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Fahmida Alam#*, Md. Asiful Islam#, Teguh Haryo Sasongko and Siew Hua Gan*

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

A R T I C L E H I S T O R Y

Received: April 23, 2016 Accepted: May 26, 2016 DOI: http://dx.doi.org/10.2174/1381612822666160527160236

Abstract: Although type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are two independent diseases, evidences from epidemiological, pathophysiological and animal stud-ies have indicated a close pathophysiological relationship between these diseases. Due to the pathophysiological similarity of T2DM and AD, which includes insulin resistance and defi-ciency, protein aggregation, oxidative stress, inflammation, autophagocytosis and advanced glycation end products; AD is often referred to as “type 3 diabetes”. In addition to the tar-geted regimens usually used for treating T2DM and AD individually, currently, anti-diabetic drugs are successfully used to reduce the cognitive decline in AD patients. Therefore, if a common pathophysiology of T2DM and AD could be clearly determined, both diseases could be managed more efficiently, possibly by shared pharmacotherapy in addition to un-derstanding the broader spectrum of preventive strategies. The aim of this review is to dis-cuss the pathophysiological bridge between T2DM and AD to lay the foundation for the future treatment strategies in the management of both diseases.

Keywords: Type 2 diabetes mellitus, Alzheimer’s disease, pathophysiology, linkage, inflammation, oxidative stress, treatment.

INTRODUCTION According to data from Global Health and Aging (2010), 8% of the world’s population was over 65 years of age in 2010, and the number of people over 65 years of age is expected to rise to 16% by the year 2050 [1]. Both type 2 diabetes mellitus (T2DM) and Alz-heimer’s disease (AD) are associated with increasing age. Addi-tionally, there are at least 347 million diabetic patients [2] and 44 million people suffering from AD. These numbers are expected to become double by the year 2030 [3]. Similarly, according to the World Health Organization (WHO) in 2014 [4], 13% of the world’s population was obese, making obesity another challenging health issue as the pathogenesis of both T2DM [5] and AD [6] showed strong associations with obesity. Undoubtedly, these data are alarm-ing and represent an emerging health-care issue because, without appropriate regulation, the combination of these two diseases is going to be one of the major socio-economic burdens of the future world population. T2DM is a peripheral metabolic disease, while AD is a neu-rodegenerative disorder. In case of T2DM, there are two underlying mechanisms involved: 1) insulin resistance and 2) inadequate insu-lin secretion by β-cells from the pancreas. In the beginning, pancre-atic β -cells increase insulin secretion in response to insulin resis-tance, resulting in hyperinsulinemia, while effectively maintaining glucose levels below the T2DM range. However, when β-cell func-tion begins to decline, insulin production become inadequate to *Address correspondence to these authors at the Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia; Tel: +609-7676803; Fax: +609-7653370; E-mails: [email protected]; and [email protected] #These authors contributed equally to this work.

overcome insulin resistance and thus blood glucose level tends to rise resulting in T2DM [7, 8]. In contrast, AD is a progressive neu-rodegenerative disorder that is characterized by senile plaques and neurofibrillary tangles resulting in memory loss. AD is also charac-terized by a gradual decline in cognitive function that eventually leads to the premature death of the individuals [9]. Nevertheless, these two diseases share common pathophysiol-ogy at both the molecular and cellular levels. Based on the epide-miological, pathophysiological and genetic studies conducted over the past three decades, there is an increasing amount of evidences on the association between T2DM and AD. The co-existence of T2DM and AD may be attributed to a number of complex synergis-tic interactions that induce or inhibit pathological pathways leading to the development of both diseases. The diseases most likely co-exist due to unregulated protein aggregation, impaired insulin sig-naling, inflammation, oxidative stress, mitochondrial dysfunction, production of advanced glycation end products (AGEs), obesity, epigenetics, impaired autophagocytosis, transforming growth factor β (TGF-β) and genetic factors. Nevertheless, the clear, complete and appropriate pathophysiological connections between T2DM and AD have not yet been elucidated. Additionally, most appropri-ate regimens targeted at reducing the progression of T2DM and AD are unsuccessful when they are individually treated. Therefore, for more appropriate management strategies for T2DM co-existing in patients with AD or vice-versa, the pathogenic relationship between these diseases must be elucidated. The objective of this review is to provide more concrete evidence of the pathophysiological links between T2DM and AD, with the aim of providing foundation for better treatment strategies in future.

Md. Asiful Islam

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Type 2 Diabetes Mellitus and Alzheimer’s Disease: Bridging thePathophysiology and Management

Type 2 Diabetes Mellitus and Alzheimer’s Disease Current Pharmaceutical Design, 2016, Vol. 22, No. 28 4431

EPIDEMIOLOGICAL LINKS BETWEEN T2DM AND AD As the predisposition to both T2DM and AD increases with increasing age, these diseases have become major alarming health issues for the elderly throughout the world [10]. In 1999, Ott et al. [11] first established that the influence of T2DM on developing AD is almost double. A longitudinal study of the American population (n=1138) revealed that T2DM was the strongest risk factor [relative risk (RR) 3.8] for developing AD [12]. According to several pro-spective studies, T2DM patients tend to develop AD in many popu-lations including Canadian (RR 4.4) [13], American (RR 3.0) [14], Finish (RR 2.5) [15], Japanese (RR 2.1) [16], Dutch (RR 1.9) [11], Chinese (RR 1.6) [17] and Swedish (RR 1.3) [18] populations. A recent meta-analysis (n=6184) showed that the RR of T2DM pa-tients to develop AD is 1.5 (95% confidence interval, 1.2-1.8) [19]. A significantly high prevalence of T2DM (p<0.05) and impaired fasting glucose (IFG) (p<0.01) were found among American pa-tients with AD [20]. Additionally, a higher prevalence of AD de-velopment was observed in patients with T2DM [21]. Recently, Sanz et al. [22] revealed that AD patients who were diagnosed with T2DM have poorer functional status [22], indicating that T2DM and AD are inter-related based on epidemiologic findings and, in part, based on their pathophysiological similarities.

