In cellular biology, theWnt signaling pathways are a group ofsignal transduction pathways which begin withproteins thatpass signals into a cell throughcell surface receptors. The name Wnt, pronounced "wint", is aportmanteau created from the names Wingless and Int-1.[1] Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarilyconserved in animals, which means they are similar across animal species from fruit flies to humans.[2][3]
Three Wnt signaling pathways have been characterized: thecanonical Wnt pathway, thenoncanonical planar cell polarity pathway, and thenoncanonical Wnt/calcium pathway. All three pathways are activated by the binding of a Wnt-proteinligand to aFrizzled familyreceptor, which passes the biological signal to theDishevelled protein inside the cell. The canonical Wnt pathway leads to regulation ofgenetranscription, and is thought to be negatively regulated in part by theSPATS1 gene.[4] The noncanonicalplanar cell polarity pathway regulates thecytoskeleton that is responsible for the shape of the cell. The noncanonical Wnt/calcium pathway regulatescalcium inside the cell.
Wnt signaling was first identified for its role incarcinogenesis, then for its function inembryonic development. The embryonic processes it controls includebody axis patterning,cell fate specification,cell proliferation andcell migration. These processes are necessary for proper formation of important tissues including bone, heart and muscle. Its role inembryonic development was discovered when genetic mutations in Wnt pathway proteins produced abnormalfruit flyembryos. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice. Wnt signaling also controlstissue regeneration in adult bone marrow, skin and intestine.[5]
This pathway's clinical importance was demonstrated bymutations that lead to various diseases, includingbreast andprostate cancer,glioblastoma,type II diabetes and others.[6][7] In recent years, researchers reported first successful use of Wnt pathway inhibitors in mouse models of disease.[8]
The discovery of Wnt signaling was influenced by research ononcogenic (cancer-causing)retroviruses. In 1982,Roel Nusse andHarold Varmus infected mice withmouse mammary tumor virus in order to mutate mouse genes to see which mutated genes could cause breast tumors. They identified a new mouse proto-oncogene that they named int1 (integration 1).[3][9]
Int1 is highly conserved across multiple species, including humans andDrosophila. In 1987, researchers discovered that the int1 gene inDrosophila was actually the already known and characterizedDrosophila gene known as Wingless (Wg).[10][3] Since previous research byChristiane Nüsslein-Volhard andEric Wieschaus (which won them theNobel Prize in Physiology or Medicine in 1995) had already established the function of Wg as asegment polarity gene involved in the formation of the body axis duringembryonic development, researchers determined that the mammalian int1 discovered in mice is also involved in embryonic development.[11]
Continued research led to the discovery of further int1-related genes; however, because those genes were not identified in the same manner as int1, the int genenomenclature was inadequate. Thus, the int/Wingless family became the Wnt family and int1 became Wnt1. The name Wnt is aportmanteau of int and Wg and stands for "Wingless-related integration site".[3]
Wnt comprises a diverse family of secretedlipid-modified signalingglycoproteins that are 350–400amino acids in length.[12] The lipid modification of all Wnts ispalmitoleoylation of a single totally conserved cysteine residue.[13] Palmitoleoylation is necessary because it is required for Wnt to bind to its carrier protein Wntless (WLS) so it can be transported to theplasma membrane for secretion[14] and it allows the Wnt protein to bind its receptor Frizzled[15][16] Wnt proteins also undergoglycosylation, which attaches acarbohydrate in order to ensure proper secretion.[17] In Wnt signaling, these proteins act asligands to activate the different Wnt pathways via paracrine and autocrine routes.[2][7]
These proteins are highly conserved across species.[3] They can be found in mice, humans,Xenopus,zebrafish,Drosophila and many others.[18]
| Species | Wnt proteins |
|---|---|
| Homo sapiens | WNT1,WNT2,WNT2B,WNT3,WNT3A,WNT4,WNT5A,WNT5B,WNT6,WNT7A,WNT7B,WNT8A,WNT8B,WNT9A,WNT9B,WNT10A,WNT10B,WNT11,WNT16 |
| Mus musculus (Identical proteins as in H. sapiens) | Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt9A, Wnt9B, Wnt10A, Wnt10B, Wnt11, Wnt16 |
