CNS & Neurological Disorders - Drug Targets, 2014, 13, 271-282 271
Fighting Alzheimer's Disease and Type 2 Diabetes: Pathological links and Treatment Strategies
Ying Dai
*,1and Mohammad A. Kamal
21Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
2Metabolomics and Enzymology Unit, Fundamental and Applied Biology Group, King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia
Abstract: The incidence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) with associated serious complications continues to grow rapidly especially in developed countries. Emerging evidence indicates that AD and T2DM share some common risk factors with comparable pathological features including insulin resistance, amyloidogenesis, glucocorticoid imbalance, inflammation, mitochondrial function and oxidative stress. T2DM has been identified as a risk factor for AD. It has even been hypothesized that AD might be “type 3 diabetes”. In addition to amyloid precursor protein processing and tau phosphorylation, commonalities between T2DM and AD in molecular mechanisms provide clues to the identification of novel therapeutic targets such as glucagon-like peptide 1, butyrylcholinesterase, and receptor for advanced glycosylation end products. Although several classes of anti-diabetic drugs are available, achieving long-term glycaemic control without side effects is often challenging. This review summarizes recent evidence for the pathological links, common therapeutic targets, currently the U.S. Food and Drug Administration approved and potential future therapies, giving special attention to ongoing clinical trials of antidiabetic drugs in AD patients and common therapeutic strategies in the management of both AD and T2DM.
Keywords: Alzheimer's disease, clinical trial, dementia, diabetes, insulin, pathogenic mechanism, therapeutic targets.
INTRODUCTION
The soaring rates of diabetes and AD are one of the most worrisome trends in public health in the 21st century. T2DM accounts for about 90–95% of diagnosed cases of diabetes [1]. There are more than 23 million T2DM patients in the United States alone [2], and the global prevalence of diabetes has increased dramatically over the last 2 decades and is predicted to double from 150 million in 2000 to 300 million by 2025 [3]. As the most common cause of dementia, AD affects over 24 million people worldwide [4]. In the United States, approximately 1 in 8 persons over 65 have AD and the estimated cost for patient care is $200 billion in 2012 [5].
Over the last decade, researchers have been busy investigating the biological basis underlying the link between AD and T2DM. Although the endocrine pancreas originates from the endoderm, it is a heavily innervated organ that shares significant molecular similarities with brain at the level of the transcriptome and proteome [6]. The neuropathological hallmarks of AD include intraneuronal neurofibrillary tangles and diffuse extracellular amyloid plaques in brain. The islet in T2DM is characterized by dramaticly decreased insulin-secreting β-cells, increased β- cell apoptosis, and islet amyloid, which is composed of extracellular fibrils of islet amyloid polypeptide (IAPP) [7].
Increasing evidences indicate several key biological
*Address correspondence to this author at the Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Room CLS- 628, Brookline, MA 02445, USA; Tel: +1 617 735 2491; Fax: +1 617 735 2910; E-mail: [email protected]
processes shared between AD and T2DM [8]. While their common risk factors including obesity, age, depression, higher cholesterol and cardiovascular disorder have been confirmed, recent evidence has identified T2DM itself as a risk factor for AD [9]. AD therefore has even been hypothesized to be ‘type 3 diabetes’ [1, 10]. In this review we explore the mechanistic linkages between T2DM and AD, with emphasis on current and future therapeutic strategies.
COMMON PATHOLOGICAL MECHANISMS IN AD AND T2DM
Increasing evidence has suggested possible associations and common links between AD and T2DM. Some of these are highlighted below (Fig. 1).
Insulin Resistance
Unlike type 1 diabetes in which the immune system destroys insulin-producing cells in the pancreas, patients with T2DM are caused by relative insulin deficiency, which may be due to insufficient insulin supply resulted from defective insulin secretion and/or reduced insulin secreting β-cell mass, and/or impaired insulin sensitivity in peripheral metabolic organs (peripheral insulin resistance), such as liver and muscle [2]. Growing evidence suggests that AD is associated with progressive brain insulin resistance in the absence of T2DM, obesity, or peripheral insulin resistance [10-12]. In addition to its peripheral functions in the maintenance of physiological homeostasis, insulin readily crosses the blood brain barrier and exerts profound effects on
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the central nervous system including the regulation of neuronal and synaptic functions within hippocampus, cortex, and cerebellum, protection of neurons against degeneration and cell death, and modulating learning and memory [13, 14]. Both insulin and amyloid-β (Aβ) peptide are substrates of insulin-degrading enzyme (IDE) which is a principal regulator of Aβ levels in neuronal and microglial cells [15].
Endogenous brain insulin may have beneficial effect on amyloid clearance by competing with Aβ for IDE in the brain, and peripheral hyperinsulinemia may inhibit endogenous brain insulin production, resulting in impaired amyloid clearance and increased risk of AD [16]. The accumulation of Aβ disrupts insulin signaling by competing with insulin or reducing the affinity of insulin binding to its own receptor [17]. Moreover, Aβ oligomers inhibit insulin- stimulated signal transmission by desensitizing and reducing the surface expression of insulin receptors [18]. Thus, it is possible that decreasing peripheral hyperinsulinemia and increasing brain insulin levels have the same beneficial effect on AD.
