Medical Hypotheses 82 (2014) 535–546

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Medical Hypotheses

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Glaucoma – Diabetes of the brain: A radical hypothesis about its natureand pathogenesis

http://dx.doi.org/10.1016/j.mehy.2014.02.0050306-9877/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +91 11 26588500x3001; fax: +91 11 26588663.E-mail address: tanujdada@gmail.com (T. Dada).

Muneeb A. Faiq a,b,c, Rima Dada b, Daman Saluja c, Tanuj Dada a,⇑a Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi 110029, Indiab Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, Indiac Medical Biotechnology Laboratory, Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 27 December 2013Accepted 3 February 2014

Glaucoma is the leading cause of irreversible blindness characterized by irremediable loss of retinalganglion cells. Its risk increases with progressing age and elevated intraocular pressure. Studies haveestablished that glaucoma is a neurodegenerative disorder in which the damage involves many braintissues from retina to the lateral geniculate nucleus. Despite lot of research, complete pathomechanismof glaucoma is not known and there is no treatment available except modification of intraocular pressurepharmacologically and/or surgically. We here present a hypothesis inspired by studies across many areasof molecular and clinical sciences in an integrative manner that leads to a uniquely unconventionalunderstanding of this disorder. Our hypothesis postulates that glaucoma may possibly be the diabetesof the brain. Based on the remarkable similarities between glaucoma and diabetes we propose glaucomaalso to be a type of diabetes. Glaucoma and diabetes share many aspects from various molecular mech-anisms to involvement of insulin and possible use of antidiabetics in glaucoma therapy. Additionally,Alzheimer’s disease has already been proposed to be diabetes type-3. We show that Alzheimer’s diseaseis cerebral glaucoma and diabetes at the same time which, by transitive property of similarities, againleads to our hypothesis that glaucoma is diabetes of the brain. Our proposition may lead to appreciationof certain important facets of glaucoma which have previously not been given due consideration. It alsomay lead to an alternative classification of diabetes as pancreatic and brain diabetes thereby wideningthe vision arena of the understanding of both these disorders.

� 2014 Elsevier Ltd. All rights reserved.

If at first the idea is not absurd then there is no hope for it.Albert Einstein

Hypothesis

We hypothesize that ‘‘Glaucoma is the Diabetes of the Brain’’.Our proposition derives support from our arguments that (i) thereare striking similarities in molecular biology of glaucoma and dia-betes, (ii) brain can also suffer from diabetes, (iii) glaucoma inflictsbrain and the brain part of eye, (iv) insulin is involved in mainte-nance of brain function, intraocular pressure and presumably otherocular functions and (v) brain diabetes is caused by same reagentswhich cause pancreatic diabetes. This hypothesis is important be-cause it may lead to understanding of certain areas of glaucomaand diabetes which have not been evaluated yet. Our hypothesis

is likely to give birth to new areas in glaucoma and diabetes under-standing and management.

Glaucoma–diabetes: a molecular crosstalk

Glaucoma is a progressive ocular neurodegeneration and sec-ond leading cause of blindness with more than 60 million peopleaffected worldwide [1]. The hallmark of glaucoma is gradual lossof retinal ganglion cells (RGCs) [2] by apoptosis [3]. Glaucomahas certain molecular and mechanistic similarities with otherdegenerative disorders of the central nervous system (CNS) likeAlzheimer’s disease (AD) and Parkinson’s disease (PD). Severalpathways for RGC death have been observed in glaucoma [2] andinsulin plays a key role in many of them. Factors implicated inglaucoma pathogenesis include rise in intraocular pressure (IOP),decreased production of neurotrophic factors, excitotoxicity andvasospastic hypoxia [4,5].

RGCs die in glaucoma by various combinations and permuta-tions of apoptosis, oxidative stress (OS), mitochondrial dysfunction,

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lack of neurotrophic factors, excitotoxicity, insulin deficiency andbrain insulin resistance. Insulin producing b-cells of pancreas(b-cells) in diabetes also suffer demise by apoptosis [6], OS andmitochondrial dysfunction [7], insulin deficiency and insulin resis-tance [8]. There are two pathways for apoptotic death in RGCs viz.intrinsic and extrinsic pathways [9,10]. The same is case withdiabetes where b-cells die by intrinsic [11] and/or extrinsic path-ways [12]. The intrinsic pathways are initiated independent ofany extracellular stimulus. These mainly include cellular stress inwhich apoptotic pathways like c-Jun N-Terminal protein kinases(JNKs) are activated leading to the production of stress associatedprotein kinases (SAPKs) [13,14]. Bcl-2 associated death promoter(BAD) and the other member of same family Bim-EL are also thepro-apoptotic molecules involved [15]. These moieties lead toimpairment in mitochondrial integrity and function which initiatesapoptotic pathways [16] with change in mitochondrial flux andconsequent release of cytochrome-C into the intracellular milieu[16,17]. Our studies also suggest mitochondrial dysfunctionin glaucomatous patients [18,19]. Various cysteine-dependentaspartate-directed proteases (caspases) particularly caspase-3and caspase-9 are then activated to execute cellular death [16].Caspase-3 and caspase-9 mediated apoptosis has been reportedin both RGC death in glaucoma [20] and b-cell death in diabetes[21]. Extrinsic apoptotic pathways have also been implicated inglaucoma and diabetes which involve the binding of certain deathreceptor ligands to various cell surface receptors to bring aboutcellular death [16,17,22] in glaucoma [23] and in diabetes [12].There are many studies which report that inhibition of caspasesenhance the survival of RGCs [24–26]. Blocking caspase-3 leadsto increased survival of RCGs in glaucoma through intrinsic path-way [24–26].

