The probability and incidence of both have increased considerably in recent years consequent to increased longevity and population growth. Progressively more links are being continuously found between inflammation and central nervous system disorders like AD, Parkinson's disease, Huntington's disease, motor neuron disease, multiple sclerosis, stroke, traumatic brain injury and even cancers of the nervous tissue. The depth of the relationship depends on the timing and extent of anti- or pro-inflammatory gene expression.
Inflammation has also been implicated in T2DM. This review appraises the roles of inflammation and abnormalities in the insulin signaling system as important shared features of T2DM and AD. The capacity of anti-cholinesterases in reducing the level of certain common inflammatory markers in particular if they may provide therapeutic potential to mitigate awry mechanisms leading to AD. Type 2 diabetes mellitus T2DM is a heterogeneous, multi-factorial and polygenic disorder and one of the most common metabolic diseases.
Its incidence is reaching epidemic proportions, and its prevalence increases with age [ 1 ]. Impaired insulin action and secretion in T2DM generates a general mayhem specific of this disease [ 2 ]. AD, a progressive neurodegenerative disorder of hitherto unknown aetiology leads progressively to severe cognitive incapacity and ultimately to death, has been described as the pandemic of the 21 st century [ 4 ]. Stress inflammatory, oxidative, nitrosative , progressive amyloidosis, atherosclerosis, obesity, metabolic syndrome are pathological mechanisms or risks related to T2DM and AD [ 5 , 6 ].
In fact metabolic syndrome, T2DM and AD are considered as low-grade systemic inflammatory conditions as recent studies have demonstrated associations between elevated levels of circulating acute phase inflammatory markers, typified by C-reactive protein CRP , and indices of insulin resistance and the development of T2DM and AD [ 7 — 9 ].
Moreover, elevated butyrylcholinesterase BuChE may represent a key trigger factor of the inflammatory processes seen in T2DM and AD consequent to down-regulation of the "cholinergic anti-inflammatory pathway" [ 10 ]. In an interesting recent review article [ 11 ], the evidence for the association of vascular risk factors such as T2DM, hypertension, obesity and dyslipidemia in relation to dementia was systematically reviewed on the basis of longitudinal population-based studies.
These risk factors often occur concomitantly and, although each has been linked to an elevated risk of dementia, its ambiguous as which imposes the greatest risk and when this occurs. During later life diabetes emerged as conveying the highest impact on dementia [ 11 ].
Clearly, vascular risk factors have long been known to favor the development of dementia, with age and the duration of exposure as important variables. Understanding the mechanisms associated with T2DM, hypertension, obesity and dyslipidemia may aid in offsetting their adverse actions as well as developing potential treatment strategies [ 11 ]. Impaired glucose tolerance is likewise associated with impaired cognition, independent of age, and there are reports of increased risk of AD with diabetes [ 12 , 13 ].
Whereas the localization and pathological features of diabetes and AD differ, there are numerous commonalities. Examples amongst many are that both are chronic progressive conditions that are present before a diagnosis is made or treatment initiated. T2DM is characterized by IR, hyperinsulinemia and glucose intolerance. The consequent hyperglycemia induces oxidative stress and non enzymatic glycation of key regulatory proteins leading to potential malfunctions in those proteins.
Abnormal glucose utilization and insulin resistance or deficiency is also early events in AD pathology that can be present without any correlation to the presence of diabetes. In a similar manner, glycation induced conformational changes have been shown to initiate the fibrillization of otherwise non pathogenic proteins that leads to the hypothesis that diabetes is a conformational disease [ 15 ]. In accord with evidence suggesting that diabetics have a higher risk for cognitive dysfunction, depression and memory impairment [ 16 ], animal models of T2DM have been described to have defective transport, uptake and neuronal concentrations of insulin [ 17 — 19 ].
Indeed, the induction of diabetes accelerates and worsens cognitive dysfunction in transgenic AD animal models, emphasizing the role of altered insulin pathways in AD brain [ 20 ].