Amyloidogenesis
Both AD and T2DM are associated with the accumulation of amyloid fibrils [19]. Amyloid protein deposits consisting of IAPP are commonly observed in pancreatic islets of T2DM patients [20]. Transgenic mice overexpressing IAPP generally develop T2DM subsequent to excess amyloid deposits, β cell dysfunction and disruption in glucose homeostasis [21, 22]. Senile plaques in AD develop from the release and accumulation of Aβ peptide, an abnormal proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP) [23]. It is well established that Aβ results from sequential cleavage of the APP by β -secretases and γ -secretases [24]. β -Secretase cleavage results in the large extracellular portion and a 99 residue transmembrane stub (C99). The C-terminal C99 peptide is then cleaved by γ-secretase at several positions, leading to the formation of Aβ40 and the pathogenic Aβ42
which can aggregate and form the amyloid plaques characteristic of AD.
Inflammation
AD and T2DM are also related by systemic inflammatory conditions. Inflammatory markers such as C-reactive protein, tumour necrosis factor-a (TNF-a), and interleukin-6 (IL-6) have been implicated in the pathophysiology of T2DM, potentially underlying their association with inhibition of insulin signaling pathway and peroxisome proliferator- activated receptor gamma (PPARγ) activities in adipocytes [25, 26]. Likewise, emerging evidence indicates that AD is associated with inflammatory processes [27, 28]. Elevated immunoreactivity to IL-6 was found in senile plaques and cerebrospinal fluid in patients with AD [29, 30]. High levels of alpha1-antichymotrypsin, IL-6 and C-reactive protein were linked with an increased risk of AD [31]. There are also reports indicating that low dose non-steroidal anti- inflammatory drugs reduced incidence of AD [32, 33]
Mitochondrial Dysfunction and Oxidative Stress
Mitochondrial dysfunction and oxidative stress play critical roles in the pathogenesis of both AD and T2DM [34].
Mitochondrial dysfunction compromises electron transport chain function, reducing ATP generation and increasing reactive oxygen species (ROS) production. Several lines of evidence suggest that oxidative changes in nucleic acids, lipids and mitochondrial proteins amplify production of ROS and trigger cells to generate Aβ, tau phosphorylation and formation of neurofibrillary tangles [35]. Oxidative stresses induced by transient hypoxia cause AD-type abnormalities including tau phosphorylation, aberrant APP cleavage with accumulation of Aβ-immunoreactive products in cortical neurons [36]. Persistence of oxidative stress leads to constitutive activation of kinases (e.g. GSK-3β) that promote aberrant hyper-phosphorylation of tau. On the other hand, recent evidence suggests a possible linkage between T2DM and mitochondrial DNA mutation [37]. Moreover, increased oxidative stress and stress-activated signaling pathways lead Fig. (1). Scheme demonstrates the possible biochemical pathways and common pathological links between Alzheimer’s disease and type 2 diabetes mellitus (P-tau = tau hyperphosphorylation; ACh =Acetylcholine; eNO = Endothelial nitric oxide; LP = Lipid peroxidation).
to both insulin resistance and impaired insulin secretion [38].
In experimental diabetic neuropathy, chronic hyperglycemia caused oxidative injury of dorsal root ganglion neurons and mitochondrial dysfunction [39]. In a rat model of T2DM, mitochondrial dysfunction is exacerbated with aging and Aβ exposure [40]. Since the CNS is heavily dependent upon ATP production and 90% of the ATP required for normal neuronal functioning came from mitochondria, mitochondrial impairment may lead to both neural degeneration and loss of metabolic control [41].
Glucocorticoid Imbalance
Adrenal glucocorticoid levels appear to predict the magnitude of hippocampal neuron loss and cognitive impairments [42]. Elevated levels of cortisol have been linked with the extent of hippocampal atrophy, decreased cognitive performance, and rapid disease progression in AD patients [43, 44]. The elevation of cortisol has also been identified as a part of the plasma biomarker signature for diagnosis of AD [45]. Increased release of cortisol from the adrenal cortex may results from the activation of the hypothalamic-pituitary-adrenal axis induced by chronic stress, a potential risk factor for AD [8]. Compared with control subjects, T2DM patients have significantly higher concentration of circulating cortisol, which may adversely affects cognitive functioning [46, 47]. In T2DM animal model, increased corticoid activity contributes impaired syn- aptic plasticity and decreased neurogenesis, thereby leading to learning and memory deficits [48]. Moreover, glucocorticoid excess results in insulin resistance by negatively impacting insulin sensitivity and insulin secretion [49, 50]. These data indicate that enhanced glucocorticoid activity is a confounding factor in both T2DM and AD.