OS has also been shown to be important in RGC death in glau-coma [27] and b-cell death in diabetes [28]. OS mediated RGCdeath in glaucoma comes about either by protein modificationand/or DNA damage [9,29,30] and, interestingly, same is the casewith diabetes [31,32]. This mechanism involves ROS superoxideburst [33]. Additionally, signal transducer and activator of tran-scription-3 (STAT3) pathway regulates neuron survival [34] bydimerization of STAT and its followed translocation to the nucleusfor expression of a battery of genes necessary for RGC survival[35,36]. Activation of the same pathway is the mechanism involvedin b-cell enhanced survival in diabetes [37] also.

Similarities between RGCs and pancreatic b-cells

b-Cells and RGCs have far-reaching similarities in their molecu-lar basis of biological activity. Both cell types show similar geneexpression pattern which includes dopamine b-hydroxylase [38],tyrosine hydroxylase [39], voltage-gated sodium channel type-2[40], glutamic acid decarboxylase [41], glutamate receptor, neuro-filament proteins [42,43], neurotrophin receptors [44,45], thyrot-ropin releasing hormone [46,47], insulin, insulin receptor (IR)[48] and many other genes. This similitude in gene expression pat-tern is indicative of many functional similarities/relations betweenthese two cell types. This may indicate that both RGCs and b-cellsmay be susceptible to similar diseases and may react to certainchallenges in same way; hence bolstering the logic of looking atdiabetes and glaucoma as the same disorder afflicting two sitesof the body. This augments our notion that glaucoma may, infact, be diabetes of the brain. With regards to the similarities inthese molecular aspects, many transcription activators includingIslet-1 [49], Beta-2 [50] and Pax6 [51] are expressed in both the celltypes. In a study performed on various cell lines, control ofexpression of such genes in both neuronal and insulin producingcells was investigated. The investigators evaluated transcriptional

repressor neuron-restrictive silencing factor/repressor elementsilencing transcription factor (NRSF/REST) in the expression of var-ious neuronal genes in insulin-producing cells. NRSF/REST being anegative repressor for neuronal specific genes is present in non-neuronal cell types while as absent in neuronal cells. Theyhave demonstrated that NRSF/REST is absent in insulin and gluca-gon producing cell lines also. Based on their findings, they arguedthat the mechanism of expression of such genes is similar in bothtypes of cells [52] indicating that the molecular impairmentsaffecting these cell types might also be similar. This indicates thatsome identical mechanisms control the molecular biology ofinsulin producing cells and neuronal cells. The b-cells and the neu-ronal cells (including RGCs) also share certain similarities byexpressing many groups of genes like catecholamines, c-aminobutyric acid, certain cell surface receptors intermediary neurofila-ments and many hormones [41,42,44,46,53,54]. Interestinglyb-cells and neurons (including RGCs) are both electrically excitableand are depolarized by exposure to glucose and certain hormones[55,56].

Furthermore, b-cells and neuronal cells express same transcrip-tion factors [57]. A typical example of such a factor is NeuroD/BETA2 [50] which is a basic helix-loop-helix transcription factor in-volved in differentiation to neurons [57] as well as b-cells for trans-activation of insulin gene [50]. Some additional genes that areexpressed by both b-cells and RGCs are trkA and trkC [58,59].Moreover, the home-containing gene paired box protein/Pax6 alsocalled aniridia type-2 protein (AN2) is expressed by both neuronalcells as well as the insulin producing b-cells. Reduced expression ofPax6 transcription factor has been associated with aniridia andglaucoma [60]. On the other hand, mutations in Pax-6 have beenimplicated in glucose intolerance in diabetes [61]. This elucidatesa similitude in molecular pathogenesis of pancreatic diabetes andglaucoma (ocular diabetes).

Insulin signaling in CNS (retina)

Insulin receptor signaling (IRS) impairment has been reportedin many neurological disorders [62]. Interventions that improvethe (CNS) insulin receptor signaling have been employed to treatvarious neurodegenerative diseases which include AD [63]. Insulinsensitizing drugs are, for this reason, an active component of clin-ical trials for AD treatment [64]. By the same rationale, insulin sen-sitizing drugs can be used to treat glaucoma also. The mechanismsof synapse regulation, maintenance and elimination are not com-pletely known but it is mainly the insulin mediated neuronal activ-ity that can be accounted for [65–67]. Synapse maintenance is alsobrought about by insulin like growth factor (IGF)-2 [68–70]. IR; atransmembrane receptor activated by insulin, IGF-1 and IGF-2 isa tyrosine kinase receptor studied extensively for its role in glucosemetabolism. IRs are expressed also in the CNS [71] but their func-tion in CNS has not been sufficiently evaluated though it has beendemonstrated that they are involved in many neuronal functions[72]. IR activates phosphoinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways which control manycellular processes involved in glucose metabolism and cell growthand differentiation [73,74]. One among these functions is theinduction and development of RGCs at the retinal margin [75]. InCNS, IR is expressed in many cell types [71] and its expression levelis developmentally regulated [76]. Maintenance of synaptic plas-ticity and neuronal survival, learning, memory and cellular lifespanmaintenance are also brought about through IR. The importance ofIR in brain circuit development in visual system was recently re-ported in Xenopus tadpoles [76]. The region receiving visual signalsfrom the RGCs (the Xenopus retinotectal system) is important forstudies involving retinal neuron plasticity in vivo. Studies have