PATHOPHYSIOLOGICAL LINKS

Insulin Resistance and Deficiency In T2DM, insulin resistance is caused by the failure of the insu-lin receptor to respond to insulin stimulation for blood glucose up-take, whereas insulin deficiency occurs due to impaired insulin secretion by pancreatic β-cells or low levels of insulin-secreting β-cells in the peripheral liver and muscle tissues of T2DM patients [23]. Although both insulin resistance and deficiency are core char-acteristics of T2DM, numerous studies have revealed their in-volvement in the pathogenesis of AD. In addition to the native insu-lin production in the brain, peripheral insulin enters the central nervous system (CNS) via selectively distributed insulin receptor proteins [24]. In the AD brain, insulin resistance develops due to the altered sensitivity of brain insulin receptors, which can affect the metabolic degradation as well as the expression of amyloid β peptide (Aβ) and tau proteins (Fig. 1) [25]. In addition, Aβ oli-gomers were observed to bind with the hippocampal neurons and trigger the removal of dendritic insulin receptor substrates (IRS) from the plasma membrane, resulting in AD pathogenesis. As a result, this phenomena has recently been referred to as “type 3 dia-betes” [26]. Acetylcholine is an organic chemical secreted by the motor neurons of the nervous system as a neurotransmitter. It is synthesized by the choline acetyltransferase (ChAT) enzyme, the expression of which is stimulated by insulin and insulin-like growth factor 1 (IGF-1). When the co-localization of ChAT in insulin or IGF-1 receptor-positive neurons is reduced, the production of ace-tylcholine is also reduced, thus leading to the progression of AD (Fig. 1) [27]. In addition to catabolizing insulin and IGF-1, the insu-lin-degrading enzyme (IDE) (a metalloprotease) efficiently de-grades deposited Aβ [28]. However, under conditions of insulin resistance, insulin competitively inhibits the IDE and impairs the proteolysis of Aβ, promoting AD [29]. Moreover, insulin resistance and deficiency were found to cause tau protein hyperphosphoryla-tion via activating glycogen synthase kinase-3β (GSK-3β), leading to the development of AD (Fig. 1) [30, 31]. Considering all of the evidences presented above, it is plausible that insulin deficiency and insulin resistance represents one of the major pathophysiologi-cal linkers between T2DM and AD.

Protein Aggregation Both T2DM and AD are protein (amyloid) aggregation-oriented diseases. In case of T2DM, amyloid deposition is progressively observed in pancreatic β-cells (Islets of Langerhans) leading to

β-cell dysfunction followed by the disruption of glucose homeosta-sis (Fig. 1). On the other hand, amyloid fibers are aggregated in AD brain causing neuronal cell loss followed by cognitive decline (Fig. 1) [32-34]. Interestingly, both depositions are similar in term of appearance (linear) and structure (β-sheeted), and both aggregates from self-assembled spherical oligomers [35]. The protein deposition in T2DM is caused by the accumulation of a 37-amino acid peptide called islet amyloid polypeptide (IAPP) or amylin, whereas, the accumulation of a 42-amino acid polypep-tide referred to as Aβ is responsible for the protein plaque in AD [36]. Under normal conditions, the shorter Aβ (39-42 amino acids) is generated by the proteolytic cleavage (by β and γ secretases) of amyloid precursor protein (APP) [37]. However, in case of AD, consistently larger Aβ (42 amino acids) are produced, and these tend to aggregate and accumulate. Under normal physiological conditions, amylin and insulin are co-secreted in a fixed proportion [38]. However, as insulin secretion is disrupted in T2DM, amylin cannot be released from β-cells; therefore, it accumulates inside the cells, which leads to the destruction of the β-cells [39, 40]. In addi-tion, Janson et al. [20] established that 90% structural similarity exists between APP and IAPP, which strengthens the pathophysi-ological link between T2DM and AD. In 2015 [41], in vivo experi-ment on transgenic mice revealed the formation of pro-IAPP and IAPP in cerebral and vascular Aβ deposits. Although the source of IAPP was unclear (it may be produced in the brain or it may travel from the pancreas), the scenario suggested a strong molecular link between T2DM and AD. Therefore, it is clear that the accumulation of large insoluble amyloids (amylin and Aβ) is one of the most common pathologic phenomena of both T2DM and AD. Tau is a microtubule-stabilizing protein abundantly found in neurons. The hyperphosphorylation of tau can induce neurofibril-lary tangles leading to AD (Fig. 1) [42]. Although the presence of hyperphosphorylated tau proteins is a common feature of AD [43], the proteins are also observed in pancreatic islet cells of T2DM in both rats [44] and humans [45]. Kim et al. [46] reported that in-creased tau phosphorylation is one of the risk factors for the devel-opment of AD in T2DM patients. Additionally, the activation of the rate-limiting enzyme GSK-3β is another common phenomenon that subsequently leads to the phosphorylation of glycogen synthase, thus contributing to the pathogenesis of both T2DM and AD [47].

