Introduction

Alzheimer's is the most common cause of dementia, a general term for memory loss and other cognitive abilities serious enough to interfere with daily life and is recognized as fifth foremost reason of decease for those aged 65 and older [1]. It has no current cure, but treatments for symptoms are available and research continues. Neurotransmitter deficits, degenerated neurons, synaptic dysfunction, extracellular buildup of Amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFT) are the major crude disfigurements present in AD [2]. To produce Aβ peptides of different lengths such as Aβ38, Aβ40, and Aβ42 due to the active enzymatic component of the gamma-secretase (γ-secretase) complex, presenilins (PS), cleaves amyloid precursor protein (APP) at several sites within the membrane. Insulin resistance is a common phenomenon, closely associated with obesity, and defined as the inability of target tissues to respond normally to insulin. Insulin resistance typically precedes the onset of type 2 diabetes (T2D) by several years. T2D is a risk factor for dementia and for AD, the most common type of dementia. Some epidemiological studies suggest that insulin resistance increases the risk for dementia and AD, even in non-diabetic populations. In vitro and animal studies indicate that insulin resistance can contribute to the pathogenesis of AD through multiple different pathways. Endocrine abnormalities especially diabetes is so common in AD that also regarded as a type of diabetes. Diabetes having an influence on memory processing (recognition and retrieval), morphology of brain (brain atrophy) and synaptic communication is a well demonstrated hazardous aspect that influences pathology of AD [3]. Type 1 diabetes is mainly observed in children and young adults while T2D is more common among adults and is responsible for 90% of the incidences globally [4]. Recent evidence indicates that AD is a brain-specific form of diabetes [5]. T2D is the commonest and imperative co-morbidity of AD, escalating the risk of AD many folds [6]. T2D is exemplified by hyperglycemia, hyperinsulinemia, insulin resistance, metabolic dysfunctions and chronic inflammation and notably all these features are shared by AD [6, 7]. Other key factors as dysfunctional protein O-GlcNAcylation, mitochondrial disparities, oxidative stress, distorted energy metabolism and cholesterol modifications that are link AD [8] and T2D [9, 10]. Hyperglycaemia affects the transduction of insulin signaling which could link to damages tissues and organs, leading to glycation reaction of antioxidant enzymes, and reduction in the activity of SOD and other enzymes [11]. In addition, the hyperinsulinaemia impairment of insulin signaling and insulin resistance are the vital factors that make the sense of keeping insulin at the center stage of both pathologies irrespective of genotype [12]. Insulin also plays an important role in cognition processes and the insulin also has the high intensity in the regions responsible for memory formation and consolidation like hippocampus [13]. Many recent studies have indicated that impaired hippocampus insulin signaling impairs the memory and other executive functions, attributing to the decline of insulin signaling and concurrent development of insulin resistance [14,15,16]. This deliberation advocates a strong link between hyperinsulinemia/insulin resistance and the resultant pathologies like T2D and AD [17]. Peripheral insulin resistance leads to decrease insulin signaling in CNS, followed by alteration in brain metabolism. Increased Aβ toxicity, Tau hyperphosphorylation, oxidative stress and neuroinflammation are attributed to central insulin resistance, which leads to neurodegeneration (Fig. 1). The work provides the basic mechanisms of the insulin resistance mediates dysregulation of bioenergetics and progress to AD as a mechanistic link between diabetes mellitus and AD, providing a potential and feasible zone to succeed in the development of therapies in AD by enhanced hypometabolism and altered insulin signaling. Based on the concept that AD may represent a brain-specific form of diabetes mellitus, the term “type-3 diabetes” indicating AD was made [18,19,20].

Fig. 1
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Schematic representation of molecular pathways linking insulin resistance and Alzheimer disease

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Insulin Signaling in the Central Nervous System