MOLECULAR LINKAGES BETWEEN AD AND T2DM PROVIDE THERAPEUTIC TARGETS
Aβ and APP
The pathogenesis of AD begins with impaired synaptic function and neuronal destruction, which may result from the accumulation of Aβ peptide, the cleavage products of APP [51, 52]. Meanwhile, Aβ deposits consisting of IAPP extracellular fibrils are also commonly observed in pancreatic islets of diabetic patients [20]. Moreover, an increased amount of amyloid plaques and neurofibrillary tangles have been found in the hippocampus in patients with diabetes [53]. IAPP-deficient mice presented enhanced insulin secretion and improved glucose tolerance [54].
Considering the pathogenetic and structural similarity between APP and IAPP, it should not be surprising that AD seems to be predisposed to insulin resistance/hypersecretion and T2DM [55, 56].
Because of the overarching hypothesis that Aβ peptides induce neurotoxic through potentiating the formation of amyloid plaque and neurofibrillary tangles, extensive research has been conducted on finding safe and effective means of preventing abnormal cleavage and processing of APP and depleting the brain of toxic Aβ deposits [57]. Aβ immunotherapy, either through active immunization with Aβ peptides or through passive transfer of Aβ-specific antibodies, has been shown to effectively clear brain amyloid
plaques and improve cognitive deficits in AD mouse models and nonhuman primates [58]. Another potential approach to preventing the accumulation of toxic Aβ is to inhibit the enzymes (e.g. γ -secretases) responsible for aberrant processing and cleavage of APP. However, while γ secretase inhibitors have been proved promising in terms of their ability to effectively decrease plasma, CSF, and brain Aβ burden [59], significant therapeutic responses such as retarded progression of dementia could not be demonstrated [60, 61].
Tau Protein
The other characteristic hallmark of AD is neurofibrillary tangles containing hyperphosphorylated tau, which were also found in pancreatic islet cells of patients with T2DM [62].
Experimental studies have implicated hyperglycemia, insulin-resistance and impaired insulin signaling with activation of stress kinases including glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase-5 (Cdk-5), p38 MAPK, and c-jun kinase (JNK), as mechanisms in the production of phosphorylated tau [10, 63]. Peripheral insulin stimulation also significantly increased tau phosphorylation at Ser202 in the brain [64]. Conversely, the accumulation of aggregated cytoskeletal proteins may exacerbate insulin resistance and neuroinflammation. Therefore, treatment targeting AD relevant kinases may reduce tauopathy and help prevent progressive brain insulin resistance and degeneration. GSK-3 is a serine/threonine kinase that phosphorylates glycogen synthase in the rate-limiting step of glycogen biosynthesis [65]. In addition to tau phosphorylation, hyperactive GSK-3β also results in alterations in APP processing and increased neuronal death, therefore GSK-3β has emerged as a attractive target for the development of novel treatments for AD and T2DM [66-69].
Chronic treatment with Lithium chloride, the first GSK-3β inhibitor discovered, reduced the prevalence of AD and increased the levels of brain-derived neurotrophic factor in subjects at risk for early onset familial AD [70]. Moreover, lithium treatment also protected against dementia and improved the performance on cognitive tests [71, 72].
Glucagon-Like Peptide 1 (GLP-1)
GLP-1 has attracted substantial attention for its advantage in treating T2DM and AD. GLP-1 is a 30-amino acid insulinotropic peptide hormone generated by cleavage of proglucagon protein. The main actions of GLP-1 are to stimulate insulin secretion and to inhibit glucagon secretion.
While GLP-1 lowers blood glucose and restores insulin sensitivity in T2DM patients, GLP-1 receptor agonists protect neurons against Aβ peptite and glutamate-induced apoptosis in cultured cells and attenuate cholinergic neuron atrophy in rats with excitotoxic brain lesions [73, 74].
Additionally, inhibition of dipeptidyl peptidase-4 (DPP-4), an enzyme that degrades GLP-1, reduced memory impairment, nitrosative stress, inflammation, and Aβ deposits in a transgenic mouse model of AD [75]. More importantly, GLP-1 can cross the blood brain barrier, and effectively decrease brain Aβ burden in AD [73, 74, 76].
Endogenous GLP-1 has a half life of only a few minutes, thus the synthetic long-lasting analogues are more practical and have proven to be effective in preserving cholinergic
neuron function [77]. The development of GLP-1 receptor agonists (e.g. Geniposide, Extendin-4) with similar neuroprotective properties as GLP-1 may provide effective and standardized long-term options for treating brain insulin resistance diseases such as AD [76, 78, 79].