Hyperinsulinemia� Hyperinsulinemia is an early hallmark of T2DM that has the potential to increase Aβ levels through various indirect mechanisms (i.e. inflammation) leading to memory decline and subsequently to AD (Fig. 1) [48-51]. Although the structure and function of brain insulin receptors differ from those of peripheral insulin receptors [52], excessive levels of insulin were found to be associated with CNS functional decline. In sporadic AD, Frolich et al. first ob-served increased insulin binding activity in the brain [53]. Although the insulin binding activity was increased, the insulin receptor ac-tivity was reduced in the AD brain [54], consistent with insulin resistance, which indicated the role of hyperinsulinemia in AD in the context of T2DM. In the AD brain, the gene expression levels of molecules that contribute to insulin and insulin growth factor signaling pathways were found to be altered [55]. In clinical stud-ies, Craft et al. [56, 57] compared the insulin levels in both CSF and plasma between patients with AD (n=25) and age-matched controls (n=14). Plasma hyperinsulinemia was detected in patients with AD but not in the controls, which indicates a link between hyperinsulinemia and AD under the condition of insulin resistance. Two longitudinal studies conducted among the American popula-tion concluded that hyperinsulinemia was associated with a higher risk of having AD [58, 59]. Therefore, it can be postulated that hyperinsulinemia is one of the major distinctive pathological bridges between T2DM and AD.

4432 Current Pharmaceutical Design, 2016, Vol. 22, No. 28 Alam et al.

Inflammation Inflammation is a localized protective mechanism provoked by the reaction of body tissues to injury or infection [60] in which redness, loss of function, swelling, pain and heat are experienced. Although short-term inflammation is beneficial for tissue repair, chronic inflammation can lead to harmful effects on the body. In-creasing evidence points toward chronic inflammatory pathways as one of the emerging factors contributing to the pathogenesis of T2DM and AD and suggests an underlying relationship between T2DM and AD [61, 62]. Insulin resistance is associated with the presence of the pro-inflammatory cytokine interleukin-6 (IL-6) at high levels and is associated with the presence of C-reactive protein (CRP), which is produced by the liver but is found in elevated levels in response to inflammation [63, 64]. Consistent with this observation, accumula-tion of inflammatory mediators in AD patients has also been ob-served [65]. AD patients were reported to have IL-6 in senile plaques as well as preeminent immunoreactivity toward IL-6 [66, 67]. In addition, the association of CRP with a higher risk of AD has been reported [68, 69]. In an AD mouse model, brain inflamma-tion with increased IL-6 and tumor necrosis factor alpha (TNF-α) as well as amyloid deposition in the blood vessels were enhanced due to diabetes, which provoked an AD-like pathology [70]. Similarly, in transgenic mouse models of AD and diabetes, cytokines and

TNF-α were detected at high levels along with an increased level of Aβ in the blood vessels, which led to synaptic dysfunction [71]. Chronic neuroinflammation is a vital indicator of AD in which microglia (resident macrophages of the brain that act as the first line of defense) become activated after ingestion of Aβ, followed by the concurrent release of IL-1β, IL-6 and TNF-α-like pro-inflammatory cytokines. Thereafter, these cytokines hasten the pathology of the AD brain with neuronal loss [72]. A study of cultured human monocyte-derived macrophages reported that a suppressive role of pro-inflammatory cytokines on Aβ degradation as well as its clear-ance in the brain was observed due to the reduction of the expres-sion of IDE [73]. A recent study (2015) conducted among Mexican T2DM patients revealed that chronic inflammation is an important risk factor for cognitive decline [74]. According to another recent finding in 2015, low-grade systemic inflammation was indicated by significantly (p<0.01) higher plasma levels of IL-1β, IL-6, TNF-α, CRP and pro-inflammatory mediators among Turkish patients with T2DM and AD compared to healthy controls. Thus, T2DM acts as a triggering factor by activating pro-inflammatory cytokines in the brain and initiating neuroinflammation, which leads to the progres-sion of AD (Fig. 1).

Oxidative Stress and Mitochondrial Dysfunction A pathophysiological link between T2DM and AD may also exist via oxidative stress and mitochondrial dysfunction (Fig. 1) [7,

Fig. (1). Bridging pathophysiology and treatments for T2DM and AD In individuals with Type 2 diabetes mellitus (T2DM), hyperinsulinemia, hyperglycemia and insulin resistant conditions create an abnormal glucose metabo-lism that induces oxidative stress and subsequently activates inflammatory responses. In turn, Aβ plaques are synthesized in neurons due to inflammation in the brain via cytokines and interleukins, which are also responsible for tau hyperphosphorylation followed by neurofibrillary tangles. In addition to destroying β-cells and causing insulin deficiency, oxidative stress further obstructs normal autophagocytosis of amylin (in the pancreas) and Aβ (in the brain) resulting in the sustainable accumulation of protein aggregates and the progression of T2DM and Alzheimer’s disease (AD), respectively. Deficiency of ApoE and mito-chondrial dysfunction are also responsible for obstructing autophagocytosis, resulting in unregulated deposition of Aβ. Common genetic and epigenetic factors also directly link T2DM and AD. The potential drugs (pink boxes) targeting both T2DM and AD pathophysiology are indicated by green arrows.