| Xenopus | Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt10A, Wnt10B, Wnt11, Wnt11R |
| Danio rerio | Wnt1, Wnt2, Wnt2B, Wnt3, Wnt3A, Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, Wnt8A, Wnt8B, Wnt10A, Wnt10B, Wnt11, Wnt16 |
| Drosophila | Wg, DWnt2, DWnt3/5, DWnt 4, DWnt6, WntD/DWnt8, DWnt10 |
| Hydra | hywnt1, hywnt5a, hywnt8, hywnt7, hywnt9/10a, hywnt9/10b, hywnt9/10c, hywnt11, hywnt16 |
| C. elegans | mom-2, lin-44, egl-20, cwn-1, cwn-2[19] |
Wnt signaling begins when a Wnt protein binds to the N-terminal extra-cellular cysteine-rich domain of aFrizzled (Fz) family receptor.[20] These receptors span theplasma membrane seven times and constitute a distinct family ofG-protein coupled receptors (GPCRs).[21] However, to facilitate Wnt signaling,co-receptors may be required alongside the interaction between the Wnt protein and Fz receptor. Examples includelipoprotein receptor-related protein (LRP)-5/6,receptor tyrosine kinase (RTK), andROR2.[7] Upon activation of the receptor, a signal is sent to thephosphoproteinDishevelled (Dsh), which is located in thecytoplasm. This signal is transmitted via a direct interaction between Fz and Dsh. Dsh proteins are present in all organisms and they all share the following highly conservedprotein domains: an amino-terminal DIX domain, a centralPDZ domain, and a carboxy-terminalDEP domain. These different domains are important because after Dsh, the Wnt signal can branch off into multiple pathways and each pathway interacts with a different combination of the three domains.[22]
The three best characterized Wnt signaling pathways are the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. As their names suggest, these pathways belong to one of two categories: canonical or noncanonical. The difference between the categories is that a canonical pathway involves the proteinbeta-catenin (β-catenin) while a noncanonical pathway operates independently of it.[20]
The canonical Wnt pathway (or Wnt/β-catenin pathway) is the Wnt pathway that causes an accumulation ofβ-catenin in the cytoplasm and its eventual translocation into thenucleus to act as a transcriptionalcoactivator oftranscription factors that belong to theTCF/LEF family. Without Wnt, β-catenin would not accumulate in the cytoplasm since a destruction complex would normally degrade it. This destruction complex includes the following proteins:Axin,adenomatosis polyposis coli (APC),protein phosphatase 2A (PP2A),glycogen synthase kinase 3 (GSK3) andcasein kinase 1α (CK1α).[23][24] It degrades β-catenin by targeting it forubiquitination, which subsequently sends it to theproteasome to be digested.[20][25] However, as soon as Wnt binds Fz andLRP5/6, the destruction complex function becomes disrupted. This is due to Wnt causing the translocation of the negative Wnt regulator, Axin, and the destruction complex to the plasma membrane.Phosphorylation by other proteins in the destruction complex subsequently binds Axin to the cytoplasmic tail of LRP5/6. Axin becomes de-phosphorylated and its stability and levels decrease. Dsh then becomes activated via phosphorylation and its DIX and PDZ domains inhibit the GSK3 activity of the destruction complex. This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside the TCF/LEF (T-cell factor/lymphoid enhancing factor)[26] transcription factors.[25]β-catenin recruits other transcriptional coactivators, such asBCL9,Pygopus[27] and Parafibromin/Hyrax.[28] The complexity of the transcriptional complex assembled byβ-catenin is beginning to emerge thanks to new high-throughputproteomics studies.[29] However, a unified theory of how β‐catenin drives target gene expression is still missing, and tissue-specific players might assist β‐catenin to define its target genes.[30] The extensivity of theβ-catenin interacting proteins complicates our understanding: β-catenin may be directly phosphorylated at Ser552 by Akt, which causes its disassociation from cell-cell contacts and accumulation in cytosol, thereafter 14-3-3ζ interacts with β-catenin (pSer552) and enhances its nuclear translocation.[31]BCL9 andPygopus have been reported, in fact, to possess severalβ-catenin-independent functions (therefore, likely, Wnt signaling-independent).[32][33][34]
