Insulin, Synaptic Function, and Opportunities for Neuroprotection

Mielke, John G.; Wang, Yu Tian

doi:10.1016/b978-0-12-385506-0.00004-1

Cited by 44 publications

(28 citation statements)

References 373 publications

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“…Insulin receptors are highly enriched in synapses 59 , localizing to both the presynaptic axon terminal 60 and the postsynaptic density compartments 61,62 , and have important effects on neurosynaptic functioning 63–66 . Briefly, insulin enhances neurite outgrowth, modulates catecholamine release and uptake, regulates trafficking of ligand-gated ion channels, regulates expression and localization of GABA, N -methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and modulates activity-dependent synaptic plasticity (that is, long-term potentiation (LTP) and long-term depression (LTD)) via NMDA receptor signalling and AKT 67 .…”

Section: Insulin and The Brainmentioning

confidence: 99%

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

et al. 2018

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Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of ‘brain insulin resistance’ and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.

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Section: Insulin and The Brainmentioning

confidence: 99%

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

et al. 2018

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“…The insulin/IGF-1-mediated activation of complex signalling cascades serves the regulation a plethora of cellular processes including growth, differentiation and metabolism [63]. In the CNS, insulin exerts further control over neurotransmission, synaptic plasticity and cognitive processes, cellular proliferation and antiapoptotic mechanisms, and antioxidant defence [64,65]. Therefore, defects in brain insulin signalling pathways result in altered brain function.…”

Section: Insulin Signalling Defects In Aging and Admentioning

confidence: 99%

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Duarte¹

2014

aging dis

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From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer's disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as well as recurrent hypoglycaemia are the factors that most likely affect brain function and structure. While difficult to study in patients, the mechanisms by which diabetes leads to brain dysfunction have been investigated in experimental models that display phenotypes of the disease. The present article reviews the impact of diabetes and AD on brain structure and function, and discusses recent findings from translational studies in animal models that link insulin resistance to metabolic alterations that underlie brain dysfunction. Such modifications of brain metabolism are likely to occur at early stages of neurodegeneration and impact regional neurochemical profiles and constitute non-invasive biomarkers detectable by magnetic resonance spectroscopy (MRS).Key words: Neurodegeneration, Diabetes, Alzheimer's disease, Insulin, Metabolism Diabetes mellitus can be defined as a chronic metabolic disorder characterized by hyperglycaemia, resulting from inappropriate insulin secretion and/or action [1]. The vast majority of the diabetes cases are included in two main categories, classified according to the underlying cause, which are type 1 diabetes (T1D) or insulindependent diabetes, generally caused by an autoimmune reaction to antigens of pancreatic β-cells, leading to impaired insulin production, and type 2 diabetes (T2D) or insulin-resistant diabetes, characterised by inefficiency of insulin action. While T1D is mainly observed in children and adolescents, T2D is more common among adults, accounting for more than 90% of the diabetes cases worldwide. The prevalence of diabetes and impaired glucose tolerance achieved now epidemic proportions, respectively at 6.9% and 8.3% of the world population, and predicted to raise to 8. 0% and 10.1% in 2035 [2]. Moreover, diabetes is nowadays a leading cause of death accounting for 8.4% of global mortality in people aged between 20 and 79 years [2]. The main contributor for the high prevalence of diabetes is the rise of obesity, related to the combination of ample food availability and a sedentary lifestyle, contrasting to less abundant food supplies and higher physical activity observed until a century ago.Diabetes is associated with the occurrence of well described microvascular complications that affect different organs, leading most commonly to retinopathy, nephropathy and peripheral neuropathy, which development is dependent on the duration of the disease and glycaemia control [3]. When the control of the disorder allowed patients to live longer and without these Volume 6, N...

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“…Given that insulin is critical for neural processes (Mielke, and Wang, 2011), and the administration of insulin to human and nonhuman animals improves cognitive abilities (Haj-ali et al, 2009;Schiöth et al, 2012), glucose induced release of insulin may contribute to replenishment. It is worth noting that cephalic phase insulin responses are elicited when taste receptors activate afferent fibers of the vagus nerve (Teff, 2011).…”

Section: Introductionmentioning

confidence: 99%

Self-regulatory depletion in dogs: Insulin release is not necessary for the replenishment of persistence

Miller

Pattison

Laude

et al. 2015

Behavioural Processes

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It has been hypothesized that self-control is constrained by a limited energy resource that can be depleted through exertion. Once depleted, this resource can be replenished by the consumption or even the taste of glucose. For example, the need to inhibit reduces subsequent persistence at problem solving by humans and dogs, an effect that is not observed when a glucose drink (but not placebo) is administered following initial inhibition. The mechanism for replenishment by glucose is currently unknown. Energy transfer is not necessary, though insulin secretion may be involved. This possibility was investigated in the current study by having dogs exert self-control (sit-stay) and subsequently giving them (1) glucose that causes the release of insulin, (2) fructose that does not result in the release of insulin nor does it affect glucose levels (but is a carbohydrate), or (3) a calorie-free drink. Persistence measures indicated that both glucose and fructose replenished canine persistence, whereas the calorie-free drink did not. These results indicate that insulin release is probably not necessary for the replenishment that is presumed to be responsible for the increase in persistence.(182 words)

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Insulin, Synaptic Function, and Opportunities for Neuroprotection

Cited by 44 publications

References 373 publications

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

Self-regulatory depletion in dogs: Insulin release is not necessary for the replenishment of persistence

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