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shown that IR is essential for optic tectal neurons to receive normalvisual input from RGCs. IR is, hence, necessary to the normalfunctioning of the visual system which involves RGCs in the visualsystem pathway. A decrease in the expression of IR (a similar con-dition to insulin resistance: as happens in diabetes type-2) leads toa corresponding impairment in visual system functioning [62]. InIR downregulation, the dendritic processes of the tectal neuronsshorten leading to visual impairment [62] presumably mimickingglaucoma. Other studies have reported IR to be very importantfor the functional integrity of the visual system [77–81]. Moreover,reduced IR expression has been demonstrated in many neurode-generative diseases including AD [82] and PD [83]. Since the path-ological characteristics of AD and glaucoma are very similar, it canbe hypothesized that IR downregulation/loss is, at least in part,responsible for glaucomatous vision loss. Amyloid b-plaques(Ab-plaques) are a common finding in glaucoma; IRS preventsthe formation of such plaques [84] and inhibits neurofibrilarytangle formation. IRS also leads to increased degradation ofAb-plaques [85,86]. This finding may play an important role ina number of pathomechanisms of glaucoma. Ab binds with IR, inso doing, decreasing its (insulin’s) effective levels subsequentlycausing OS [87,88] leading to mitochondrial involvement andneuronal cell death. Ab also reduces the IRS by inhibiting Aktactivation. Since Akt pathway is neuroprotective, increased Aband consequently decreased IRS leads to loss of neuroprotectionensuing enhanced neuronal cell death [89]. This is one of the path-ways for RGC loss in glaucoma. Antisense morpholino oligonucleo-tides (AMOs) specifically knockdown IR while preserving the IGF-1receptor. Neurons transfected with AMO suffer from visualresponse insufficiency in vivo. Decrease in IRS by any mechanismdecreases visual responses indicating its significant role invision-neuron function. As ameliorating insulin signaling is beingtried on various neurodegenerative diseases like AD [63,64], weargue, on this premise, glaucoma also is a potential candidate.

In addition to its central role in glucose uptake, insulin playsimportant functional roles in neurons including neuronal growthand maintenance, neuronal degradation by apoptosis, synapticmaintenance and many other CNS centered functions [90]. Gener-ally it is considered that brain is obligatory glucose user uptakingglucose independent of insulin but expression of GLUT-4 in re-sponse to insulin in CNS (particularly RGCs) has been demon-strated [91]. IGF-1 is required for CNS glucose metabolism inmice [92]. Insulin also regulates CNS glucose metabolism in hu-mans [93]. Insulin resistance in CNS is thought to play many rolesin neurodegeneration [94]. The role of insulin resistance in neuro-degenerative disease like AD and glaucoma can be evaluated byinactivation of IR gene in CNS. Markus et al., have reported thedevelopment of brain/neuron-specific insulin receptor knockout(NIRKO) mice model to investigate insulin resistance and neurode-generation [90]. Using this model for conditional inactivation ofIR gene in CNS, they have been able to demonstrate that downreg-ulation of IR in CNS causes impairment in Akt and glycogensynthase kinase-3-beta (GSK-3b) activity and hyperphosphoryla-tion of tau [90]. These impairments are invariably seen in AD andglaucoma pathology though additional mechanisms are alsoinvolved. Insulin resistance in NIRKO mice leads to tau hyper-phosphorylation (typically 3.5-fold) [90], a major part of neurofi-brillary lesions in AD and glaucoma. IRS is important for insulininduced antiapoptotic activity in neurons [90]. Insulin also inhibitsapoptosis in cerebral granule cells [95]. Antiapoptotic activity ofinsulin may be important for many neuronal cell types whichmay include those involved in AD, schizophrenia and glaucoma.On the basis of these findings, it seems obvious that glaucomaand diabetes are mechanistically closely related and may essen-tially be the same molecular conglomeration at two sites of thebody.

Insulin signaling in glaucoma and RGC survival

The brain derived neurotropic factor (BDNF) produced by thetectum [96], leukemia inhibitory factor produced by the astrocytes[97] and IGF-1 produced by astrocytes [98] enhance RGC survival[99]. Insulin and IGF-1 are necessary for RGC survival. Tyrosinephosphorylation of b-subunit of IRs and IGF-1 receptors in culturedchick forebrain neurons and consequently neurite growth andenhancement of neurofilamentous proteins has been reported[100,101]. Insulin also activates protein phosphatase-2-A (PP2A),a serine/threonine phosphatase with broad substrate specificity[102] which regulates the phosphorylation through activation ofGSK-3b [103]. Tau phosphorylation is a vital molecular feature ofglaucoma. The expression of insulin and IGF-1 in human and mon-key RGCs have been confirmed (immunohistochemically) [104].Meyer et al., reported increased RGC survival by insulin and IGF-1 in 8 day old rats [99]. Improvement of RGC survival by insulinis thought to be executed through many pathways [103] includingprotein kinase-C-a (PKCa) activation without translocation [105],PP1 and PP2A activation [106] and maintenance of Bcl2 expressionin stress conditions. Bcl2 activates antioxidant pathways therebylowering free radical formation [107]. Therefore, insulin also en-sures RGC survival by taking care of the OS. Insulin induced Bcl2expression enhances the repair of injured and damaged axons ofRGCs (and those of CNS also) [108]. In a study, exposure of RGCsto insulin enhanced the survival rate by 30% [101]. Insulin inducedBcl2 also ameliorates mitochondrial dysfunction by regulating pro-ton flux [109] and prevents RGC apoptosis.

Avian and mammalian eyes contain neural stem cells and neu-ral stem cells at the retinal margin of post hatch chicken lead todevelopment of certain neurons that integrate into retinal edge[110]. Chick ciliary margin zone (CMZ) cells produce amacrineand bipolar neurons [111]. These cells become restricted to specificcell types with time [112]. It is important to note that the RGCs arenot produced by retinal stem cells in mammals or in birds [75].Keeping that in view, Andy et al., conducted a study about certaingrowth factors that lead to the development of RGCs at the retinalmargin. They interestingly found that insulin leads to the inductionand production of RGCs [75]. RGC development and differentiationby insulin is indicative of some important mechanism by whichinsulin plays the role of an integrative molecule in metabolism ofRGCs in addition to b-cells. It specifies that (a) IRs are continuouslyexpressed in retinal cells, (b) insulin may be important for RGCgrowth and development and (c) insulin signaling is vitally rele-vant to glaucoma. All these factors point to common etiopatho-mechanistic interactomes between glaucoma and diabetes. Thisshows that glaucoma and diabetes are alternative or ectopic formsof each other. Andy and coworkers further reported that insulinalone is sufficient to the proliferative induction of RGCs at retinalmargin [75] giving insulin an important stature in prospectiveglaucoma therapy in addition to diabetes management.