The noncanonical planar cell polarity (PCP) pathway does not involve β-catenin. It does not use LRP-5/6 as its co-receptor and is thought to useNRH1,Ryk,PTK7 orROR2. The PCP pathway is activated via the binding of Wnt to Fz and its co-receptor. The receptor then recruitsDsh, which uses its PDZ and DIX domains to form a complex with Dishevelled-associated activator ofmorphogenesis 1 (DAAM1). Daam1 then activates the smallG-proteinRho through aguanine exchange factor. Rho activatesRho-associated kinase (ROCK), which is one of the major regulators of thecytoskeleton. Dsh also forms a complex withrac1 and mediatesprofilin binding toactin. Rac1 activatesJNK and can also lead toactinpolymerization.Profilin binding to actin can result in restructuring of the cytoskeleton andgastrulation.[7][35]
The noncanonical Wnt/calcium pathway also does not involveβ-catenin. Its role is to help regulate calcium release from theendoplasmic reticulum (ER) in order to control intracellular calcium levels. Like other Wnt pathways, upon ligand binding, the activated Fz receptor directly interacts with Dsh and activates specific Dsh-protein domains. The domains involved in Wnt/calcium signaling are the PDZ and DEP domains.[7] However, unlike other Wnt pathways, the Fz receptor directly interfaces with a trimeric G-protein. This co-stimulation of Dsh and the G-protein can lead to the activation of eitherPLC or cGMP-specificPDE. If PLC is activated, the plasma membrane componentPIP2 is cleaved intoDAG andIP3. When IP3 binds its receptor on the ER, calcium is released. Increased concentrations of calcium and DAG can activateCdc42 throughPKC. Cdc42 is an important regulator of ventral patterning. Increased calcium also activatescalcineurin andCaMKII. Calcineurin induces activation of the transcription factorNFAT, which regulates cell adhesion, migration and tissue separation.[7] CaMKII activates TAK1 andNLK kinase, which can interfere with TCF/β-Catenin signaling in the canonical Wnt pathway.[36] However, if PDE is activated, calcium release from the ER is inhibited. PDE mediates this through the inhibition of PKG, which subsequently causes the inhibition of calcium release.[7]
The binary distinction of canonical and non-canonical Wnt signaling pathways has come under scrutiny and an integrated, convergent Wnt pathway has been proposed.[37] Some evidence for this was found for one Wnt ligand (Wnt5A).[38] Evidence for a convergent Wnt signaling pathway that shows integrated activation of Wnt/Ca2+ and Wnt/β-catenin signaling, for multiple Wnt ligands, was described in mammalian cell lines.[39]
Wnt signaling also regulates a number of other signaling pathways that have not been as extensively elucidated. One such pathway includes the interaction between Wnt andGSK3. During cell growth, Wnt can inhibit GSK3 in order to activatemTOR in the absence of β-catenin. However, Wnt can also serve as a negative regulator of mTOR via activation of thetumor suppressorTSC2, which is upregulated via Dsh and GSK3 interaction.[40] Duringmyogenesis, Wnt usesPA andCREB to activateMyoD andMyf5 genes.[41] Wnt also acts in conjunction withRyk andSrc to allow for regulation of neuron repulsion duringaxonal guidance. Wnt regulatesgastrulation whenCK1 serves as an inhibitor ofRap1-ATPase in order to modulate the cytoskeleton during gastrulation. Further regulation of gastrulation is achieved when Wnt uses ROR2 along with theCDC42 andJNK pathway to regulate the expression ofPAPC. Dsh can also interact with aPKC,Pa3,Par6 andLGl in order to control cell polarity andmicrotubule cytoskeleton development. While these pathways overlap with components associated with PCP and Wnt/Calcium signaling, they are considered distinct pathways because they produce different responses.[7]
In order to ensure proper functioning, Wnt signaling is constantly regulated at several points along its signaling pathways.[42] For example, Wnt proteins arepalmitoylated. The proteinporcupine mediates this process, which means that it helps regulate when the Wnt ligand is secreted by determining when it is fully formed. Secretion is further controlled with proteins such asGPR177 (wntless) andevenness interrupted and complexes such as theretromer complex.[7][25]
Uponsecretion, the ligand can be prevented from reaching its receptor through the binding of proteins such as the stabilizersDally andglypican 3 (GPC3), which inhibit diffusion. In cancer cells, both the heparan sulfate chains[43][44] and the core protein[45][46] of GPC3 are involved in regulating Wnt binding and activation for cell proliferation.[47][48] Wnt recognizes a heparan sulfate structure on GPC3, which contains IdoA2S and GlcNS6S, and the 3-O-sulfation in GlcNS6S3S enhances the binding of Wnt to the heparan sulfate glypican.[49] A cysteine-rich domain at the N-lobe of GPC3 has been identified to form a Wnt-binding hydrophobic groove including phenylalanine-41 that interacts with Wnt.[46][50] Blocking the Wnt binding domain using a nanobody called HN3 can inhibit Wnt activation.[46]
