatory and pro-apoptosis cascades.…”

Section: Discussionmentioning

confidence: 99%

“…Impairments in insulin signalling results in neurodegeneration due to increased activity of kinases that aberrantly phosphorylates tau, generation of reactive oxygen species that damages proteins, nucleic acids and lipids, leads to accumulation of amyloid beta monomers and plaques, causes mitochondrial dysfunction and increase signalling through pro-inflammatory and pro-apoptosis cascades. [35][36][37][38] Also insulin resistance is associated with down-regulation of genes needed for cholinergic function, thereby further compromising neuronal plasticity, memory and cognition. 36,38 The basis of the neuroprotective effects of the test formulation is corroborated by several studies in animals and humans.…”

Section: Discussionmentioning

confidence: 99%

Combination Treatment with a Novel Polyherbal Formulation and Metformin: A Single Blind Placebo-Controlled Study in Patients with T2DM and Cognitive Impairments

Dubey¹,

Sadhu²,

Upadhyay³

et al. 2015

Diabetes Res Open J

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CitationDubey GP, Sadhu A, Upadhyay P, et al. Combination treatment with a novel polyherbal formulation and metformin: a single blind placebocontrolled study in patients with T2DM and cognitive impairments. ABSTRACTBackground: Older people suffering from Type 2 Diabetes Mellitus (T2DM) are at major risk for age related cognitive dysfunction and dementia, mainly due to vascular complications. Studies have shown that T2DM is also associated with Alzheimer's Disease (AD) and is responsible for accelerating the pathology through insulin resistance. A polyherbal drug containing Bacopa Monnieri, Hippophae rhamnoides and Dioscorea bulbifera has shown a potent neuroprotective effect in management of cognitive deficits in elderly; and metformin a well-accepted antidiabetic agent responsible for lowering blood glucose in T2DM, can together provide an intriguing potential combination therapy for prevention and amelioration of cognitive impairments in T2DM patients. Objective: The present study is aimed to evaluate the combined effect of a polyherbal drug and metformin on improving cognitive functions in patients suffering from T2DM. Method: Elderly patients with an age range of 60-75 years diagnosed for T2DM were enrolled in the study and randomized into two groups; Group I=T2DM patients given metformin and placebo, Group II=T2DM patients given metformin and polyherbal drug. The subjects received the combination therapy of metformin (500 mg) and placebo or metformin (500 mg) and polyherbal drug (500 mg) twice daily for a period of 24 weeks. Estimation of Mini Mental State Examination (MMSE) score, blood glucose, HbA1c, insulin, lipid profile (total cholesterol, LDL-c, HDL-c, triglycerides), homocysteine, Interleukin-6 (IL-6), TNF-α and C-reactive protein (CRP) were measured at baseline and were repeated at three months and six months. The primary end point was a change from baseline to week 24 in MMSE score. Key secondary end points included change from baseline to week 24 in Digital Symbol Substitution (DSS); subtest of the Wechsler Adult Intelligence Scale-Revised), word recall (digital memory apparatusMedicaid systems, Chandigarh, India), attention span (Attention Span Apparatus -Medicaid systems, Chandigarh, India), Functional Activity Questionnaire (FAQ) and Hamilton Depression Scale (HDS) score. Further inflammatory markers and level of oxidative stress were analysed using standard biochemical tests. Result: The trial was performed in 120 elderly diabetic patients out of whom 112 patients

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A Neonatal Mild Defect in Brain Insulin Signaling Predisposes a Subclinical Model of Sporadic Alzheimer's to Develop the Disease

2021

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Insulin Resistance, Cognitive Impairment and Neurodegeneration: Roles of Nitrosamine Exposure, Diet and Lifestyles

Cited by 3 publications

References 183 publications

Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

Combination Treatment with a Novel Polyherbal Formulation and Metformin: A Single Blind Placebo-Controlled Study in Patients with T2DM and Cognitive Impairments

A Neonatal Mild Defect in Brain Insulin Signaling Predisposes a Subclinical Model of Sporadic Alzheimer's to Develop the Disease

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