75]. Abnormal glucose metabolism in the liver also affects the brain and tends to increase the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The overproduction of ROS and RNS further challenges the antioxidant capacity of cells via protein and/or lipid peroxidation leading to T2DM [76] and AD [77]. In case of AD, ROS [hydrogen peroxide (H2O2), hydroxyl (HO•) and superoxide (O2

•-)] targets and damages nucleic acids, lipids and mitochondrial proteins, which in turn amplify ROS pro-duction and trigger Aβ generation, tau phosphorylation and forma-tion of neurofibrillary tangles [78-80]. Although the brain repre-sents only 20% of the body weight, it requires approximately 20% of the total body oxygen consumption. For the normal functioning of neurons, mitochondria utilize 90% of the generated adenosine triphosphate (ATP). However, due to mitochondrial dysfunction, metabolic ability is lost leading to neuronal degeneration [81, 82]. Oxidative stress contributes as one of the most common patho-genic factors leading to insulin resistance and �-cell dysfunction in T2DM [83]. Increased oxidative damage was observed in the brains of experimentally induced hyperglycemic rats [84]. Oxidative stress provokes inflammation and subsequently increases inflammatory mediators such as cytokines and ILs, which play further roles in the pathogenesis of AD. On the other hand, inflammation is recognized as an important pathophysiological finding in T2DM that may have a role in the susceptibility of T2DM patients to develop AD and in the progression of T2DM in AD patients [85, 86].

Dysfunction of Autophagocytosis Autophagocytosis (self-eating) is a natural process by which insoluble proteins are aggregated, damaged and dysfunctional or-ganelles are engulfed by the membrane and degraded by lysosomes [87]. Although it is one of the major degradative pathways essential for the survival of neurons, defective autophagocytosis is observed in AD. A variety of abnormalities of the endosomal-lysosomal sys-tem (responsible for arranging Aβ plaques) have been identified in the neurons of the AD brain including the progressive disruption of autophagocytosis leading to the massive buildup of incompletely digested substrates within dystrophic axons and dendrites [88-90]. Similarly, β-cells of T2DM have signs of altered autophagocytosis, which may contribute to the loss of β-cell mass [91, 92]. A recent in vivo study [93] confirmed that the cerebral cortex and hippocampus of T2DM and 3xTg-AD mice are characterized by mitochondrial and autophagocytosis impairments contributing to the loss of syn-aptic integrity. These observations reinforce the idea that T2DM increases the risk of developing cognitive deficits and AD and sug-gest that mitochondrial biogenesis and autophagy may represent important targets for therapeutic intervention. It is plausible that aging and oxidative stress are two of the major causes of altered autophagocytosis as both T2DM and AD are age-related diseases characterized by oxidative stress. Therefore, all of these factors associated with mitochondrial dysfunction and oxidative stress may contribute to the progression of both T2DM and AD (Fig. 1).

Obesity Among T2DM patients, approximately 80-90% is diagnosed with obesity, which clearly indicates a link between T2DM and obesity. Although insulin resistance, β-cell failure, mitochondrial dysfunction, inflammation and impaired fatty acid metabolism are common mediators that link these two pathogenic conditions, the relative importance of each has not been yet indistinguishably de-fined. In obesity, the prolonged exposure of cells to excess nutrients leads to detrimental cellular stresses such as impaired mitochondrial function, lipid metabolism, inflammation and overproduction of ROS [94], which consequently provokes metabolic impairment. Obesity-induced metabolic impairment can favor insulin resistance as well as progressive β-cell dysfunction, which further contributes to insulin deficiency. Excess nutrients in the insulin deficiency state

lead to the increased accumulation of glucose in the blood. Al-though not all obese people become hyperglycemic, it has been reported that, when β-cell dysfunction co-exists with nutrient ex-cess, T2DM tends to develop [5]. The relationship between obesity and AD has been investigated by many researchers, and obesity in middle age is thought to strongly influence the occurrence of AD, although conflicting re-sults have been observed. According to the “Baltimore Longitudinal Study of Aging”, weight gain between 30 to 45 years of ages (men) and BMI >30 at 30, 40, and 45 years of ages (women) contributed to higher incidences of AD [95]. A meta-analysis claimed that higher body weight in middle age can fuel the possibility of devel-oping dementia [96]. According to an 18-year follow-up Swedish study, every 1.0 increase of body mass index (BMI) at 70 years of age increases the risk of AD by 36% [97]. Nevertheless, some con-flicting reports exist regarding the risk of developing dementia at later ages. For instance, higher body weight at age >70 years is predicted to increase the risk of dementia [97]; however, a 40% decrease in the risk of dementia at age ≥65 with BMI >30 is also reported. Nevertheless, more reliable indicators for the measure-ment of obesity are needed for the elderly because the composi-tional change in the body with increasing age makes BMI an insuf-ficient indicator of obesity [98]. In addition, although the follow-up period for mid-life studies usually ends long before dementia is diagnosed, the average length for late-life studies is only 5-6 years, by which time the patients have already developed dementia in the prodromal phase [99]. Therefore, information from future studies on longer periods of observation in late life is needed.

Apolipoprotein E (ApoE) ApoE is a class of lipoprotein, mainly expressed in the liver and the brain and involved in the transportation of cholesterol. Defi-ciency of ApoE results in an increase in the plasma cholesterol level. This hypercholesterolemia directly contributes to the patho-physiology of T2DM and is also considered as an independent risk factor for AD (Fig. 1) [100]. Among the ApoE isoforms, the fre-quency of ApoE ε3 was the highest in Caucasian AD patients (59.4%) [101]; whereas, ApoE ε4 is believed to be one of the major isoforms found in patients with T2DM who developed AD or vice-versa [102-104]. In AD patients, ApoE ε4 possessed the ability to deposit Aβ and obstructed its clearance [7]. In T2DM, increased ApoE was found to bind to amylin resulting in higher accumulation of amylin in islet β-cells which consequently lead to the worsening of T2DM condition [105]. Consequently, decreased levels of cogni-tive function were observed in diabetic ApoE ε4 carriers [106]. On the other hand, in AD patients carrying the ApoE ε4 allele, reduced levels of IDE were observed, which is usually involved in the deg-radation of cerebral Aβ [107].