Insulin regulates intraocular pressure (IOP)

IOP elevation leads to optic disc cupping and defects in visualfield ensuing glaucoma [113]. Studies have reported various riskfactors for glaucoma of which IOP is of the greatest importance be-cause of being the only modifiable risk factor [114]. Lowering IOPreduces the risk of glaucoma [115]. Elevated IOP has been shownto be associated with diabetes also [116,117] suggesting someimperative link between glaucoma and diabetes. Moreover, obesityalso can serve as a modifiable risk factor for elevated IOP [118] and,therefore, glaucoma. Leptin might, for this reason, serve as a ther-apeutic agent in glaucoma [20]. IOP elevation has been reported tobe associated with insulin resistance [119] and conversely insulin

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induced hypoglycemia acutely lowers IOP [120]. These findingsstrongly suggest greater underlying molecular similarities betweenIOP elevation (consequently glaucoma) and diabetes. Many inves-tigators have reported elevation of IOP with elevation in the fastingblood glucose [116,117,121,122] which strongly implies patholog-ical and mechanistic similarities between IOP and glucose metab-olism or, in other words, glaucoma and diabetes. Since insulinregulates the blood glucose levels and insulin deficiency/insulinresistance (diabetes type-1/type-2) is associated with diabetes, itis plausible that insulin deficiency and/or insulin resistance maylead to elevation in IOP [123]. In a recent study conducted on943 human subjects and using HOMA-IR and McAuley index, itwas concluded that there is a strong association between insulinresistance and IOP elevation. In this study, IOP was elevated corre-sponding to the level of insulin resistance [120] even after control-ling the confounding factors [120]. At the current status ofliterature, it can be postulated that insulin activates many signal-ing pathways in retinal neurons many of which play role in cellproliferation, differentiation and expression of various glucosetransporters [91]. Insulin acts in similar ways in pancreatic b-cellsto ward off diabetic pathogenic picture.

Notes from streptozotocin

2-Deoxy-2-[methyl-(nitrosoamino) carbonyl] amino-D-gluco-pyranose (a nitrosamide methylnitrosourea linked to the C2 posi-tion of D-glucose) also called streptozotocin (STZ) is known tocause diabetes mellitus in experimental models. Recently, STZhas been reported to produce biochemical and molecular hall-marks of diabetes mellitus in neurons of CNS. STZ operates throughelevation in OS and consequent DNA damage by release of N-nitr-osoureido mediated production of nitric oxide, superoxides andhydrogen peroxide [124]. As STZ is taken up by the cells that pro-duce insulin, it is taken up by b-cells and also by CNS neurons indi-cating insulin production in CNS. Rat models of cranial diabetesmellitus are produced by intracerebral injection of STZ (ic-STZ).Brain insulin resistance has been established by ic-STZ injections[125]. Reduced cerebral glucose utilization [125], impairment inoxidative metabolism [126], inhibition of IR function [127], cogni-tive deficit and deranged cerebral bioenergetics is a common find-ing post ic-STZ [128]. Many of these impairments occur inglaucoma. In addition to that, the pancreatic cytoarchitecture andinsulin immunoreactivity are same as that in controls in post ic-STZ mice [129]. There are clear regions of brain atrophy in thesemodels in spite of no damage to pancreas. Such models havepathologies typical for glaucoma like glia activation, p53 immuno-reactivity, hyperphosphorylated tau protein and amyloid precursorprotein (APP)-Ab plaques [130,131]. In addition to that, expressionof neurons (Hu), myelin associated glycoprotein-1 (MAG-1) andcholine acetyltransferase (ChAT) and simultaneous elevation inthe expression of p53 [132], tau, APP [130,131], allograft inflam-matory factor-1 (AiF-1) and glial fibrillary acidic protein levels sug-gest an apoptotic mechanism of cell loss in brain diabetes which isquite similar to the cell loss mechanism in glaucoma.

The multifaceted pathological picture of reduced insulin/IGFexpression, impaired insulin/IGF receptor expression, derangementin insulin signaling pathways precipitated by ic-STZ and conse-quent changes in the expression of genes producing a pathologicalpicture mimicking glaucoma (and AD) justify brain diabetes in-duced by ic-STZ independent of pancreatic diabetes. It also sug-gests that insulin sensitizers and insulin supplementation mayameliorate neurodegenerative conditions like glaucoma and AD.Moreover, the molecular derangements that are characteristic ofglaucoma like GSK-3b activation, tau hyperphosphorylation, re-duced survival of neurons can be reproduced by blocking the insu-

lin and its signaling pathways in CNS [133,134]. Molecularnetworks of glaucoma (and diabetes) being intricately interwoven,tau is regulated by insulin and IGF-1 [135] and its ubiquination andphosphorylation is elevated in OS and activation of GSK-3b [136]the way it goes with ic-STZ. APP is also upregulated in neuronalOS [137,138] which explains APP-Ab buildup in both glaucomaas well as ic-STZ treated models.

Pax6 gene involvement in glaucoma and diabetes

Pax6, a highly conserved transcription factor, is the master reg-ulator of eye and retinal development in both invertebrates andvertebrates [139–141]. Mutations in Pax6 which lead to loss offunction present with a ‘no eye’ or ‘small eye’ phenotype [142].Impairment in the Pax6 expression pattern leads to many ocularmalformations which mainly includes developmental defects ofthe anterior chamber of the eye [143–145]. Various enhancers reg-ulate Pax6 expression in neural as well as non-neural ocular tissues[145,146]. Many neural cell types in vertebrate retina express Pax6in different patterns [147].

Pax6 is highly expressed in surface ectoderm and optic cup de-rived cells in mammalian eye development [148]. Optic cup widen-ing (increase in the cup-to-disc ratio) is an important diagnosticfeature of glaucoma. In a pioneering study, Cre/loxP approach wasemployed for selective inactivation of one Pax6 allele in developingdistal optic cup [149]. This relative downregulation of Pax6 in dis-tal optic cup resulted in maldevelopment of iris with no effect inlens [60]. Pax6 insufficiency derived trabecular meshwork (TM)failure leads to elevation in IOP which in turn causes glaucoma[60].

