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Targeting protein misfolding to protect pancreatic beta-cells in type 2 diabetes
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ScienceDirect Targeting protein misfolding to protect pancreatic beta-cells in type 2 diabetes Safia Costes The islet in type 2 diabetes is characterized by beta-cell dysfunction and deficit, increased beta-cell apoptosis and amyloid deposits that derived from islet amyloid polypeptide (IAPP). In species such as humans that are vulnerable to developing type 2 diabetes, IAPP has the propensity to form toxic oligomers that contribute to beta-cell dysfunction and apoptosis, defining type 2 diabetes as a protein misfolding disorder. In this report, we review mechanisms known to contribute to protein misfolding and formation of toxic oligomers, and the deleterious consequences of these oligomers on beta-cell function and survival. Finally, we will consider approaches to prevent protein misfolding and formation of toxic oligomers as potential novel therapeutic targets for type 2 diabetes and other protein misfolding diseases. Address IGF, CNRS, INSERM, University of Montpellier, Montpellier, France Corresponding author: Costes, Safia ([email protected])
Current Opinion in Pharmacology 2018, 43:104–110 This review comes from a themed issue on Endocrine & metabolic diseases Edited by James Bowe and Shanta Persaud
https://doi.org/10.1016/j.coph.2018.08.016 1471-4892/ã 2018 Elsevier Ltd. All rights reserved.
Introduction: type 2 diabetes as a protein misfolding disease The islet in type 2 diabetes (T2D) is characterized by beta-cell deficit and dysfunction, increased beta-cell apoptosis and amyloid deposits composed of islet amyloid polypeptide (IAPP), a protein co-expressed and secreted with insulin by pancreatic beta-cells. IAPP and other amyloidogenic proteins have the propensity to misfold and form membrane-permeant toxic oligomers [1]. Protein misfolding diseases are typically manifest in ordinarily long-lived cells such as neurons and pancreatic beta-cells, initially leading to cellular dysfunction and eventually cell loss. Examples of protein misfolding disorders include Alzheimer’s disease, Motor neuron disease, Parkinson’s disease and T2D. In this Current Opinion in Pharmacology 2018, 43:104–110
review, we will mainly discuss the mechanisms involved in misfolding, aggregation and toxicity of IAPP. IAPP is one of the most aggregate-prone protein of all amyloidogenic proteins, and while its aggregation properties have been extensively investigated in vitro by structural biologists, the potential inhibition of IAPP aggregation as a therapeutic target has largely been neglected by the diabetes field. Therefore strategies that inhibit formation and alleviate toxicity of oligomers of misfolded amyloidogenic proteins represent a promising avenue for novel therapeutic targets in T2D. The two principal client proteins of the ER secretory pathway in pancreatic beta-cells are insulin and IAPP. The burden of protein synthesis, folding and processing of these client proteins is increased with insulin resistance and/or a decreased beta-cell number. The former is a known risk factor for T2D and, given the increased risk of low birth weight with subsequent T2D, it is likely that an innate low beta-cell mass is also a risk factor for T2D [2]. Experimentally, beta-cell dysfunction and death may be induced by increasing the expression of IAPP per beta-cell either by manipulating the gene dosage or insulin sensitivity [3,4]. These experimental models reveal that even in healthy beta-cells, if a critical threshold of expression rate of an aggregate-prone protein is exceeded, toxic oligomers may form and further compromise the capacity of the cell to eliminate misfolded proteins by the degradative pathways introducing a negative cycle. It is therefore logical that formation of toxic protein oligomers in betacells can be avoided indirectly by enhancing insulin sensitivity, or directly, by strategies that suppress misfolding and formation of toxic protein oligomers. The deleterious actions of protein misfolding and toxic oligomers might also be selectively suppressed as a third therapeutic approach.
