Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach

Cholerton, Brenna; Baker, Laura D.; Montine, Thomas J.; Craft, Suzanne

doi:10.2337/ds16-0041

Cited by 100 publications

(90 citation statements)

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“…Under physiological conditions when insulin binds to the IR, a cascade regulates key downstream serine/threonine kinases such as, protein kinases B (AKT/PKB), mechanistic target of rapamycin (mTOR), and extracellular signal-regulated kinases (ERK), that eventually phosphorylate serine/threonine residues of the insulin receptor substrates (IRS), inhibiting insulin signalling in a negative feedback regulation ( Figure 1 ) [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 44 , 45 , 46 ]. In neurons, the phosphoinositide 3-kinase (PI3K), AKT, glycogen synthase kinase 3β (GSK3β), BCL-2 agonist of cell death (BAD), fork-head box (FOX), mTOR and the mitogen activated protein kinase (MAPK) pathways are critical for cell survival signalling and are regulated by the activity of the IR [ 43 , 47 , 48 ]. Therefore, alteration of the physiological activity on these pathways might be the source of alteration in normal neuronal performance, supporting the hypothesis that brain insulin resistance could promote LOAD, precisely by inhibition of these pathways [ 39 , 41 , 45 ].…”

Section: The Hippocampal Insulin Receptor Is a Key Target In Physimentioning

confidence: 99%

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

et al. 2018

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Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.

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Section: The Hippocampal Insulin Receptor Is a Key Target In Physimentioning

confidence: 99%

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

et al. 2018

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“…In particular, brain levels of insulin and insulin receptors (IRs) are reduced in AD patients and in experimental models of AD [5][6][7][8][9][10]. Such molecular links between deregulated insulin signaling in AD and 86 AF Batista et al diabetes have raised the prospect for novel therapeutic strategies based on anti-diabetic agents [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Batista

Forny-Germano

Clarke

et al. 2018

The Journal of Pathology

191

135

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Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…11 Some mechanisms may underlie these associations, including the consequences of chronic hyperglycemic conditions, peripheral metabolic disorders due to insulin resistance or type-2 DM that indirectly damage the brain, vascular brain injury due to insulin resistance vasculopathy and type-2 DM, impaired insulin ability to perform tasks normally in the brain in patients with type-2 DM, or due to a combination of these things. 12 In type 2 diabetes, the gradual erosion of beta cell function causes hyperglycemia to increase while resistance to insulin action can cause hyperinsulinemia. The combination of beta cell dysfunction and/or insulin resistance can cause chronic hyperglycemia and glucose toxicity which has profound implications for the body, including the brain in this case cognitive function.…”

Section: Methodsmentioning

confidence: 99%

“…8 The central nervous system is rich in insulin receptors, which are most prominent in important areas for learning and memory, including the hippocampus, amygdala, parahippocampal gyrus, thalamus, and caudate-putamen. 12 The mechanism by which insulin affects memory may be related to a number of pathways. First is the role of insulin in brain energy metabolism.…”

Section: Methodsmentioning

confidence: 99%

Association of glycated haemoglobin (HbA1C) level with working memory on type-2 diabetes mellitus and prediabetic patients

2019

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Background: Deleterious effects of diabetic glucose levels on brain structure, have been reported in many studies. Moreover, prediabetic and type-2 diabetes mellitus are associated with lower cognitive function. Author aimed to discover the association of blood glucose and working memory on type 2 diabetic and prediabetic patients.Methods: In this cross-sectional study there are two groups (diabetic and prediabetic) consist of 30 patients each (men 31, women 29). Mean age 40.233±7.862. Blood glucose was measured with HbA1c. All patients were tested with MMSE (Mini Mental State Examination), forward digit span, and backward digit span.Results: There was no difference between diabetic and prediabetic group in MMSE (p 1.000). In diabetic group, mean LDSF (Longest Digit Span Forward) was 5.700±0.877 and there was relation between HbA1c and LDSF (r -0.604). In prediabetic group, mean LDSF was 6.233±0.858 and there was relation between HbA1c and LDSF (r -0.565). There was significant difference between those groups in LDSF (p 0.041). In diabetic group mean LDSB (Longest Digit Span Backward) was 3.767±0.817 and there was relation between HbA1c and LDSB (r -0.545). In prediabetic group, mean LDSB was 4.300±0.750 and there was relation between HbA1c and LDSB (r -0.575). There was significant difference between those groups in LDSB (p 0.024).Conclusions: Results indicated that there was significant difference between diabetic and prediabetic patient in working memory test although there was no difference in general cognitive function.

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Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach

Cited by 100 publications

References 100 publications

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Association of glycated haemoglobin (HbA1C) level with working memory on type-2 diabetes mellitus and prediabetic patients

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