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The brain is clearly an insulin-sensitive organ, where insulin plays a significant role in normal brain physiology [ 21 ], and disturbances in its signaling can impact synaptic plasticity as well as cell viability. Insulin receptors are localized throughout the brain, with particularly dense distributions in the hippocampus, entorhinal cortex and hypothalamus [ 22 ]. This same pathway likewise induces the synthesis of nitric oxide, additionally affecting learning and memory processes [ 30 ].
Thus, any defects in insulin signaling and IR may have adverse consequences on synaptic maintenance and remodelling through direct effects on energy production and glucose uptake. Notably, AD patients have reduced insulin levels and a lowered expression of insulin receptors and IRS proteins [ 31 ].
Diabetes Types and Insulin Resistance in Alzheimer's Disease
Correction of insulin levels in AD subjects has also been correlated with improved cognition [ 31 , 32 ]. Furthermore, insulin has been also described to regulate tau phosphorylation [ 33 ]. This can stimulate tau protein hyperphosphorylation. In this context, it is worth noting that elevated oxidative stress is an established feature of both T2DM and AD. Zhao et al. Taken together, research suggests that insulin signaling plays a central role in learning and memory, and, in particular, in deficits when signaling is aberrant. Bomfim et al. In accord with earlier reports, they proposed that in AD brain insulin signaling becomes stalled by processes leading to IR, as it does in diabetes.
Similar findings were additionally obtained in non-human primates. This provides additional support for a striking resemblance between inflammation-associated brain IR in AD and chronic inflammation-induced IR in peripheral tissues in T2DM that is discussed later [ 39 ]. Extending this work, Talbot et al. The bottom line from both studies is that insulin orchestrates numerous neuronal processes that impact synaptic plasticity, involving both the expression as well as trafficking of key receptors e. Extending their results, Bomfim et al. Confirming prior studies [ 49 — 51 ], exendin-4 treatment in AD transgenic mice in the Bomfim et al.
In addition, it has been suggested that the JNK pathway induction, likewise, leads to phosphorylation of c-Jun and tau in brains of AD patients [ 52 — 54 ]. However, the exact molecular mechanisms linking the two remain underinvestigated. It is suggested that disturbances in insulin cause hyperactivation of adipocyte hormone sensitive lipase, which eventually leads to high levels of free fatty acids FFA. Hence, new comprehensive research approaches towards dissecting mechanisms that underpin the coexistence of T2DM and AD may be helpful in not only understanding the pathophysiologic similarities between these two disorders but also ways to potentially offset or ameliorate these two progressive disorders.
Evidence supports the concept that AD and T2DM can be considered related systemic inflammatory conditions that can potentially be mitigated, at least in part, by normalizing common pathways associated with this systemic inflammation. Changes in human behaviour and lifestyle over the last century have resulted in burgeoning rates of obesity and metabolic syndrome, leading to a dramatically increasing prevalence of T2DM. The mechanisms that tie obesity to various metabolic abnormities in T2DM, such as insulin resistance, dyslipidemia and hyperglycemia, remain to be fully elucidated.
Hence, these inflammatory cytokines, adipocytokines and transcription factors result in hyperglycemia, which is the biochemical hallmark of T2DM. Notably, an inflammatory response is likewise involved in atherosclerosis, which can lead to diabetic cardiovascular complications, stroke and AD [ 59 , 60 ].
Conversely, IL-1RA treatment at high doses improves glucose sensitivity, insulin processing, and suppresses inflammation and infiltration of immune cells in a diabetic rat model [ 64 ]. Diabetes is associated with the production of AGE, the derivatives of lipids, proteins and nucleic acids.
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AGE interacts with their receptors RAGE and this interaction induces reactive oxygen species mediated inflammatory responses that are widely considered as the major culprits behind diabetic complications [ 65 — 67 ]. Toll like receptor TLR signal pathways have also been implicated in mediating inflammation associated with diabetes. This promotes vascular oxidative injury, leukocyte adhesion, and atherogenesis [ 75 ].