At the Fz receptor, the binding of proteins other than Wnt can antagonize signaling. Specificantagonists includeDickkopf (Dkk),Wnt inhibitory factor 1 (WIF-1),[51][52]secreted Frizzled-related proteins (SFRP),Cerberus,Frzb,Wise,SOST, andNaked cuticle. These constitute inhibitors of Wnt signaling. However, other molecules also act as activators.Norrin andR-Spondin2 activate Wnt signaling in the absence of Wnt ligand.
Interactions between Wnt signaling pathways also regulate Wnt signaling. As previously mentioned, the Wnt/calcium pathway can inhibit TCF/β-catenin, preventing canonical Wnt pathway signaling.[7][25]Prostaglandin E2 (PGE2) is an essential activator of the canonical Wnt signaling pathway. Interaction ofPGE2 with its receptors E2/E4 stabilizes β-catenin through cAMP/PKA mediated phosphorylation. The synthesis of PGE2 is necessary for Wnt signaling mediated processes such as tissue regeneration and control of stem cell population in zebrafish and mouse.[5] Intriguingly, the unstructured regions of several oversizedintrinsically disordered proteins play crucial roles in regulating Wnt signaling.[53]
Wnt signaling plays a critical role in embryonic development. It operates in bothvertebrates andinvertebrates, including humans, frogs, zebrafish,C. elegans,Drosophila and others. It was first found in the segment polarity of Drosophila, where it helps to establish anterior and posterior polarities. It is implicated in otherdevelopmental processes. As its function inDrosophila suggests, it plays a key role inbody axis formation, particularly the formation of theanteroposterior anddorsoventral axes. It is involved in the induction ofcell differentiation to prompt formation of important organs such aslungs andovaries. Wnt further ensures the development of these tissues through proper regulation ofcell proliferation andmigration. Wnt signaling functions can be divided into axis patterning, cell fate specification, cell proliferation and cell migration.[54]
In early embryo development, the formation of the primary body axes is a crucial step in establishing the organism's overall body plan. The axes include the anteroposterior axis, dorsoventral axis, and right-left axis. Wnt signaling is implicated in the formation of the anteroposterior and dorsoventral (DV) axes. Wnt signaling activity in anterior-posterior development can be seen in mammals, fish and frogs. In mammals, theprimitive streak and other surrounding tissues produce the morphogenic compounds Wnts,BMPs,FGFs,Nodal andretinoic acid to establish the posterior region during lategastrula. These proteins form concentration gradients. Areas of highest concentration establish the posterior region while areas of lowest concentration indicate the anterior region. In fish and frogs, β-catenin produced by canonical Wnt signaling causes the formation of organizing centers, which, alongside BMPs, elicit posterior formation. Wnt involvement in DV axis formation can be seen in the activity of the formation of theSpemann organizer, which establishes the dorsal region. Canonical Wnt signaling β-catenin production induces the formation of this organizer via the activation of the genes twin and siamois.[37][54] Similarly, in avian gastrulation, cells of theKoller's sickle express different mesodermal marker genes that allow for the differential movement of cells during the formation of the primitive streak. Wnt signaling activated by FGFs is responsible for this movement.[55][56]
Wnt signaling is also involved in the axis formation of specific body parts and organ systems later in development. In vertebrates,sonic hedgehog (Shh) and Wnt morphogenetic signaling gradients establish the dorsoventral axis of thecentral nervous system duringneural tube axial patterning. High Wnt signaling establishes the dorsal region while high Shh signaling indicates the ventral region.[57] Wnt is involved in the DV formation of the central nervous system through its involvement inaxon guidance. Wnt proteins guide the axons of thespinal cord in an anterior-posterior direction.[58] Wnt is also involved in the formation of the limb DV axis. Specifically, Wnt7a helps produce the dorsal patterning of the developing limb.[37][54]