Butyrylcholinesterase (BuChE)
Recent studies reported that plasma and tissue concentrations of BuChE and acetylcholinesterase (AChE) are increased in both T2DM and AD. These two enzymes may play an etiological role via influencing inflammation, insulin resistance and lipid metabolism, and therefore open new avenues for potential treatment [80, 81]. Their common substrate, acetylcholine, has a regulatory role on dopamine, serotonin and other neuropeptides. Further, acetylcholine modulates interactions between the nervous and immune systems through inhibiting the release of TNF-a, IL-1, IL-6, migration inhibitory factor, high-mobility group B1 protein and the expression of nuclear factor kappaB (NF-kB) [82, 83]. A recent study using high fat diet fed rats revealed that a Chinese herbal extract, SK0506, significantly inhibits BuChE activity and ameliorates elevated levels of inflammatory markers (e.g. TNF-a and IL-6) [83]. Moreover, it reduces central obesity, improves the glucose tolerance and insulin sensitivity in high fat diet fed mice [84].
Receptor for Advanced Glycosylation End Products (AGEs)
AGEs are a heterogenous group of molecules that are generated through non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids [85]. AGEs accumulate in various cells due to normal aging, but the rate of accumulation is significantly elevated in conditions associated with hyperglycaemia such as diabetes mellitus [86]. It has been confirmed that the interactions between AGEs, resulted from impaired glucose tolerance and diabetes, and their receptor may play a role in the pathogenesis of diabetic vascular complications and neurodegenerative disorders including AD [87]. AGEs can be found in senile plaques and neurofibrillary tangles, the pathologic hallmarks of AD [88], and AGEs receptor is a specific cell surface receptor for Aβ peptide, thus eliciting neuronal damage [87]. A novel and non-toxic inhibitor of receptor for AGEs, FPS-ZM1, blocks Aβ binding to the receptor, decreases amyloid deposits, restores cognitive performance, reduces oxidative stress and suppresses neuroinflammation in an AD mouse model [89]. These findings provide new hope in AD therapy, especially in light
of the recent phase 2 trial in AD patients with an azol-based AGE receptor inhibitor that was terminated because of the toxicity observed at higher doses of the drug.
CURRENT AND EMERGING THERAPIES FOR AD AND T2DM
Treatments for AD
Although the U.S. Food and Drug Administration (FDA) has approved five drugs (Table 1) that temporarily improve symptoms of AD, no treatment is available today to alter the underlying course of this terminal disease.
A deficiency of cholinergic neurons in subcortical areas has been observed in AD patients with progressive dementia, which leads to the development of therapy for enhancing concentrations of cholinergic neurotransmitters in the CNS.
Cholinesterase inhibitors have been used to improve cognition and indirectly help function and behaviour in AD patients. In 1993, the FDA approved tacrine for use in mild to moderate AD, but a high incidence of enhanced alanine aminotransferase and hepatotoxicity limited its utility.
Subsequently, donepezil was approved for clinical use. In a parallel-group, double-blind study, 248 patients with severe AD (mini mental state examination score 1-10) were treated with either donepezil or placebo. Patients treated with donepezil improved more in SIB scores and declined less in ADCS-ADL-severe scores after 6 months of treatment compared with baseline than did controls [90]. Improved cognition and global clinical function with delayed symptomatic progression were also seen in the short (up to 24 weeks) and long term (up to about 1 year) in patients with mild to moderate AD [91]. Moreover, the FDA has approved Rivastigmine, a cholinesterase inhibitor that inhibits both BuChE and AChE, for the treatment of mild to moderate dementia of the Alzheimer’s type. In 2006, Rivastigmine became the first product approved globally for the treatment of mild to moderate dementia associated with Parkinson's disease.
The N-methyl-D-aspartate (NMDA) glutaminergic antagonist, memantine, has also been approved for use in late-stage AD and in conjunction with cholinergic drugs. In a study by Reisberg and colleagues, there were better results from memantine on a few scales that reflected functional behavior compared to the use of placebo, but there was no change in three main measures of cognitive performance [92]. Memantine improved cognitive performance and function in people with AD over a 6-month period compared with placebo [93]. Modest effects on behaviour were also Table 1. FDA-Approved Drugs for AD Treatment
Generic Mechanism of Action Year Approved Clinical Use Side Effects
Tacrine Cholinesterase inhibitor 1993 Mild to moderate* Possible liver damage, nausea and vomiting Rivastigmine Cholinesterase inhibitor 1998 Mild to moderate Nausea, vomiting, loss of appetite, increased bowel movements
Donepezil Cholinesterase inhibitor 1996 All stages Nausea, vomiting, loss of appetite, increased bowel movements Galantamine Cholinesterase inhibitor 2001 Mild to moderate Nausea, vomiting, loss of appetite, increased bowel movements
Memantine NMDA receptor antagonist 2003 Moderate to severe Headache, constipation, confusion and dizziness
*Tacrine is now rarely prescribed because of associated side effects.
found in a pooled analysis of six studies which included AD patients with MMSE<20, with delusions, agitation/
aggression and irritability as the most responsive symptoms [94].
Severe depression adds to impairment and disability in patients with AD and should be treated with antidepressants.