To the contrary, CD36 knockout transgenic mice exhibit improved insulin signaling and reduced inflammation [ 76 , 77 ]. It has been widely shown that inflammatory mechanisms are classically associated with AD [ 78 ].
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Studies have revealed that systemic administration of IL-1 lowered extracellular acetylcholine ACh levels within the hippocampus and suggest that raised levels of IL-1 could be involved in AD consequent to ACh reductions [ 83 ]. The neurotrophin NGF is indispensable for the maintenance and differentiation of basal forebrain cholinergic neurons [ 85 ], which are one of the major neuronal populations affected that progressive degeneration in AD.
It has become increasingly clear that alterations in NGF transport and signaling may play a key role both in development and progression of sporadic AD, leading to the proposition that "neurotrophic imbalance" i.
The role of insulin in Alzheimer's disease
The formation and accumulation of AGEs has also been identified immunohistochemically within senile plaques and neurofibrillary tangles, the pathological hallmarks of AD [ ]. RAGE is also expressed in neurons, microglia and astrocytes [ — ]. An increased expression of RAGE has been observed in AD pathology afflicted regions of brain, including the hippocampus [ ].
RAGE mediated microglia activation and neuro-inflammation has been experimentally demonstrated using double transgenic mice that over-express both the human RAGE gene and human amyloid precursor protein [ ]. These effects were mitigated by blocking the RAGE mediated signal transduction. Brought together, these findings support the concept that inflammation is an underlying thread in the coexistence of T2DM and AD. In general, drug developments, particularly for neurological disorders, are a field of high risk and attrition, but also of huge gain - if successful [ — ].
BuChE, in addition to its role in co-regulating ACh levels and cholinergic neurotransmission, has non-cholinergic functions related to differentiation, proliferation and apoptosis [ ]. Likewise, ACh modulates interactions between the nervous system and the immune system. Progress in the characterization of both disease mechanisms and drug targets has provided the insight that a number of common players are involved across a broad variety of biological cascades, and thus relatively focused approaches such as i restoring ACh levels by selectively inhibiting the catalytic activity of BuChE, and ii selectively inhibiting pro-inflammatory cytokines e.
ACh, to extend this example, has a regulatory role on dopamine, serotonin as well as several neuropeptides, providing a close interaction between immune responses and neurotransmission [ ]. Elevated levels of BuChE, are reported in diabetes and AD and have been hypothesized to result in a low-grade systemic inflammation often seem in the elderly, and associated with geriatric depression [ ] as well as sarcopenia [ , ] and other disorders [ ] , consequent to dysregulation of the described pathway Fig.
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Elevated systemic BuChE activity is a marker of low-grade inflammation, is found in Alzheimer brain, and may have a role in the altered lipoprotein metabolism in hyper triglyceridemia associated with insulin insensitivity or insulin deficiency in T2DM, and thus may be a target worth pursuing [ , ]. Interestingly, the BuChE K variant allele is more common among subjects with T2DM versus non-diabetics, suggesting a close association of the BuChE gene 3q26 with T2DM that could be related to an identified susceptibility locus on chromosome 3q27, but independent of islet function [ , ].
The normalization of elevated BuChE activity found in AD [ — ] may hence be of value for T2DM, which, as indicated, is associated with incidence of AD and drives its progression. The design and development of cymserine analogues for brain BuChE inhibition [ — ], and application of innovative and quantitative enzyme kinetic analyses [ — ] provides an immediately clinically translatable approach [ ].
Other approaches too have moved forward, as exemplified by Nizri et al. Their bi-functional compounds showed a novel pharmacokinetic profile providing an alternative potential strategy for future drug modalities.
A growing body of research continues to associate AD to T2DM, as well as with obesity and cardiovascular disease.