Adenosine Monophosphate-Activated Protein Kinase (AMPK) AMPK is an enzyme that regulates cellular energy homeostasis and can be activated by cellular stresses responsible for ATP deple-tion. Activation of AMPK results in increased glucose uptake and insulin sensitivity in the muscle tissues. In T2DM patients, the level of activated AMPK is compromised leading to insulin resistance. Recently, AMPK was implicated as a potential inducing factor of autophagocytosis. More specifically, ULK1/2 kinase phosphoryla-tion mediated by AMPK was reported to be responsible for initiat-ing autophagy [108]. In T2DM patients, compromised AMPK ac-tivity cannot lead to the generation of autophagosomes for auto-phagocytosis, while the mechanism of initiation of autophagocyto-sis was reported to be deficient in AD [109]. The decreased activity of AMPK results in the accumulation of misfolded proteins and dysfunctional mitochondria in T2DM patients and consequently increases the risk for AD through the buildup of misfolded proteins in the brain. In a recent study in 2015, it was reported that AMPK activation contributed to cognitive impairment in an streptozotocin


(STZ)-induced diabetic rat model [110], further indicating the in-volvement of AMPK as a common pathophysiological bridge be-tween T2DM and AD.

Butyrylcholinesterase Butyrylcholinesterase, an enzyme that belongs to the esterase family, is associated with glial and endothelial cells [111]. In previ-ous reports, both T2DM and AD were investigated in relation to butyrylcholinesterase based on ethnicity [112, 113]. Thereafter, propositions were made to claim the linkage of butyrylcho-linesterase with T2DM and AD [33, 114]. Higher involvement of butyrylcholinesterase in increased level was identified in the plaques with attenuated amyloid formation in the brains of demen-tia, as well as in the localization of its neurofibrillary tangles, con-tributing to AD pathology [115]. Similarly, in T2DM pathogenesis, butyrylcholinesterase may either modify the phenotypic expression of insulin resistance or the deposition of amyloid fibrils in pancre-atic islets [33]. The deposition of amyloid fibrils in pancreatic islets leads to apoptotic death of β-cells via free radicals and inactivation of RNS [116]. Butyrylcholinesterase interacts with amylin to at-tenuate the amylin fibril and its oligomer formation. However, an in vitro experiment with butyrylcholinesterase exerted a protective effect on cultured β-cells against amylin cytotoxicity [115]. Bu-tyrylcholinesterases have been reported to show an inclination for β-sheet formation, which may be related to amyloidogenesis. In a French cohort, a locus on chromosome 3q27-qter in the vicinity of the chromosomal locus of butyrylcholinesterase was found to be linked to T2DM [117]. Thus, the reduction of butyrylcholinesterase levels may lead to the progression of both diseases (Fig. 1).

Transforming Growth Factor Beta (TGF-β) TGF-β, a protein present in many cell types, functions to main-tain cellular proliferation, differentiation, apoptosis and other cellu-lar functions. It exists in three structurally and functionally similar isoforms known as TGF-β 1, 2, and 3 [118]. In diabetic patients, the expression of TGF-β1 is triggered by hyperglycemia; thus, in-creased TGF-β1 was present in diabetes patients when compared with healthy people [119]. As TGF-β1 is an anti-inflammatory im-mune mediator, the induction of TGF-β1 production can exert prominent inhibitory effects on chronic inflammatory diseases [120]. In the brain, TGF-β is secreted by neuronal cells where it con-fers some protection from CNS inflammation and injury [121], and it also regulates neuronal growth and survival [122]. In a transgenic animal model of AD, TGF-β1 was reported to contribute to the clearing of microglial Aβ and plaques [123]. Therefore, the benefi-cial role of TGF-β can be targeted as a novel therapeutic approach to treat AD via the prevention of Aβ deposition. It has been reported that neuronal cells mainly express the TGF-β2 receptor, the reduction of which leads to the pathogenesis of the disease in the AD brain [124]. In mice with AD, neurodegeneration with age was observed due to the reduction of neuronal TGF-β signaling with progressive accumulation of Aβ. Similar results were also reported in cultured cells [125] indicating that the reduction of TGF-β signaling in neurons can contribute to AD with increasing age.

Advanced Glycation End Products (AGEs) AGEs (non-enzymatically produce by glucose-protein conden-sation reactions) are a group of heterogeneous molecules that carry irreversibly added adjacent groups with them [126]. Although, gen-erally, AGEs are normally synthesized during aging [127], the pro-duction rate is extremely high in patients with T2DM [128] and AD [129] (Fig. 1). In T2DM, accelerated AGE formation is anticipated to occur as a result of high plasma glucose levels [130], while oxi-dation of glycated proteins is one of the major causes of AD [131, 132]. Gironès et al. [129] observed high levels of carboxymethyl-

lysine (an AGE) in both T2DM and AD patients, further strengthen-ing the pathophysiological linkage between T2DM and AD via AGEs.

Genetic Linkage between T2DM and AD From the recent findings, it is evident that a close genetic asso-ciation exists between AD and T2DM. The IDE gene is located on chromosome 10q; this portion of the chromosome is believed to be involved in the pathogenesis of late-onset of AD [133, 134]. The expression of Islet-Brain 1 (IB1), which promotes cell death and functions as a neuronal scaffold, is restricted to pancreatic β-cells and neurons [135]. In a French family with T2DM, IB1 was found to be mutated, resulting in decreased insulin secretion [136]. An-other study revealed that a polymorphism of the gene encoding the IB1 protein was associated with an increased risk of developing AD [137]. A recent study (2015) revealed that none of the genome-wide significant loci of T2DM (11 genes across 32 genetic variants) played a major role in the development of AD [138]. However, a recent (2015) genome-wide association study (GWAS) with 927 single nucleotide polymorphisms (SNPs) (associated with both AD and T2DM) suggested that 395 of the shared GWAS SNPs have the same risk allele (overlap p value of 7.66E-6, overlap OR=1.2) for AD and T2DM [139], which further suggests a common patho-physiological mechanism behind the development of both AD and T2DM.