The use of trazodone, haloperidol, thioridazine, risperidone, and related antipsychotics may suppress some of the aberrant behavior and hallucinations when these are problems, making life more comfortable for both AD patient and family. Small doses of diazepines, such as lorazepam, are useful when sleep is severely disturbed, but they often increase confusion as well.
Several potential therapies either modulating β/γ secretase or directly targeting the aggregation of Aβ are being assessed in clinical trials. The development of γ secretase inhibitors is an obvious and attractive prospect to prevent production of Aβ because this is a key part of the formation of the toxic Aβ42 peptide. At least eight γ secretase inhibitors have reached clinical testing:
semagacestat (LY-450139), tarenflurbil, MK-0752, E-2012, BMS-708163, PF-3084014, begacestat (GSI-953), and NIC5-15. Whereas semagacestat reduces Aβ concentrations in the plasma and Aβ production in human CNS [60], two large phase 3 trials to study semagacestat in patients with mild-to-moderat AD were stopped because preliminary results showed it did not slow disease progression and was associated with worsening of clinical measures of cognition.
Similarly, tarenflurbil, another γ-secretase modulator, seemed to be promising in phase 2 clinical trials, but did not show significant benefits in subsequent larger randomised controlled trials [95]. Development of γ secretase inhibitors presents challenges mostly because it is involved in intramembranous cleavage of several other proteins, including Notch receptor and various neuronal substrates (e.g., ErbB4, p75NTR neurotrophin receptor and N- cadherin). Therefore Notch-sparing γ -secretase inhibitors (second-generation inhibitors) are under development:
begacestat was tested in phase 1 and BMS-708163 in phase 2 randomised controlled trials in patients with prodromal or mild-to-moderate AD. On the other hand, evidence for the neurotoxic and synaptotoxic activity of Aβ oligomers constitutes the scientific basis for the development of compounds that directly inhibit Aβ aggregation.
Tramiprosate, a non-peptidic anti-aggregant, binds preferentially to soluble Aβ and maintaining it in non- fibrillar form. Despite promising preclinical and human phase 2 studies, tramiprosate did not show clinical efficacy in the phase 3 study in patients with mild-to-moderate AD [96]. PBT2 is a second-generation inhibitor of metal-induced Aβ aggregation that binds to the Aβ-copper or Aβ-zinc complex, thereby preventing Aβ oligomerisation, promoting Aβ oligomer clearance, and decreasing plaque burden with positive effects on cognition [97]. In a 12-week, phase 2 trial in patients with mild AD, PBT2 was well tolerated, reduced Aβ CSF concentrations, and improved executive function [98]. However, recommendations about the usefulness of this agent must await positive results from rigorous Phase 3 studies.
Treatments for T2DM
Patients with T2DM are usually treated with pharmacologic agents in combination with dietary and exercise modification. A healthy diet is critical to controlling blood sugar levels and decreasing the risk of diabetes-related complications. It is recommended that patients with T2DM eat a consistent, well-balanced diet that is high in fiber, low in saturated fat, and low in concentrated sweets. Regular exercise can help body weight management, improve blood sugar control in people with diabetes and can help prevent or delay the onset of T2DM. It has been reported that Aerobic exercise leads to a decrease in HbA1C and improved insulin sensitivity [99].
In the United States, 11 unique classes of drugs (Table 2) are approved by the FDA for the treatment of hyperglycemia in T2DM [98, 100]. Metformin is currently recommended as the first line drug therapy for the management of T2DM because of proven effects on blood glucose control with a decreased risk of hypoglycemia, and low cost [101].
Metformin lowers blood glucose primarily by decreasing hepatic glucose output and reducing insulin resistance. It may also exert protective effects on pancreatic islet cells.
Metformin is used as monotherapy or most often in combination with sulfonylureas for management of T2DM.
Sulfonylureas are widely used to treat T2DM because they stimulate insulin secretion from pancreatic β-cells by binding to the ATP-sensitive potassium channel, which plays a major role in controlling the β-cell membrane potential [102].
Patients who respond best to sulfonylureas include those with a diagnosis of T2DM before 40 years of age, duration of disease less than 5 years before initiation of drug therapy and a fasting blood glucose level of less than 16.7 mmol per L [103]. With a rapid onset time and relatively short half- life, meglitinides is a class of oral antidiabetic agents that have the advantage of controlling postprandial hyperglycemia and reducing the risk of hypoglycemia [104].
Therefore, meglitinides can be used preferentially in the elderly with diabetes or patients with reduced renal function or those experiencing troublesome hypoglycemia with sulfonylureas. The thiazolidinediones, also known as TZDs, are a unique drug class of “insulin sensitizers” that act as PPAR-γ ligands and promote skeletal muscle glucose uptake and reduce hepatic glucose production in the liver [105].