Insulin, hormone that regulates glucose levels in the blood and that is produced by the beta cells of the islets of Langerhans in the pancreas and consists of two polypeptide chains, A (21 amino acids) and B (30 amino acids) connected by disulfide linkages. Insulin initiates its action by binding to implanted glycoprotein receptor formed by two α and two β-subunits [17]. Insulin binding to α-subunit of the receptor fabricate confirmative alterations that lead to its activation and autophosphorylation of several Tyr residues at β-subunit cytosolic region [21, 22]. Autophosphorylated remnants are then acknowledged by insulin receptor substrate (IRS), out of which IRS-1 and IRS-2 are the two major players and the common intermediaries in insulin signal propagation. IRS is ideal and suitable for the configuration of molecular complexes which mediates intracellular signaling pathways. Insulin and Insulin like growth factors (IGF-1) connect to tyrosine kinase receptors, the insulin receptor (IR) and IGF-1. Insulin binding is highest in the olfactory bulb; cerebral cortex and hippocampus besides that insulin receptors are also expressive on endothelial cells of blood brain barrier and are responsible for transport of insulin and IGF-1 through blood–brain barrier (BBB) into CNS [23]. While the exact mechanism of how insulin gets into the brain still remains controversial, insulin circulating in the blood can cross the BBB through a receptor mediated active transport system [23]. This pathway is consistent with studies showing that insulin levels in the cerebrospinal fluid (CSF) increase proportionally with blood insulin after peripheral insulin infusion [21,22,23]. However, the amount of insulin produced in the brain and whether this pool of insulin is physiologically relevant still remains elusive. It is possible that both the centrally and peripherally derived pools of insulin are important for signaling in the brain.

Insulin and IGF-1 are conferred with functions which are important for neuronal survival and maintenance of CNS integrity. Insulin receptors and insulin signaling affect glucose homeostasis, neuronal integrity, cognition, through influencing several receptor mediated mechanisms including Calcium influx, neurotransmitter build up and synaptic connections, apoptosis and neurogenesis [23]. Insulin also regulate expression and levels of gamma aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA) and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mediated mechanisms which have strong influence over long-term potentiation (LTP) and long-term depression (LTD). Furthermore, insulin is crucially involved in expansion and preservation of excitatory synapses [24] and dendritic spine formation through activation of phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and Ras-related pathways [13, 25] which are integral to insulin signaling [26]. Insulin also influence cell survival by modulating apoptotic pathways and the intermediates involved in apoptotic cascade [27, 28]. Thus insulin through influencing any of these pathways alter the neuronal performance and integrity which may ends up in the defects in learning, memory and other features of AD. Previous studies indicated that brain insulin was equally reduced in AD patients and age-matched controls, indicating that reductions in brain insulin are likely a result of age, not AD [29]. Ultimately, a greater understanding of insulin in the brain relative to the severity of AD and age-matched controls needs to be obtained in order to fully comprehend insulin’s function in healthy and diseased brains. Thus, reduced insulin levels in the CNS can lead to reduced levels of antiamylogenic proteins, and both the overproduction and an impaired clearance of Aβ (Fig. 2).

Fig. 2
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Some potential insulin pathways and insulin mediated dysfunctional status as the common mediators between T2D and AD

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Role of Insulin Resistance in Alzheimer's Disease

Insulin resistance in AD and diabetes can lead to hyperinsulinemia, thereby, saturating insulin-degrading enzyme (IDE) for insulin and Aβ degradation. Recently, many studies indicated that the incidence of AD is higher in T2D patients and obese individuals, implying common mechanisms driving these disorders [12, 30, 31]. Insulin resistance could be a main feature which shared among diabetes, obesity, and AD [32]. The neuronal glucose uptake may not depend on insulin totally, thus the concept of insulin resistance in brain is more related to impaired insulin signaling pathways. The malfunction of insulin signaling pathways and resultant state of hypometabolism observed are considering among factors in altered bioenergetics that connects AD and T2D [6]. The insulin resistant state could lead to compromised neuron functions and cognitive skills accompanied by extreme rise of insulin and relatively declined insulin activity in the periphery as an important predictor of T2D [33, 34]. Consequently, this leads to development of neuritic plaques, hippocampal atrophy, cognitive performance and lower cerebrocortical glucose metabolism which closely may correlate with the memory impairments [7]. A previous study revealed that increased p-Ser312IRS1 manifested in prodromal AD patients that sustained these alterations a decade then, as AD patients [35], suggesting that insulin resistance in AD develops years before clinical manifestations and that neural-derived exosomes carries potential for early AD diagnosis. Due to lack of insulin response, down regulation of insulin receptor, reduced binding of insulin receptors or faulty activation of the insulin signaling cascade that cause the defective brain insulin signaling in AD and T2D. The major consequence of this altered cascade is the decreased neuronal glucose uptake that is manifested as impaired neuroplasticity, neurotransmitter deficits, collapse of bioenergetics mechanism and initiation of fateful inflammatory cascade. Overall the consequences of impaired insulin signaling are attributed to impaired metabolism in brain that may lead to brain malfunction, providing possible explanations for the connection between diabetes, obesity, and AD [14].