Epigenetics Epigenetic mechanisms are believed to be directly involved with the pathogenesis of T2DM via the regulation of gene expres-sion and environmental factors [140-143]. Dysfunction of glucose homeostasis and insulin resistance were observed and attributed to epigenetic alterations of histone deacetylases (HDACs) affecting H3 and H4 acetylations at the proximal promoter of pancreatic and duodenal homeobox factor 1 (Pdx-1) in pancreatic β-cells, thus contributing to T2DM [144]. In patients with T2DM, DNA methyl-transferase (Dnmt) and HDACs induced histone modifications in GLUT4, resulting in reduced GLUT4 transcription [145]. As only 1-5% of AD cases are currently assumed to be familial [146], the remaining major undefined spectrum of pathogenesis may be influ-enced predominantly by epigenetic factors [147]. Feng et al. [148] observed impaired learning and memory in mice lacking both Dnmt1 and Dnmt3a when they were stimulated in CA1 synapses, which could possibly contribute to the pathogenesis of AD. Expo-sures to environmental factors have been shown to play major roles in the enhanced mRNA expression levels of APP [149, 150]. Aging is another vital epigenetic factor that can affect AD severity via subsequent alterations of DNA methylation status [151, 152]. In 2014, for the first time, Want et al. [153] established that epigenet-ics have a major influence on T2DM in the development of AD. Therefore, epigenetic modification is an emerging factor in T2DM patients developing AD or vice-versa, which can provide another potential link between T2DM and AD pathogenesis.

Animal Models: Linkage between T2DM and AD Several experimental studies using animal models have re-vealed the development of T2DM in AD or vice-versa. In tau trans-genic mice, Ke et al. [154] established that defective insulin secre-tion accelerates the onset and progression of neurofibrillary tangle formation. Jolivalt et al. observed that, in transgenic mice with AD, hypoinsulinemia increases AD pathology [155]. Several studies of STZ-induced mice revealed increased tau phosphorylation [156-160] and Aβ formation [155, 157, 161], which further explains the pathogenesis of AD. In 2013 [162], significantly higher Aβ was observed in 11-month-old T2DM mice, and these mice exhibited similar types of behavioral and cognitive anomalies. In a group of mice fed with high fat, cholesterol-containing diet, increased tau phosphorylation and impaired insulin signaling were observed [163]. Nevertheless, although the pathophysiology was not clearly


elucidated, it was clear that diet can contribute to the development of both diseases. A recent study using a diabetic AD mouse model suggested that the synergistic interaction between the effects of T2DM and AD on the mitochondria may be responsible for brain dysfunction, which is a common feature of both T2DM and AD [164].

TREATMENTS Epidemiological and animal-based investigations have indi-cated possible associations between T2DM and AD. Several clini-cal trials in which anti-diabetic drugs usually prescribed for T2DM were investigated targeting AD have already been completed (Fig. 1) with the hope that the connections between these seemingly un-related diseases can be further clarified.

Humanin (HN) HN is a peptide derived from the mitochondria. In animal mod-els, HN has been reported to improve cognitive decline [165]. However, HN has been identified as having neuroprotective effects in response to AD-related insults [166]. In AD, HN can inhibit the neurotoxicity mediated by Aβ and can modify intracellular toxic mechanisms, consequently can suppress the neuronal cell death [167]. HN also exerts cytoprotective effects by preventing Aβ fibril formation as well as Aβ aggregation [168]. HN can prevent apopto-sis and cell death in the CNS and can inhibit Aβ-mediated smooth muscle cell death in the cerebrovascular region in humans [169]. HN has the potential to protect cells from oxidative stress [170] and to antagonize the effect against the progression of inflammation by decreasing pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α [45, 46]. HN (transducible) containing an extended caspase-3 cleavage sequence (tHN-C3) was applied for the treatment of AD [171]. The prevention of the infiltration of inflammatory cells into the brain is thought to be the probable mechanistic therapeutic strategy. Inflammation, being one of the pathophysiological links between T2DM and AD, represents a promising role for managing T2DM by tHN-C3. In non-obese diabetic mice [172], HN shields β-cells from apoptotic death by reducing inflammation as well as infiltration of cells involved in the immune system, which makes HN therapeutically beneficial for T2DM treatment.

Cholinesterase Inhibitors Cholinesterase inhibitors are one of the currently obtainable symptomatic treatment choices for AD, and the long-term use of cholinesterase inhibitors has been stated to be beneficial for AD patients [173]. These inhibitors help to slow down the degradation of synaptic acetylcholine, which further prolongs its ability to stimulate postsynaptic receptors followed by amplifying acetylcho-line release naturally in the brain [174]. Donepezil is an extremely selective acetylcholinesterase inhibitor. In AD patients, although few side-effects are reported, it is considered to be beneficial for cognition and daily living. [175]. Galantamine is a selectively re-versible inhibitor of acetylcholinesterase that is prepared from a tertiary alkaloid compound [176]. The drug helps to release more acetylcholine and activates neurons by modulating presynaptic and postsynaptic nicotinic receptors, respectively [175].

AGE Inhibitors Aminoguanidine, an AGE inhibitor, is just beginning to be recognized as a potential therapeutic agent for the treatment of AD. On the other hand, it is currently under clinical trials for the purpose of treating diabetes-related complications. Tenilsetam, which has been involved in two phase II trials, has been reported to provide continuous improvement in cognitive behavior and memory throughout the three months trial period. These AGE inhibitors are thought to be beneficial for inhibiting AGE-Aβ deposition in AD. They can also interfere with the early step of the AGE-induced signal transduction pathway by altering Aβ structure [177].