Pax6 is also important in signaling of the development of irido-corneal angle [60]. Obstructions in the TM aqueous outflow and theclosure of iridocorneal angle in Pax6flox/+;LeCre mice has beendemonstrated to lead to almost 25% increase in the basal IOP level.In humans, closure of iridocorneal angle leads to more acute eleva-tion of the IOP where it can raise by a factor of 100% [60] becausethe uveoscleral outflow pathway is not as active in humans, mon-keys and rabbits as it is in mice [150]. IOP elevation operatesthrough axonal damage in optic nerve head (ONH) [151]. Pax6-flox/+;Le-Cre mice develop severe degeneration of axons in the opticnerve similar to other models of glaucoma [152].

It is evident that (a) impairment in aqueous outflow secondaryto developmental defects in TM and (b) iridocorneal angle closurecontribute to juvenile glaucoma in aniridia [60]. Same thing hap-pens in Pax6flox/+;Le-Cre mice viz. TM dysgenesis and closure of iri-docorneal angle caused by iridocorneal adhesions. Both themechanisms cumulatively contribute to optic nerve damage andconsequently glaucoma. Same may be the case in humans also[60].

Pax6 expression has been demonstrated in lens ectoderm, lensplacode, lens vesicle and optic vesicle in the early developmentof mouse ocular system [153,148]. Pax6 has also been reportedin later stages in epithelia of conjunctiva, cornea, lens, ciliary bodyand retinal neurons [154]. The importance of Pax6 in ocular devel-opment can be understood by the finding that the homozygousSmall Eye (Sey) mice harboring mutations in Pax6 gene [142] donot develop eyes and nasal cavities [148,155]. Heterozygous Seymice exhibit smaller eyes with many defects in associated tissues[156]. Heterozygous Pax6 mutations have been implicated in ani-ridia in humans [157] in addition to Peter’s anomaly, certain kera-titis and foveal defects [158]. In our studies, we reported two novelmutations (viz. g.31815391Cytosine > Thymine and g.31823250Thymine > Guanine) in Pax6 gene in cases of ocular malformationamong north-Indians [159]. About 50–75% of patients with aniridiadevelop glaucoma [160] indicating that Pax6 malfunction is

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engaged in glaucomatous phenotype. Aniridia secondary to Pax6mutations leads to elevation of IOP [160,161].

The pathway for glaucoma pathogenesis secondary to Pax6mutation derived aniridia is not completely understood but it isthought that anterior chamber dysgenesis plays an important role.Malformations in the anterior chamber lead to impaired aqueousoutflow which leads to elevation in IOP [162]. Abnormal differen-tiation of TM and absence of Schlem’s canal have been reportedin aniridia on histopathological examinations [163]. This suggeststhat TM dysgenesis can also be due to Pax6 mutations ensuingglaucoma. However, anterior chamber dysgenesis has been indi-cated in other gene defects also like Pitx2, Pitx3, Foxc1, Foxe3,Lmx1b, Maf. It is interesting to note that Pax6 controls the expres-sion of many transcription factors which includes Maf [164].

In an important study Daniela et al., examined the role of Pax6in anterior segment development in heterozygous Pax6LacZ+ defi-cient mice [165] and found that Pax6 haplo-insufficiency is respon-sible for impaired anterior chamber mesenchyme differentiation,TM dysmorphogenesis and maldevelopment of Schlemm’s canal[166]. All these are important factors for development of varioustypes of glaucoma. In a case study involving two children with ani-ridia and Wilm’s tumor, deletion of short arm of chromosome-11was reported [167]. Pax6 is located on chromosome-11 short arm.

TM is embryologically derived from neural crest [168]. Pax6 isimportant for the cranial neural crest derived tissue morphogene-sis as shown in Sey rats where the migration of neural crest cellsfrom mid brain to craniofacial locations is hampered [169]. Pax6insufficiency is also involved in defects in many other neural crestderived ocular tissues [156]. Pax6 expression has been reported inoptic cup neuroectoderm derived ocular cells also [153,148,154].Iris and eye size impairments are not there in Pax6+/+-Pax6+/� chi-meric mice [170].

Lot of work has been done in understanding the mechanismsthat maintain and regulate insulin producing b-cell function[171,172]. Pax6 plays very important role in the development ofocular tissues and pancreas [173] and also CNS. Heterozygous lossof function mutations in Pax6 in mammals lead to many ocularabnormalities while the homozygotes are born without eyes aswell as pancreatic malformations and die at birth [142,174]. Thissuggests that Pax6 seems to be intricately involved in both pancre-atic diabetes and ocular diabetes (glaucoma). Development andspatial organization of islet cell precursors require Pax6[174,175]. Pax6 is regulated by the transcription factor pancreaticand duodenal homebox-1/insulin factor promoter-1 (Pdx1) [176].Following the development of the pancreatic cytoarchitecture,Pax6 controls the expression of insulin, glucagon, somatostatinand pancreatic polypeptide [175,177].

Since many developmentally active gene regulating moietiescontinue to be active in later stages also [172,178]; Pax6 being ex-pressed in both development of eyes and pancreas and then per-sisting in both the tissues in adult stages [179–181] suggests thatit has key roles to play in the maintenance of ocular and pancreatictissue functional integrity. In addition to predisposition to glau-coma through aniridia and IOP elevation, heterozygous Pax6 muta-tions have been reported to predispose humans to diabetes also[179–182].

In a study carried on conditional Pax6 mouse mutants (tamox-ifen inducible Cre deletion strain), it was demonstrated that assoon as the loss of functional Pax6 occurs, diabetes symptoms oc-cur with acute penetrance [183]. The investigators also reportedsevere impairment in production of many pancreatic hormones,transcription factors and insulin processing enzymes with Pax6functional deficit in these mice indicating Pax6 is essential to b-cellfunction and maintenance of pancreatic functionality [183].