Insulin resistance or dysfunction of insulin signaling is a universal feature of T2D, due to altered glucose metabolism and its interdependence on cell death pathways form the basis of linking T2D with AD. Dysfunctional insulin pathways and resistance of insulin is a status of receptor dysfunction, altered receptor expression, deviations in receptor binding and malfunctioned events in phosphorylation chain or the altered activities related to kinases involved in phosphorylation. At the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a signaling cascade collectively known as PI3K/Akt/mTOR signaling pathway. Recent studies suggested that the pathway operates as a bistable switch under physiologic conditions for certain types of cells, and insulin response may well be a threshold phenomenon [16, 36, 37]. The pathway's sensitivity to insulin may be blunted by many factors such as free fatty acids, causing insulin resistance (Figs. 3, 4). It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouples, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics [38, 39].

Fig. 3
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Insulin actions in the central nervous system (CNS), and proposed concequences of insulin resistance in the CNS

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Fig. 4
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Potential molecular mechanisms underlying defective insulin signaling in Alzheimer’s disease (AD). Liraglutide an GLP1-R agonist is able to restore insulin signaling and is a potential therapy for AD, TNFα tumor necrosis factor α, IKKβ IκB kinase, NFκB nuclear factor κB, PKR protein kinase RNA-activated, JNK Janus kinase, IRS-1 insulin receptor substrate, PI3K phosphoinositide 3-kinas, PIP3 phosphatidylinositol (3, 4, 5)-triphosphate, PIP2 phosphatidylinositol-4 5-bisphosphate, AKT protein kinase B, GSK3β glycogen synthase kinase 3β, eIF2α eukaryotic translation initiation factor α, PTEN phosphatase and tensin homolog, GLP1R glucagon-like peptide-1 receptor, p phosphorylation

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Interestingly, impaired insulin signaling is present in several transgenic and nontransgenic mouse models of AD. Some previous clinical studies have reported that AD patients could have glucose intolerance, suggesting a bidirectional relationship between the two conditions [40, 41]. There were a reduced levels of IRS-1 associated to the membrane of hippocampal extracts [42] and a decreased activation of IRS-1 and PI3K in the hippocampus and cortex that were observed by 10 months of age [43]. Markers of insulin resistance were also reported in the hypothalamus of APP/PS1 mice [44] since the IRS-1 phosphorylated in serine 616 in the hippocampus at 9 months of age was higher than that of control [45], and increased levels of IRS-1 phosphorylated in serine 636 and 312 in the frontal cortex at 13 months [46] also demonstrated. In combination with peripheral insulin resistance, there were an increased inhibitory phosphorylation of IRS-1 in serine 612 in the hippocampus of 5-month-old tg2576 mice was also reported [43]. Remarkably, the central infusion of Aβ oligomers lead to peripheral insulin resistance, which was further observed in the APP/PS1 and in the 3xTgAD mouse models of AD [47]. Table 1 provides the main mechanisms linking brain insulin/ insulin-like growth factor resistance to AD pathology [41]. To confirm these concepts, further evidence is still required to investigate the mechanisms whereby AD affects the diabetic phenotype.

Table 1 Summary of mechanisms linking brain insulin/ insulin-like growth factor resistance to Alzheimer’s pathology
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Hypometabolism in Alzheimer’s Disease