Troglitazone was the first agent of this drug class introduced in the U.S. market, but was withdrawn from the market in 2000 due to an increased incidence of drug-induced hepatitis. Although the newer thiazolidinediones, rosiglitazone and pioglitazone, do not increase the risk of hepatitis or hypoglycemia, and has more durable action controlling hyperglycemia than sulfonylureas and metformin, they were either withdrawn from the market or put under selling restrictions due to concerns of the increased risk of myocardial infarction or bladder cancer [106]. In addition to diabetes medications, some patients with T2DM may also need insulin therapy as well. According to the American Diabetes Association (ADA)-issued guidelines on the management of hyperglycemia in patients with T2DM, if a patient’s HbA1c is more than 9.0%, two agents or insulin should be considered. If it is 10.0% to 12.0%, insulin should
be strongly considered from the outset [107]. Moreover, interventional surgery (e.g. biliopancreatic diversion) might be considered a reasonable therapeutic alternative for overweight and obese (BMI <35 kg/m²) patients with T2DM who do not respond to medical therapy [108].
Common Strategies to Manage T2DM and AD Anti-Inflammatory Approach
Chinese herbal medicine has been in continuous use in China for over two thousand years to treat a wide array of diseases. Andrographolide is the primary bioactive component of the medicinal plant Andrographils paniculate Nees. This component has many bioactivities including anti- inflammatory via different mechanism (e.g. NF-kB inhibition), antioxidant and hepatoprotective effects [109, 110]. In vitro, pretreatment with andrographolide suppressed the TNF-α induced activation of NF-kB signaling pathway and the expression of downstream inflammatory factors, therefore attenuating insulin resistance in 3T3-L1 adipocytes [111]. In vivo, andrographolide lowered blood glucose, increased insulin and prevented loss of β cells, stimulated
glucose transport protein subtype 4 membrane translocation in alloxan-induced diabetic mouse model [112].
Numerous marine bioactives have been recently identified with considerable potential in the prevention and treatment of various chronic inflammatory disorders, such as diabetes, diabetic nephropathy, and neurodegenerative diseases [113]. Hymenialdisine is an alkaloid isolated from marine sponges, such as Acanthella aurantica and Stylissa massa [114]. Its anti-inflammatory properties have been reported, achieved through its ability to decrease IL-8, IL-1β and TNF-α production by inhibition of NF-kB [115, 116]. It also inhibits several proteins including GSK-3β, Cdk-5 and casein kinase 1 by competing with ATP for binding to these kinases [117]. In this manner, it decreases the phosphorylation of the protein tau with promising potential against AD [118]. Astaxanthin, the main carotenoid pigment, was found in algae and aquatic animals, present in many popular seafoods (trout, salmon, shrimp, and lobster) [119].
Clinical studies have demonstrated its ability to promote reductions in the cardiovascular risk markers of inflammation and oxidative stress, as well as improvement in blood status [120, 121]. In addition, it has been reported that astaxanthin has a protective efficacy against several Table 2. Leading FDA-Approved Drugs for T2DM Treatment
Class Compound(s) Year Approved Mechanism of Action Side Effects
Biguanides Metformin 1995 Activates AMP-kinase; Decrease
hepatic glucose production Diarrhoea, abdominal cramping, Vitamin B12 deficiency
ulfonylureas
Glipizide 1984 Closes K channels on β cell plasma membranes; Increase Insulin
secretion
Hypoglycaemia, weight gain, myocardial ischaemic preconditioning
Glimepiride 1995
Glyburide 2000
Meglitinides
Repaglinide 1997 Closes K channels on β cell plasma membranes; Increase insulin
secretion
Hypoglycaemia, weight gain, myocardial ischaemic preconditioning
Nateglinide 2000
Thiazolidinediones Pioglitazone 1999 Activates PPAR-γ; Increase insulin
sensitivity Weight gain, oedema / heart failure, bone fractures, bladder cancer
Rosiglitazone* 1999 α-Glucosidase
inhibitorsa
Acarbose 1995 Slows intestinal carbohydrate digestion/absorption
Gastrointestinal side effects (flatulence, diarrhoea)
Miglitol 1996
DPP-4 inhibitors Sitagliptin 2006 Increase insulin secretion; Decrease
glucagon secretion Urticaria/angiooedema, pancreatitis
Saxagliptin 2009
Bile acid
sequestrants Colesevelam 2008
Binds bile acids in intestinal tract, increasing hepatic bile
acid production
Gastrointestinal side effects (flatulence, diarrhoea), increased triacylglycerols
Dopamine-2
agonists Bromocriptine 2009
Activates dopaminergic Receptors; Increase insulin
sensitivity
Dizziness/syncope, nausea, fatigue, rhinitis
GLP-1 receptor agonists
Exenatide 2005 Increase insulin secretion; Decrease glucagon secretion; Slows gastric
emptying
Nausea/vomiting, C cell hyperplasia, acute pancreatitis
Liraglutide 2010
Amylin mimetics Pramlintide 2005
Activates amylin receptors;
Decrease glucagon secretion; Slows gastric emptying
Nausea/vomiting
Insulins Human insulin 1982 Increase glucose disposal; Decrease hepatic glucose production
Hypoglycaemia, weight gain
Lispro 1996
*Prescribing highly restricted in the USA; withdrawn in Europe. DPP-4, dipeptidyl peptidase IV.