Role of Pax6 in insulin production has been studied [175,177],regulatory regions described [175,177,184] and expression of

Pax6 in b-cells confirmed [179,180]; lending support to the obser-vation that glucose regulation and insulin kinetics is deranged inindividuals with heterozygous Pax6 mutations [179,180,185].Pax6 acts upstream of Pdx1 and Nkx6.1; owing to their downreg-ulation with Pax6 loss of function in adults. On the other hand,Pdx1 acts upstream of Pax6 during embryonic development (a typ-ical example of cross regulated reciprocal feed loop) [183]. Thisindicates that Pdx1 and Pax6 are very intricately connected forthe development and maintenance of pancreas. Correlatively,Pax6 and Pdx1 have been reported to be colocalized with glu-cose-dependent insulinotropic polypeptide (GIP) in mouse retinalcells [186] indicating their synergistic function in developmentand maintenance of retinal cells also.

Hyperinsulinemia in diabetes type-2 is caused by impairments inproinsulin processing with prohormone convertase (PC) 1/3 and PC2and carboxypeptidase E [187]. PC1 and PC3 are drastically downreg-ulated in mice with Pax6 null mutations [188] meaning that Pax6affects insulin processing showground either directly or throughPdx1. Patients with aniridia secondary to Pax6 mutations harborhigher levels of proinsulin in their prediabetic states [183].

Similarities between glaucoma and Alzheimer’s disease

Glaucoma and AD share many characteristics [189,190] on thebasis of which it has been postulated that glaucoma and AD isthe same disease affecting different parts of the brain. Glaucoma,for this reason, has been referred to as ‘‘Ocular Alzheimer’s Dis-ease’’ [191]. Both eye and optic nerve develop embryologicallyfrom the third ventricle [192]. Intraocular and intracranial spaceshave similar ranges for physiological pressure and also respondin a similar manner to intra-abdominal and intra-thoracic pressuredynamics [193]. IOP generation and maintenance is dependent onthe rate of production and outflow of aqueous humor in the ante-rior chamber of the eye [194,195]. The path followed by the aque-ous fluid is production by ciliary body epithelium, passing throughthe pupil and exiting through TM just before entering the systemiccirculation through Schlem’s canal. Similarly, intracranial pressure(ICP) is generated and maintained through production by choroidplexus (neuroepitheluim), passage through brain ventricles andreabsorption of CSF into the lymphatic system [194]. Since, retinais an extension of brain and glaucoma involves degeneration ofRGC (which are neurons), glaucoma is typically seen as a neurode-generative disorder. For this reason both glaucoma and AD areslowly progressing age related neurodegenerative disorders[196,197]. One of the pathological pictures for AD is decreased le-vel of Ab [198] and increased levels of tau in CSF [199]. Decreasedlevels of Ab and increased levels of tau have been reported also inthe vitreous fluid of glaucoma and diabetic retinopathy patients[200]. Ab-plaque accumulation has been reported in RGCs of ratmodels of glaucoma. Both glaucoma and AD involve activation ofcaspases in their pathogenesis. It is the caspase activation and con-sequent APP misprocessing that leads to Ab-plaques in AD [201]while it is the same thing that happens in RGCs in glaucoma. Glau-comatous death of RGCs involves activation of caspase-3 which issimilar to that of the apoptotic mechanism of b-cells in diabetes[202]. Based on these findings, it is thought that pathogenic mech-anisms of glaucoma are same as that of AD [191]. The way IOP ele-vation occurs in glaucoma, ICP is presumably elevated in AD [203].And there are cases of normotensive glaucoma [204] the way thereare normotensive AD cases.

Similar pathology of glaucoma, Alzheimer’s and diabetes

AD shares a great deal of biochemical, pathological and mecha-nistic abnormalities with diabetes [205,206] and glaucoma [129].

540 M.A. Faiq et al. / Medical Hypotheses 82 (2014) 535–546

AD and glaucoma present with many common characteristicsincluding increased cell death, abundant neurofibrillary tangles,consequent dystrophic neuritis, impaired deposits of APP, Ab-pla-ques, pTau protein deposition, increased expression of apoptoticgenes with corresponding increase in relevant signal transductionpathways, deranged energy metabolism and mitochondrial dys-function with elevated OS causing DNA damage. These two dis-eases are substantially similar in many respects and may,therefore, be the same disease finding expression at two differentlocations of the same organ (i.e. brain). This notion can be justifiedif the pathogenic mechanisms of both the disorders are strikinglysimilar. A coherent pathological picture that explains all these phe-nomena is likely to describe many aspects of these two disordersand may pave way for development of novel and effective thera-pies [137]. Insulin signaling dysfunction explains many aspects ofsuch a picture. Insulin/IGF-1 bind to corresponding receptors onthe cell surface and activate a plethora of intricately connected sig-nal transduction pathways including autophosphorylation of tyro-sine kinases [207,208] in consequence phosphorylating IRs[207,209]. The process activates extracellular signal-related ki-nase/mitogen-activated protein kinase (ERK/MAPK) and PI3K/Akt(protein kinase B) pathways inhibiting GSK-3b. These pathwaysare involved in inhibition of apoptosis, cell growth (and prolifera-tion) and reduction in OS [209–213]. Chronic brain insulin resis-tance and insulin deficiency has been reported in AD[137,138,209,214] and improvement in cognitive function by useof insulin sensitizers and intranasal insulin has also been reported[130,215,216]. Conversely cognitive impairments have been testi-fied in animal models of type-2 diabetes [217,218].