Hypometabolism, characterized by decreased brain glucose consumption, is indispensable for neuronal survival, synaptic connections, maintenance of integrity of BBB. Major preconditioning risk factors such as cardiovascular dysfunction, diabetes, metabolic syndrome, traumatic brain injury, and stroke are shared by the sporadic AD [48,49,50,51]. The quantitative evaluation of reduced glucose metabolism in the AD brain was first performed by arterio-venous difference studies 20–30 years ago [52,53,54]. The continuous and optimum presence of glucose as energy substitute is highly desired in CNS which ultimately depends upon the transportation of glucose across BBB. The reduction in glucose supply may end with the state of reduced energy metabolism which may lead to neuropathological consequences like AD. Several previous studies revealed that glucose hypometabolism is present well before any measurable cognitive dysfunction or AD-specific pathological alterations and therefore represents the early presymptomatic signature of AD development [55,56,57,58]. Also, epidemiological findings strongly verify the fact that affected glucose-energy metabolism and resultant hypometabolic state multiplies the risk of developing AD [59, 60]. This abnormal glucose metabolism seems the main contributor towards the synaptic dysfunction and loss observed in the brains of AD patients [61]. Therefore, altered brain metabolism in T2D is measurable after the onset of dementia symptoms which may be strongly linked with insulin resistance or reduced insulin actions in the brain [14]. The state of insulin resistance, diabetes and metabolic abnormalities could share large features of AD thus nowadays AD is categorically classified as metabolic-cognitive syndrome [62,63,64]. Probably, the insulin resistance may directly lead to accumulation of senile plaques and hyperphosphorylation of tau in AD via inflammatory factors, mitochondrial dysfunction, and oxidative stress, apoptosis, excitotoxicity and overactivation of protein kinases [55]. In addition, compared to mice that ate a normal diet, mice that ate the high-fat, high-sugar diet had significantly higher markers of inflammation, insulin resistance, and cellular stress in area of the hippocampus believed to be involved in AD progression [65]. Nutrition can have a profound effect on brain function, unhealthy diets high in fat and sugar can cause hypothalamic inflammation, which could be linked with the diseases.

In many previous studies focusing on insulin resistance in the AD brain, the important role of insulin in glucose uptake is reviewed [50, 55]. Insulin roles the major determinant for entry of glucoses into brain and the process is facilitated by presence and activated state of glucose transporters, this process of glucose entry and transportation through transporters is hampered by metabolic deformities including insulin resistance [66]. The insulin resistant state and deviations in insulin signaling cascade affect glucose levels through reduced transportthrough decreased glucose transporter 1 (GLUT1) and -3 levels which has been detected in AD brains [67]. The diminished glucose transport directly impacts hyperphosphorylation of tau protein, density of neurofibrillary tangles (NFTs) and hippocampal atrophy [68] thus proving a substantial link between insulin signaling, diminished glucose transport and pathological changes in AD. This altered permeability leads to decreased brain insulin levels and decreased insulin-facilitated neural and glial activity. Conversely, T2D also directly damages BBB, and increase the permeability to a variety of substances [69, 70] and this unchecked entry exit process may lead to infiltration of undesired and toxic substances into brain.

Among factors leading to energy deficiency and oxidative stress, neuro-inflammation, and insulin resistance are characterized by common brain pathologies [71, 72]. Inflammation and provoked inflammatory cascade could be an event in the progression of insulin resistance which are fundamental to pathologies of T2D and AD [19, 73]. The scarcity of glucose and a state of hypometaboilsm created by insulin resistance in CNS is sensed by the glial cells which triggers higher ketone body production, activation of NFκB pathway and reticence or diminished activity of AMP-activated protein kinase [74]. Furthermore, chronic inflammation exacerbates insulin and IGF1 resistance significance contribute to AD [50, 75] through provoking proinflammatory mediators, including tumor necrosis factor-α (TNF), IL-6 and IL-1β [74, 76,77,78]. These inflammatory mediators are also involved in macrophage activation/infiltration into adipose tissue and are also involved in pathophysiology of metabolic disorders [77, 78]. Insulin resistance leads to aberrant activation of c-Jun N-terminal kinase (JNK) which in turn activates inflammatory/stress signaling networks, endoplasmic stress signals, the stress kinases IKK and double-stranded RNA dependent protein kinase. These pathways are in dominance to play a role in hippocampal dysfunction in AD [79]. Insulin and insulin signaling have a strong influence over cellular bioenergetics and impairment of glucose metabolism or insulin signaling directly affect the cell survival. Recent studies of preclinical and clinical on the efficacy of anti-diabetic, insulin-sensitizing drugs on multiple aspects of AD pathology [14, 80] in human patients and animal model that were summarized in Table 2.