deleterious effects caused by high glucose exposure in proximal tubular epithelial cells, as documented by suppressed expression of inflammatory proteins such as inducible nitric oxide synthase and cyclooxygenase-2, and reduced levels of lipid peroxidation and total reactive species, which indicating that astaxanthin should be explored further as a potential antidiabetic remedy for the treatment of diabetic nephropathy. Long-chain n−3 polyunsaturated fatty acids, found in oily fish and fish oils, are able to decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species [122]. Thus, polyunsaturated fatty acids (n−3) are potentially potent anti-inflammatory agents and may be of therapeutic use in a variety of inflammatory settings including AD and T2DM.
Antioxidant
There is now compelling biochemical evidence indicating that oxidative stress may play a role in the pathogenesis of T2DM and AD [123, 124], therefore antioxidant supplementation individuals afflicted with these diseases may be beneficial [125, 126]. Honey, a natural product consisting of sugars and bioactive enzymes (e.g.
glucose oxidase, diastase, catalase and peroxidase) is claimed to possess several health-beneficial properties such as hypoglycemic, antioxidant, antihypertensive and anti- inflammatory effects [127, 128]. Honey administration to diabetic rats led to a significant increase in total antioxidant status and activities of glutathione S-transferase, glutathione reductase, catalase and glutathione peroxidase. This antioxidant effect of honey was accompanied by improvements in renal pathology as evidenced by reduced mesangial matrix expansion and glomerular basement membrane thickening [128, 129]. Additionally, honey supplementation significantly reduced elevated levels of malondialdehyde and restored the activities of superoxide dismutase and catalase in pancreas of diabetic rats [130].
Grape seed extract is abundant in phenolic antioxidants and pro-anthocyanidins. Several studies have shown that the polyphenol enriched grape seed extract can reduce Aβ accumulation and protect against neurotoxicity and oxidative stress in cell and animal models of AD [131, 132], suggesting that the polyphenols present in grape seed extract are potent anti-amyloidogenic agents.
Vitamin E, another antioxidant, has been proposed as a treatment to delay neurodegeneration, protect against cognitive impairment and dementia in AD patients based on both laboratory- and population-based data [133-135].
Vitamin E was also reported to increase the activities of superoxide dismutase and catalase, and reduce lipid peroxidation and protein oxidation in small intestine of diabetic rats [136].
Transition metal ions, including Al (III), Fe (III), Zn (II) and Cu (II) have been proposed to cause neurotoxicity and neurodegeneration in AD [137, 138]. Excess accumulation of transition metal ions may lead to oxidative stress, tau hyperphosphorylation and formation of amyloid fibrils of Aβ42 [137, 139, 140]. Chelation therapy has been shown to be neuroprotective by preventing the aggregation and fibrillarization of Aβ and tau, and reducing ROS production [139, 141, 142]. In a two year, single-blind study, daily injections of trivalent ion chelator, desferrioxamine slowed
the progression of dementia in patients with probable AD [143]. In another uncontrolled clinical trial, chelation therapy with clioquinol afforded AD subjects with modest improvements in clinical ratings [144].
Biomedical Informatics Approach
Biomedical informatics technologies have been developed and applied to AD and T2DM care and management [145]. Genetic studies have led to the identification of three deterministic genes for AD: APP, presenilin-1 (PS-1) and presenilin-2 (PS-2) [146-148].
Additionally, the E4 allele of the apolipoprotein E (ApoE) gene has been identified as a risk factor, which is implicated in about 20 percent to 25 percent of AD. Although health professionals do not currently recommend routine genetic testing for AD, genetic tests are available for people with such family histories.
Electronic medical records (EMRs) lie at the center of any computerized health information system. EMRs provide quick access to all of a patient's information, from the results of the last routine checkup to computed tomography scans from an emergency hospital admission. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a large, highly collaborative longitudinal cohort study designed to validate the use of biomarkers including blood tests, tests of cerebrospinal fluid, and magnetic resonance imaging/
positron emission tomography imaging for AD clinical trials and diagnosis. All clinical and imaging data in ADNI have been made public without any embargo through its website.
Based on magnetic resonance imaging scans obtained from ADNI database, researchers found that the enlargement in the temporal horn region of the ventricular system is a sensitive biomarker of AD [149], which may provide the window of opportunity for treatment and an objective approach to monitor response to treatment.
Clinical Trials of Antidiabetic Drugs in AD
It has been proposed that AD fundamentally represents a metabolic disease characterized by the same molecular and biochemical changes identified in peripheral insulin resistance diseases [150]. Therefore, it may be beneficial to treat or prevent progression of AD based on stage and severity of brain insulin resistance, similar to approaches used to treat T2DM.