There is significantly lower number of RGCs in optic nerves ofAD cadavers as compared to controls [219]. Glaucoma patientswith elevated IOP present with optic nerve characteristics similarto those of AD which includes thinning of retinal nerve fiber layer(RNFL), increased optic cupping and abnormal electroretinogram[220]. It is interesting to note that loss of vision begins with lossof axons in mid brain and then the damage progresses anteriorlyengulfing optic nerve and the fundoscopically visible area in mouse[221] and primate models of glaucoma [222,223]. AD diagnosis isdifficult owing to expensive neuroimaging methods and invasivesampling of the CSF. Glaucoma is the most common retinal disor-der that has been matched up to AD [224].

Though glaucoma is idiopathic, ONH cupping, nerve fiber layer(NFL) thinning and activation of glia are commonly seen leading toRGC death and consequent vision loss [225] thereby putting glau-coma into the class of true neurodegenerative disorders. This is fur-ther supported by the fact that transynaptic degeneration has beenshown in lateral geniculate nucleus in visual cortex of glaucomapatients [226,227]. Though IOP is the most common modifiablefactor in glaucoma [228], but IOP reduction does not reverseONH cupping and retinal degeneration and, therefore, almost allpatients develop optic neuropathy [225,229]. In addition, manyopen angle glaucoma patients have IOP within the normal range[230]. Increased prevalence of glaucoma in AD is now well known[231–233]. In a study 25.9% of AD patients also presented withglaucoma as compared to 5.2% in control group [231]. As is the casewith AD, glaucoma patients also present with impaired congnitivefunctions [232] although there are studies that do not support this[233].

Glaucoma and AD having strikingly common pathologies [234];the retinal regions that are affected in AD are same as those af-fected in glaucoma viz. RGC death [235] and NFL thinning in ADand RGC death, NFL thinning and optic nerve hypoplasia in glau-coma [235–237]. Like glaucoma, glial activation secondary toRGC loss has also been demonstrated in AD [238]. The retinalhemodynamic parameters of AD patients also are similar to thoseof glaucoma patients with both featuring narrowing of vessels

and reduced blood flow [239–241] which leads to increase in theactivity of Hypoxia-inducible factors (HIFs) [242]. pTau has beenreported in the inner retina [243], optic nerve and peripappilaryglia [244] of glaucoma patients [245]. pTau has also been impli-cated in neurofibrillary threads and tangles (NFT) formation inAD. Reddy et al., reported decrease in Ab in AD [246]. Retinal gliais activated in both AD [247] and glaucoma [234].

Alzheimer’s disease as type-3 and glaucoma as type-4 diabetes

In one of our previous studies we provided strong rationale toestablish a link between diabetes and encephalization [248] fromevolutionary point of view. We argued that diabetes has evolution-ary links with neurons and brain activity in humans. Our studiesare also supported by studies inspired by human evolution andanthropology [249]. Impaired cerebral glucose utilization and de-ranged bioenergetics in AD is precipitated early in the develop-ment of disease [250–252] and same is the case with glaucoma[253,254]. Owing to many similarities AD has recently been pro-posed to be another form of diabetes representing ‘‘type-3 diabe-tes’’ [129,137]. By the same token, glaucoma can also beproposed to be another type of diabetes, may be ‘‘diabetes type-4’’.

Irrespective of the types, diabetes is, for the most part, derange-ment in insulin functioning machinery precipitating hyperglyce-mia. Type-2 is the most common form of diabetes mellitus and ismediated by insulin resistance as a consequence of reduction inIR expression, impairment in IR-tyrosine kinase functioning, insu-lin receptor substrate type-1 expression [255]. AD shows up withthe characteristics of both type-1 and type-2 diabetes by present-ing insulin resistance as well as hypoinsulinemia restricted to theCNS [129]. Malfunction of the insulin machinery causes cognitivedysfunction in AD [137,138] explained by the fact that expressionand phosphorylation of tau gene and its protein product respec-tively are regulated by insulin and IGF [256,257]. Studies havedemonstrated that many hallmarks of neurodegeneration thatare seen in AD can be reproduced by mutilation of insulin path-ways [258–260].

By studying the post mortem tissues of advanced AD patients,Suzanne et al., showed that AD type neurodegeneration is hand-cuffed with significant aberrations in expression of insulin andgenes involved in its downstream pathways [129,130,137]. Highlyreduced levels of insulin and IGF-1 and their receptor genes wasreported by these authors in advanced cases of AD. They arguedthat the signaling pathways that are activated by insulin andIGF-1 (which are mediators for neuronal viability, tau expression,neuronal bioenergetics and mitochondrial function) were de-ranged in their subjects. The Suzanne et al., study is important inthe sense that they showed insulin to be linked with neurodegen-eration (AD in particular); owing to the striking similarities seen inAD brain (in patients without any diabetes) and diabetes (bothtypes) which included impairments in IGFs [129,130,261] thatare indispensible for b-cell function [262,263]. On the rationaleof the above discussions, it can be speculated that AD and diabetesis the same disease with manifestation in two different organs.Therefore, the term ‘‘diabetes type-3’’ for AD has found its placein literature. This paper is centered upon providing conceptual ba-sis of the idea that same could be the case with glaucoma and it isapt to think of glaucoma as diabetes type-4.

Brains at different severity stages (Braak stages) of AD havebeen studied to test if the extent of derangement in insulin/IGFdeficiency in the brain corresponds with the severity of the disor-der [264,265]. In these studies insulin, IGF-1, IGF-2, IR, tau, APPexpression was shown to be regulated in a way that correspondswith the Braak staging of AD. This indicates that insulin mediatedpathogenesis underlies the mechanism of AD [138]. These studies

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demonstrated that impairments in insulin, IGF signaling and theirdownstream processes lie in the genesis of AD and are immenselyimportant to understand the disease.