Table 2 Recent preclinical and clinical studies on the efficacy of anti-diabetic, insulin-sensitizing drugs on multiple aspects of Alzheimer’s disease (AD) pathology
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Therapeutic Approaches to Insulin Resistance in Alzheimer’s Disease

Diabetes and AD have traditionally been thought to be independent disorders. However, the results of recent epidemiological and basic science investigation have suggested possible associations and some common pathophysiological mechanisms. Insulin resistance is well known as an essential feature of T2D, therefore treatment strategies for T2D, particularly those aimed at improving insulin sensitivity, may also benefit those patients at risk for AD at the early stages. Due to the overlapping yet distinct pathological features among diabetes, insulin resistance and cognitive decline, multitargeted drug therapies along with lifestyle interventions are also explored [81] from the perspective of research in the pharmaceutical industry including nutraceuticals, antioxidant activity, polyphenols [82], omega-3 fatty acids as well as ketogenic diet, lifestyle support and brain-gut connections.

Among nutraceuticals produce curcumin as a brain permeable compound with the ability to target abnormal protein aggregates [83]. Curcumin may also thwart “proapoptotic signaling pathways in primaryhippocampal neuron cultures”. Forthcoming research inimproving bioavailability of curcumin may have the potential to lift the veil on promising naturalsubstances for AD patients. Previous research has also shown the benefit of metformin in mice when coupled withcurcumin and piperine supplementation, particularly regarding enhanced insulin sensitivity, signaling, and better systemic glucose tolerance [83]. However, the anti-inflammatory benefits of fruits and vegetables have been widely publicized for decades, particularly regarding antioxidant action in reducing inflammatory damage [77]. Rodent research has linkedvarious vegetables and fruits as protective “against cognitive and brain neuropathology fromdietary oxidative stress” due to innumerable bioactive constituents like carotenoids, antioxidant vitamins, polyphenols and flavonoids [8]. While current research has identified many different polyphenols from various families of flavonoids, it has been estimated that we have only scratched the surface with the potential therapeutic implications that they provide in vivo [84]. This has significant potential to advance our understanding of proactive approaches toward preventing AD and inhibiting progression. The essential role of omega-3 fatty acids in brain development and maintenance has been well recognized, particularly in the past ten years, yet only recently “have their effects on brain aging been explored” [85]. Diets rich in omega-3 fatty acids and naturally low in omega-6fatty acids may hold the key for nutritional therapy for AD patients [86]. The ketogenic diet may even diminish and clear beta amyloid plaques within the brain, while convalescing damaged mitochondria and reducing universal inflammation [87]. New research has shown that glycated ApoE4 protein and faulty insulin signaling leads not only to impaired energy transport for brain tissues, but also impaired lipid transportation, mainly cholesterol [87, 88]. There is no pharmaceutical intervention that has ever existed that has been more potent in improving overall vasculature throughout the body, than exercise [89]. This also has extensive implications for AD patients and type 2 diabetics thanks to increases in quality of life, neurochemical messaging within the brain, restorative power over insulin resistance, and the ability to clear beta-amyloid plaques in certain individuals [89]. The concept of the gut-brain axis, the bidirectional communication between gut and brain, contributing significantly to the pathogenesis of AD that has been supported by many experimental and clinical studies.

Conclusion

Glucose being an indispensable source of energy and obligate for survival interlinks various pathological mechanisms in T2D and AD as both are aftermaths of glucose metabolism and energy failure that involve disturbance of glucose metabolism by GLUT1 deficiency, O-GlcNAcylation of proteins, disturbed mTOR signaling, mitochondrial dysfunction, and reduced cholinergic transmission, aggregation of toxic Aβ plaques, tau hyperphosphorylation and autophagy. Increasing the knowledge and awareness of the term type 3 diabetes has the potential to pave the way for disease treatment, prevention and possibly even deliver a cure. Currently, there have been no particular treatments with established efficacy in counteracting cognitive decline and/or AD, so the implications of identifying AD as a disorder with an etiology rooted in faulty insulin signaling and irregular energy pathways could be critical in disease management. While the specific mechanisms between AD and all forms of diabetes remain convoluted and unclear, increasing the awareness of AD as a third form of diabetes, T3D has the potential to provide a plethora of proactive and therapeutic strategies to current patients. For now, it seems that the testing of more anti-T2D drugs with beneficial effects against cognitive impairment has a certain promising future.