Glucagon-Like Peptide 1 Receptor (GLP1R) Agonists and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In T2DM patients, GLP1R agonists and DPP-4 inhibitors are currently frequently used as preferred treatments [178]. Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone secreted by pe-ripheral intestinal L cells and nuclei of the solitary tract found in the brain [179]. When GLP-1 enters the circulation, it is rapidly de-graded by the DPP-4 enzyme. Therefore, the half-life of GLP-1 is normally <2 minutes, and this can be extended by inactivating the DPP-4 enzyme using DPP-4 inhibitors [180]. GLP-1 improves insu-lin sensitivity and increases β-cell mass with increased pancreatic insulin secretion in response to the presence of glucose in the blood, and it slows down pancreatic glucagon secretion [181]. The decline in insulin signaling as a causative factor for the development of AD can be improved using GLP1R agonists because of their ability to activate pathways that can by-pass insulin resistance. GLP-1 can also amplify the pathways related to insulin signaling [182]. GLP-1 is reported to be a controller of synaptic plasticity and memory formation [183]. In transgenic mouse models of AD, GLP1R ago-nists such as exendin-4 and liraglutide are observed to restore im-pairment in insulin signaling, provide protective effects on neurons and synapses, enhance cognition and decrease Aβ accumulation in the brain [184, 185]. GLP1R agonists can minimize Aβ levels when administered chronically, which will be beneficial for treating carri-ers of the ApoE ε4 allele [186]. In rats, sitagliptin and vildagliptin, as DPP-4 inhibitors, improved the cognitive and brain mitochon-drial function [187, 188].

Metformin Metformin (N, N-dimethylimidodicarbonimidic diamide) is an orally active biguanide and is the first-line drug of choice for T2DM treatment. It improves insulin resistance and lowers blood glucose levels by decreasing gluconeogenesis in the liver. It en-hances the oxidation of fatty acids and decreases glucose absorption from the intestine [7]. Metformin administration decreased cogni-tive injuries in patients with T2DM and AD compared with un-treated patients [189]. This outcome suggests that neuronal net-works of the brain are stimulated by anti-diabetic drugs, which benefits AD patients by maintaining cognitive behavior. In mice, metformin can reduce tau protein phosphorylation in cortical neu-rons [190]. In primary cortical neurons, metformin played a neuro-protective role against apoptosis [191]. In an in vitro model of ischemia, treatment with metformin increased the viability of neu-ronal cells [192]. Metformin has even been shown to protect against oxidative imbalance stimulated by T2DM in the brain [193]. Inves-tigation of epidemiological studies revealed that long-term met-formin treatment of T2DM patients led to a slightly higher possibil-ity of developing AD compared with patients who did not take the drug [194], with a 35% reduction in the risk of dementia following 8 years of treatment of T2DM patients with metformin and sul-phonylureas [195].

Anakinra In T2DM where dysfunction of β-cells is facilitated by inflam-mation, the IL-1 cytokine mediates inflammatory progression at the β-cell level. In an in vitro study, the apoptosis of β-cells was in-duced by hyperglycemia along with the production of IL-1β by β-cells. This hyperglycemia-mediated β-cell death is inhibited by the use of the natural IL-1� inhibitor interleukin-1 receptor antagonist (IL-1Ra) [196]. Anakinra, a recombinant IL-1Ra, has been shown to inhibit the IL-1 activity in T2DM patients followed by glycemic improvement as a result of the improved secretory function of β-cells [197]. A recent study of impaired glucose tolerance subjects reported that treatment by anakinra enhanced first-phase insulin secretion with improved insulinogenic index [198]. Thus, the blockade of IL-1β by anakinra may be a potent management tool for T2DM that improves β-cell survival as well as β-cell insulin


secretion [199, 200]. In AD pathogenesis, the IL-1β cytokine of the CNS plays a role in neuroinflammation that leads to neurodegenera-tion [201]. Therefore, anakinra may exert its therapeutic effect in AD by blocking IL-1β.

Antioxidants Oxidative stress is an intensive contributor to the pathophysiol-ogy of AD and T2DM. Mitochondrial dysfunction, Aβ and acti-vated glial cells in AD brains contribute to oxidative stress by pro-ducing ROS, which leads to the production of inflammatory cytoki-nes. Therefore, compounds with antioxidant potential can be used as therapeutic agents for preventing the progression of AD and T2DM [202-204]. In transgenic AD mice, the oral administration of rutin (a flavonoid) significantly diminished memory deficits and IL-1 and IL-6 cytokine levels in the brain with increased superoxide dismutase (SOD) activity and glutathione (GSH) / glutathione di-sulfide (GSSG) ratio [205]. In another study of neuroblastoma cells, the dose-dependent use of rutin inhibited aggregation and cytotox-icity of Aβ with reduced oxidative stress, mitochondrial damage, and production of pro-inflammatory cytokines in microglia [206]. The oral administration of rutin along with pioglitazone signifi-cantly reduced the levels of IL-6 and TNF-α cytokines and restored the antioxidant status in the liver of T2DM rats [207]. In transgenic AD mice, quercetin (a flavonoid), exerted neuroprotective effects by reducing learning and memory impairments, scattered senile plaques and mitochondrial dysfunction by restoring ROS and ATP levels [208]. On the other hand, in a mouse model of T2DM, quer-cetin supplementation decreased total cholesterol levels, increased SOD activity and GSH peroxidase in the liver, improved the status of hyperglycemia and antioxidants [209], and ameliorated hyper-glycemia and oxidative stress by reducing free radical induced tox-icity [210]. Naringenin (a flavanone compound) was also found to exert antihyperglycemic and antioxidant effects in diabetic rats [211]. It also protected mice with AD-type neurodegeneration against cognitive impairments, neuronal loss and oxidative stress [212]. Pterostilbene (a phenolic compound) with antioxidant and anti-inflammatory properties was reported to be an effective modu-lator of AD-associated cognition and cellular oxidative stress [213]. In diabetic rats, the oral administration of resveratrol (a polypheno-lic phytoalexin) reduced hyperglycemia and enhanced oxidative stress markers, SOD activity, cytokine (TNF-α and IL-6) levels and polymorphonuclear cell-mediated NF-κB function [214].