In theembryonic differentiation waves model of development Wnt plays a critical role as part a signalling complex in competent cells ready to differentiate. Wnt reacts to the activity of the cytoskeleton, stabilizing the initial change created by a passing wave of contraction or expansion and simultaneously signals the nucleus through the use of its different signalling pathways as to which wave the individual cell has participated in. Wnt activity thereby amplifies mechanical signalling that occurs during development.[59][60]
Cell fate specification orcell differentiation is a process where undifferentiated cells can become a more specialized cell type. Wnt signaling induces differentiation ofpluripotent stem cells intomesoderm andendodermprogenitor cells.[61] These progenitor cells further differentiate into cell types such as endothelial, cardiac and vascular smooth muscle lineages.[62] Wnt signaling induces blood formation from stem cells. Specifically, Wnt3 leads to mesoderm committed cells withhematopoietic potential.[63] Wnt1 antagonizes neural differentiation and is a major factor in self-renewal of neural stem cells. This allows for regeneration of nervous system cells, which is further evidence of a role in promoting neural stem cell proliferation.[61] Wnt signaling is involved ingerm cell determination,gut tissue specification,hair follicle development, lung tissue development, trunkneural crest cell differentiation,nephron development, ovary development andsex determination.[54] Wnt signaling also antagonizes heart formation, and Wnt inhibition was shown to be a critical inducer of heart tissue during development,[64][65][66] and small molecule Wnt inhibitors are routinely used to produce cardiomyocytes from pluripotent stem cells.[67][68]
In order to have the mass differentiation of cells needed to form the specified cell tissues of different organisms, proliferation and growth ofembryonic stem cells must take place. This process is mediated through canonical Wnt signaling, which increases nuclear and cytoplasmic β-catenin. Increased β-catenin can initiate transcriptional activation of proteins such ascyclin D1 andc-myc, which control theG1 toS phase transition in thecell cycle. Entry into the S phase causesDNA replication and ultimatelymitosis, which are responsible for cell proliferation.[69] This proliferation increase is directly paired with cell differentiation because as the stem cells proliferate, they also differentiate. This allows for overall growth and development of specific tissue systems during embryonic development. This is apparent in systems such as the circulatory system where Wnt3a leads to proliferation and expansion of hematopoietic stem cells needed for red blood cell formation.[70]
The biochemistry ofcancer stem cells is subtly different from that of other tumor cells. These so-called Wnt-addicted cells hijack and depend on constant stimulation of the Wnt pathway to promote their uncontrolled growth, survival and migration. Incancer, Wnt signaling can become independent of regular stimuli, through mutations in downstream oncogenes and tumor suppressor genes that become permanently activated even though the normal receptor has not received a signal. β-catenin binds to transcription factors such as the proteinTCF4 and in combination the molecules activate the necessary genes. LF3 strongly inhibits this bindingin vitro, in cell lines and reduced tumor growth in mouse models. It prevented replication and reduced their ability to migrate, all without affecting healthy cells. No cancer stem cells remained after treatment. The discovery was the product of "rational drug design", involving AlphaScreens and ELISA technologies.[71]
Cell migration during embryonic development allows for the establishment of body axes, tissue formation, limb induction and several other processes. Wnt signaling helps mediate this process, particularly during convergent extension. Signaling from both the Wnt PCP pathway and canonical Wnt pathway is required for proper convergent extension during gastrulation. Convergent extension is further regulated by the Wnt/calcium pathway, which blocks convergent extension when activated. Wnt signaling also induces cell migration in later stages of development through the control of the migration behavior ofneuroblasts,neural crest cells,myocytes, and tracheal cells.[72]