Neuronal and oligodenroglial cell viability depends on the prop-er functioning of insulin and IGF interactome in the brain[138,130,131,260,266–268], derangements which lead to impair-ment in neuronal bioenergetics, mitochondrial dysfunction, proin-flammatory cytokine expression, activation of microglia andrelated neuronal inflammation [130,138,268] and APP expressionin early stages of AD [269] which increases OS [136]. Same pro-cesses are activated in glaucoma pathogenesis also. It must benoted that microglia activation and increased expression of astro-cytic genes lead to further increase in CNS insulin/IGF-deficiency/resistance in AD [129]. Activation of microglia leads to APP-Abbuildup [269–273]. The diabetes type-3 based mechanism of ADseems to be mediated through impaired insulin/IGF signalingwhich increases OS [127,128,259] mediated by increased APPexpression and cleavage [136]. Elevated APP expression and Abbuildup form adducts which are neurotoxic [273–275]. These ad-ducts are seen in glaucoma also and may contribute to RGC death.

There is also an insulin mediated mechanism for cytoskeletalcollapse in AD. Braak stage dependent decreased expression inChAT and its reduced colocalization with insulin/IGF-1 receptorsuggest that neuronal ChAT is regulated by insulin/IGF-1 [267]. De-cline in ChAT and tau functionalities lead to cytoskeletal collapse,loss of neuronal plasticity, synaptic degeneration and decreasedproduction of neurotransmitter acetylcholine. Insulin/IGF, there-fore, are at the center-stage of AD pathology and, hence, AD canbe thought of another form of diabetes [129].

Glaucoma and antidiabetic drugs

Insulin/IGF deficiency, insulin resistance very early in glaucomapathogenesis and subsequent derangements in insulin signalingpathways and downstream processes [137,138]; in addition tothe fact that brain diabetes can be caused by ic-STZ indicate thatglaucomatous and AD neurodegeneration could be prevented or,at least, delayed by intracerebral delivery of insulin, insulin-sensi-tizing drugs like peroxisome proliferator-activated receptor (PPAR)agonists (a group of nuclear receptor isoforms). Through their tran-scription activity, they lead to the activation of insulin responsiveelements and allied signaling pathways. All the three isoforms ofPPAR viz. PPAR-a, PPAR-c and PPAR-d are expressed in adult brainin humans [269]. In an experiment involving ic-STZ treated rats,the effect of low doses of PPAR (PPAR-a: 25 lg/kg, PPAR-d: 2 lg/kg,or PPAR-c: 20 lg/kg) isoforms was evaluated with respect toprevention of neurodegeneration, rescue of insulin/IGF responsivecells [130]. PPAR agonists presumably rescued insulin responsivecells (neurons and oligodendria) [129]. Additionally, there is an in-crease in the insulin receptor expression and insulin binding in re-sponse to PPAR treatment in ic-STZ treated rats [129]. This may bethe raison d’être for further studies involving insulin sensitizers fortreatment of glaucoma. PPAR agonists bring about increasedexpression of ChAT by rescuing ChAT cells. ChAT cells are abundantin retina which includes ganglion cells [276] with the abundance of11.5% in the ganglion cell layer [277]. Additionally, minocycline (anantibiotic) is a neuroprotective agent which has been reported toameliorate neurodegeneration in both AD models [278–280] andRGC loss in glaucoma [281–283].

How to test the hypothesis?

Insulin influences a number of central nervous functions inaddition to maintenance of blood glucose levels. If glaucoma is dia-betes of the brain then insulin and other related antidiabetics

should be able to ameliorate glaucomatous conditions. A studycould be designed where glaucomatous animal models (geneticsand other confounding factors ruled out) are treated with insulindelivered specifically to the brain. The two main problems in sucha study are brain specific delivery of insulin and safety of such aninsulin administration. Delivery of insulin exclusively to brain non-invasively has not been achieved to the best of our knowledge.However, partial brain specific insulin delivery can be executedby either intracerebroventricular administration of insulin oradministration of insulin intranasaly. After administration intran-asaly, insulin enters the CSF from nasal mucosa through bulbusolfactorius and intercellular clefts [284]. The improvement in glau-coma symptoms in subjects as against controls will partially con-firm the hypothesis. However, there will be a number ofconfounding factors which need to be ruled out. The safety of intra-nasal delivery of insulin to otherwise non-diabetic glaucomatousindividuals needs to be worked out before clinical trials areexecuted.

Discussion

In this paper, we discuss the molecular biology that is strikinglysimilar between glaucoma and diabetes. The molecular biology andetiopathogenesis of glaucoma and diabetes share a number ofimportant features. RGCs are the cells that die in glaucoma whileb-cell death stands the hallmark of diabetes. RGCs and pancreaticb-cells are similar in many respects important in the etiopathogen-ic and mechanistic picture of their respective diseases. Literaturesuggests that insulin signaling is important in CNS and RGC growthand differentiation. IR and insulin signaling is important in thedevelopment and maintenance of visual system. Insulin also hasantiapoptotic activities for RGCs. To add to this, insulin regulatesthe IOP in addition to the regulation of blood glucose concentra-tion. The way STZ causes diabetes in experimental models; ic-STZ causes brain diabetes like condition. This means that there issomething called brain diabetes which can be precipitated by thesame moiety used to establish pancreatic diabetes. This is animportant etiological handcuff between CNS neurodegeneration(including glaucoma) and pancreatic diabetes. Pax6 gene is veryimportant in the development and maintenance of eyes across allvertebrates. At the same time, it is now well established thatPax6 gene is similarly important in the development and mainte-nance of b-cells. Since AD has striking similarities with glaucomaas well as diabetes (AD has been proposed to be diabetes type-3),it is natural to think of glaucoma as a type of diabetes. This discus-sion indicates that diabetes and glaucoma may essentially be thesame disease with manifestation at different sites of the body. Thatwill help us in understanding glaucoma from a different perspec-tive which may improve our understanding of its etiological, mech-anistic and therapeutic aspects. We also put emphasis on thepotential use of antidiabetic drugs in treatment of glaucoma.

Conflict of interest

All the authors declare ‘‘No conflict of interest’’.

Acknowledgement

Muneeb Faiq thankfully acknowledges Senior Research Fellow-ship from Indian Council of Medical Research.

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