Peroxisome Proliferator-Activated Receptor-Gamma (PPARγ) Agonists In the AD brain, inflammation is one of the causative factors of plaque formation in which PPARγ activators can play an inhibitory role and thus can improve cognitive decline. Anti-diabetic drugs, particularly rosiglitazone (RSG) and pioglitazone (POG) of the thiazolidinediones class, are potential PPARγ agonists. These drugs, being insulin sensitizers, can ameliorate insulin resistance [215] and can decrease cerebral inflammatory effects [216] by in-hibiting IL-6 and TNF-α, which is thought to be advantageous for treating AD patients. In hippocampal cultures, RSG improves syn-apse formation and plasticity impairment induced by Aβ42 oli-gomers via increasing dendritic and spinal mitochondrial numbers through the PPARγ-dependent pathway [217]. In rats, RSG miti-gated memory impairments caused by Aβ42 oligomers in a dose-dependent manner by inhibiting IL-1β and interferon gamma (IFN-γ) inflammatory cytokines [218]. In an AD mouse model, RSG provided protective effects against learning and memory-related injuries by alleviating the hyperphosphorylation of tau and neuro-filament proteins [219]. In rats, RSG was found to improve learning and memory impairments by decreasing IDE expression, GSK-3β activity and phosphorylation of the tau protein [220]. RSG (4 mg, daily) treatment was found to improve memory and selective atten-tion in early AD patients [221]. According to a meta-analysis, RSG can ameliorate cognitive impairments of AD patients [222]. In

mice, POG exerted a neuroprotective effect against scopolamine-induced cognitive impairment [223]. In insulin-resistant AD rats, POG improved cognitive function through the activation of PPARγ [224]. Recently, POG was reported to ameliorate spatial memory of AD mice by inhibiting the activity of cyclin-dependent kinase 5 [225].

Intranasal Insulin (INI) Although intravenous insulin (IVI) administration has been linked to the improvement of impaired memory in humans [226], the IVI technique is extremely invasive and can lead to hypoglyce-mia with damaging effects on brain function. On the other hand, INI has proven to be therapeutically effective for the fast distribu-tion of insulin to the brain [227]. INI is considered clinically safe as it neither causes nasal irritation nor destroys the olfactory epithe-lium or glomerular projections [228]. INI by-passes the blood brain barrier and directly enters the brain where it be identified in the cerebrospinal fluid within 30-40 minutes after the administration [229]. Currently, INI administration is emerging as a therapeutic approach for treating AD patients. In the brain, insulin stimulates IDE formation, which further degrades Aβ and its accumulations [230], inhibits tau protein phosphorylation [231], maintains synap-tic density [232] and lessens the binding of Aβ-derived diffusible ligands (pathogenic CNS neurotoxins) to neuronal synapses of the hippocampus to inhibit AD progression [233]. Daily intake of INI for 3 weeks was reported to improve delayed story recall in AD adults [234], and INI detemir (40 IU) was reported to improve the verbal memory of adults with AD who were ApoE ε4 allele carriers [235]. In T2DM rat brains, INI treatment was reported to reduce tau hyperphosphorylation [44]. In older adults with T2DM, INI was also reported to improve cognitive function through vasoreactivity mechanisms [236]. As insulin dysfunction strongly correlates be-tween T2DM and AD, INI as an anti-diabetic treatment option can be used for restoring neurological function in AD.

CONCLUSION T2DM and AD are the most common age-dependent diseases having epidemiological and pathophysiological links via insulin resistance and deficiency, protein aggregation, oxidative stress, inflammation, autophagocytosis and AGEs. Therefore, shared pre-ventive and pharmacotherapy treatments may be effective for the proper management of both T2DM and AD. Finally, physicians maintaining follow-up with the elder patients should take precau-tion regarding the increased risk of one condition when the other condition already exists.

LIST OF ABBREVIATIONS AD = Alzheimer’s disease AGE = Advanced glycation end products AMPK = Adenosine monophosphate-activated protein

kinase ApoE = Apolipoprotein E Aβ = Amyloid β peptide CNS = Central nervous system GLP = Glucagon-like peptide IAPP = Islet amyloid polypeptide IDE = Insulin-degrading enzyme IL = Interleukin PPARγ = Peroxisome proliferator-activated receptor-gamma ROS = Reactive oxygen species T2DM = Type 2 diabetes mellitus TGF = Transforming growth factor TNF-α = Tumor necrosis factor alpha


CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS We would like to acknowledge Universiti Sains Malaysia (USM) for the Research University (RU) grant (1001/PPSP/ 812115). We would also like to acknowledge USM Global Fellow-ship (2014/2015) and USM Vice-Chancellor Award (2015/2016) awarded to Fahmida Alam and Md. Asiful Islam, respectively, to pursue their PhD degrees.

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Current Pharmaceutical Design - Monash University