Wnt signaling is involved in another key migration process known as theepithelial-mesenchymal transition (EMT). This process allows epithelial cells to transform into mesenchymal cells so that they are no longer held in place at thelaminin. It involves cadherin down-regulation so that cells can detach from laminin and migrate. Wnt signaling is an inducer of EMT, particularly in mammary development.[73]
Insulin is apeptide hormone involved inglucosehomeostasis within certain organisms. Specifically, it leads to upregulation ofglucose transporters in the cell membrane in order to increase glucose uptake from thebloodstream. This process is partially mediated by activation of Wnt/β-catenin signaling, which can increase a cell's insulin sensitivity. In particular, Wnt10b is a Wnt protein that increases this sensitivity in skeletal muscle cells.[74]
Since its initial discovery, Wnt signaling has had an association withcancer. When Wnt1 was discovered, it was first identified as a proto-oncogene in amouse model for breast cancer. The fact that Wnt1 is ahomolog of Wg shows that it is involved in embryonic development, which often calls for rapid cell division and migration. Misregulation of these processes can lead to tumor development via excess cell proliferation.[3]
Canonical Wnt pathway activity is involved in the development ofbenign andmalignant breast tumors. The role of Wnt pathway in tumor chemoresistance has been also well documented, as well as its role in the maintenance of a distinct subpopulation of cancer-initiating cells.[75] Its presence is revealed by elevated levels of β-catenin in the nucleus and/or cytoplasm, which can be detected withimmunohistochemical staining andWestern blotting. Increasedβ-catenin expression is correlated with poor prognosis in breast cancer patients. This accumulation may be due to factors such as mutations inβ-catenin, deficiencies in the β-catenin destruction complex, most frequently by mutations in structurally disordered regions ofAPC, overexpression of Wnt ligands, loss of inhibitors and/or decreased activity of regulatory pathways (such as the Wnt/calcium pathway).[53][76][77] Breast tumors canmetastasize due to Wnt involvement in EMT. Research looking at metastasis of basal-like breast cancer to the lungs showed that repression of Wnt/β-catenin signaling can prevent EMT, which can inhibit metastasis.[78]
Wnt signaling has been implicated in the development of other cancers as well as indesmoid fibromatosis.[79] Changes inCTNNB1 expression, which is the gene that encodes β-catenin, can be measured in breast,colorectal,melanoma,prostate,lung, and other cancers. Increased expression of Wnt ligand-proteins such as Wnt1, Wnt2 and Wnt7A were observed in the development ofglioblastoma,oesophageal cancer andovarian cancer respectively. Other proteins that cause multiple cancer types in the absence of proper functioning include ROR1, ROR2,SFRP4, Wnt5A, WIF1 and those of the TCF/LEF family.[80] Wnt signaling is further implicated in the pathogenesis of bone metastasis from breast and prostate cancer with studies suggesting discrete on and off states. Wnt is down-regulated during the dormancy stage by autocrineDKK1 to avoid immune surveillance,[81] as well as during the dissemination stages by intracellularDact1.[82] Meanwhile Wnt is activated during the early outgrowth phase byE-selectin.[83]
The link between PGE2 and Wnt suggests that a chronic inflammation-related increase of PGE2 may lead to activation of the Wnt pathway in different tissues, resulting incarcinogenesis.[5]
Diabetes mellitus type 2 is a common disease that causes reduced insulin secretion and increasedinsulin resistance in the periphery. It results in increased blood glucose levels, orhyperglycemia, which can be fatal if untreated. Since Wnt signaling is involved in insulin sensitivity, malfunctioning of its pathway could be involved. Overexpression of Wnt5b, for instance, may increase susceptibility due to its role inadipogenesis, sinceobesity and type II diabetes have highcomorbidity.[84] Wnt signaling is a strong activator ofmitochondrial biogenesis. This leads to increased production ofreactive oxygen species (ROS) known to cause DNA and cellular damage.[85] This ROS-induced damage is significant because it can cause acute hepatic insulin resistance, or injury-induced insulin resistance.[86] Mutations in Wnt signaling-associated transcription factors, such asTCF7L2, are linked to increased susceptibility.[87]