Peroxisome Proliferator-Activated Receptor (PPAR) Agonists
PPARs are ligand activated transcription factors that modulate target gene expression to enhance insulin sensitivity, modulate glucose and lipid metabolism, stimulate mitochondrial function, and reduce inflammatory responses [151-153]. PPAR agonists improve learning and memory, attenuate pathological markers in AD animal models [154, 155] and patients [55, 156, 157]. The PPAR-γ agonist, rosiglitazone, has been most widely studied in human clinical trials due to its insulin sensitizing and anti- inflammatory properties, and its ability to increase expression of the glucose transport protein subtype 4 transporter and glucose metabolism. In a double-blind, placebo-controlled study, rosiglitazone treatment significantly preserved performance on delayed recall and
attention tasks in patients with early AD and amnestic mild cognitive impairment [158]. In the Rosiglitazone Efficacy in AD Clinical Trial (REFLECT), exploratory analyses suggested that rosiglitazone therapy may confer cognitive and functional improvement in patients who were ApoE-ε4- negative [159]. However, in two phase 3 studies that evaluated the efficacy and safety of rosiglitazone as adjunctive therapy to acetylcholine esterase inhibitor treatment in mild-to-moderate probable AD, there was no evidence rosiglitazone improve cognition or global function and no interaction between treatment and ApoE status was detected [160]. Treatment with pioglitazone daily for 6 months in patients with mild AD accompanied with T2DM led to enhanced insulin sensitivity, and improved cognitive function and regional cerebral blood flow in the parietal lobe [161].
Intranasal Insulin
Intranasal insulin can be administered to AD subjects to avoid the harmful side effects (e.g. hypoglycaemia) induced by systemic insulin treatment. At least three randomized, placebo-controlled studies that explored the effects of intranasal insulin on memory in individuals with mild cognitive impairment or mild AD have been reported [16, 162, 163]. Insulin treatment conferred greater improvement on two measures of verbal memory in memory-impaired adults. Interestingly, the protective effects were stronger for subjects with the ApoE-ε4 allele (ε4+) than those without ε4 allele (ε4-) [16]. In memory-impaired adults with AD, intranasal insulin administration increases brain insulin levels, improves performance on verbal memory tasks, and modulates plasma Aβ without influencing on plasma glucose and insulin levels [162]. Insulin-treated subjects also showed improved attention and functional status with an increased Aβ40/42 ratio [163]. Reducing the relative amounts of Aβ42 should be neuroprotective as it is the neurotoxic form of the secreted peptide. Although the results of clinical trials reveal some statistically significant differences between intranasal insulin and placebo, these studies were preliminary and require larger sample size.
Metformin
Metformin was introduced in the United States in 1995.
It is a dimethyl biguanide oral anti-hyperglycemic drug that is used to treat T2DM through the suppression of gluconeogenesis and the improvement of glucose uptake and insulin sensitivity. Metformin treatment reduced the incidence of neurological complications of T2DM, including cognitive impairment and cerebral vascular disease [164].
Based on the fact that hyperinsulinemia and T2DM are important potential risk factors for cognitive decline and AD, a phase 2 double blinded, placebo controlled, randomized clinical trial of metformin is currently underway to test the hypothesis that lowering peripheral insulin in overweight persons with amnestic mild cognitive impairment can decrease the risk of cognitive decline and progression to AD [1]. However, in a population-based case-control study, a slightly higher risk of AD was associated with in long-term users of metformin, but not other antidiabetic drugs such as sulfonylureas, thiazolidinediones, or insulin [165].
CONCLUSION & PERSPECTIVE
AD and T2DM have traditionally been considered to be independent disorders. However, increasing evidence has suggested possible associations and some common pathophysiological mechanisms. From a clinical perspective, the pathological links would indicate that common therapeutic strategies should be explored and current anti- diabetic drugs might be beneficial in treating AD patients.
Further investigation of the mechanisms underlying AD and T2DM should identify more potential treatment targets. It is important to acknowledge that these two disorders are the end result of the degeneration cascade that targets different aspects of cellular physiology and homeostasis. It is therefore anticipated that multi-pronged approaches in addition to FDA-approved drugs will be needed. Research emphasis should also be placed on lifestyle improvement, nutrient supplement and consumption of natural compounds to prevent or treat AD and T2DM.
LIST OF ABBREVIATIONS Aβ = Amyloid-β peptide AChE = Acetylcholinesterase AD = Alzheimer’s disease APP = Amyloid precursor protein FDA = Food and Drug Administration GLP-1 = Glucagon-Like Peptide 1 GSK-3β = Glycogen synthase kinase-3β IAPP = Islet amyloid polypeptide
PPARγ = Peroxisome proliferator-activated receptor gamma T2DM = Type 2 Diabetes Mellitus
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS Declared none.
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