Islet misfolding-prone proteins Islet amyloid polypeptide
IAPP is a 37–amino acid peptide that is coexpressed and cosecreted with insulin by pancreatic beta-cells. Because of an amyloid-prone sequence (aa 20–29), IAPP has the propensity to form amyloid fibrils in species at risk of spontaneously developing diabetes (e.g. nonhuman primates, cats and humans) [2]. Indeed, more than 90% of individuals with T2D have IAPP deposits in pancreatic islets [5,6]. A missense mutation in the IAPP gene (S20G) that increases IAPP amyloidogenicity [7] is associated with beta-cell dysfunction and early onset T2D [8], www.sciencedirect.com
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further supporting a role of IAPP misfolding in the development of T2D. In contrast, in rodents, the propensity of IAPP to misfold and aggregate is decreased by three proline substitutions in the amyloidogenic sequence, and rodents do not spontaneously develop T2D [9]. However, transgenic expression of human-IAPP (h-IAPP) in rodents has induced diabetes and recapitulated islet pathology that is comparable to that in humans with T2D [2,9,10]. IAPP forms aggregates of different sizes and properties ranging from small oligomers, larger soluble oligomers, protofibers and large amyloid fibrils [2]. The nature of toxic aggregates and the mechanisms of toxicity are still subject of debate [9,11] but it is now generally accepted that the most toxic form of protein aggregates of amyloidogenic proteins, including IAPP, are small oligomers such as hexamer with a cylindrical barrel structure that has been termed a cylindrin [12]. Proinsulin
Proinsulin, the precursor of insulin, is also prone to misfold in beta-cells. Proinsulin misfolding occurs in the ER in consequence of disordered post-translational processing with mispaired disulfide bonds, including both intramolecular and intermolecular disulfide mispairing [13]. The link between proinsulin misfolding and diabetes progression is supported by genetic studies of patients with mutant INS geneinduced Diabetes of Youth (MIDY), where all MIDY alleles encode a misfolded proinsulin [14]. Misfolded proteins known from neurodegenerative disorders
Other amyloid-prone proteins have been found to misfold and aggregate in beta-cells in T2D. Aggregated amyloid beta and hyperphosphorylated Tau, biological markers in Alzheimer’s disease, were detected in the pancreatic islets of humans with T2D [15]. In addition, the levels alpha-synuclein, an amyloidogenic protein that accumulates in brain in Parkinson’s disease, were increased in islets of T2D patients [16]. These findings highlight the closely shared molecular pathology between neurodegenerative disorders and T2D.
Mechanisms involved in protein misfolding in islets in type 2 diabetes Exceeding the threshold of misfoded-prone proteins in beta-cells is an important determinant of aggregation and toxicity. The threshold can be outreached by several processes such as increased production rate, defective chaperone activity in the ER, naturally acquired or transmitted mutations and defective clearance of misfolded/ aggregated proteins. Increased IAPP production
IAPP is assembled in the ER as an 89-amino acid preproIAPP, and then enzymatically processed to its mature 37-amino acid form within the secretory pathway. Processed IAPP is stored with insulin in the secretory vesicles. The ER www.sciencedirect.com
and the secretory vesicles provide a protective microenvironment (pH, zinc) and chaperones to favor appropriate folding and maturation of IAPP ( for review see Ref. [2]), but disturbance of this microenvironment is likely to favor IAPP aggregation. In the context of high insulin demand such as insulin resistance, not only insulin but also IAPP production is increased [3,17,18]. Insulin resistance plays thus a key role in IAPP misfolding and aggregation since it leads to an increased IAPP production that, when reaching a certain threshold, will favor its aggregation. This negative circle involved in IAPP production may be further accentuated by the increased transcriptional expression of IAPP mediated by Thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor induced by high glucose in beta-cells [19]. Altered degradation of IAPP
In long-lived secretory cells, such as beta-cells, that bear a high burden of protein synthesis and folding, the removal of misfolded proteins is also particularly important. The autophagy/lysosomal pathway plays a key role in clearance of misfolded proteins, damaged organelles and oligomerization-prone proteins. Autophagy is crucial for betacell homeostasis under high-fat diet conditions [20,21]. But most importantly, autophagy is a major pathway for IAPP degradation [22], and lack of beta-cell autophagy leads to an accumulation of IAPP toxic oligomers in transgenic mouse beta-cells [22–24]. Evidence of altered autophagy and accumulation of intracellular IAPP toxic oligomers in beta-cells of humans with T2D [1,25], further suggest that defective autophagy/lysosomal system contributes to IAPP aggregation in T2D. In addition to autophagy, IAPP may also be degraded by enzymes such as neprilysin [26,27], matrix metalloproteinase-9 [28] and insulin-degrading enzyme [29]. Whereas their exact contribution in IAPP degradation remains to be clarified, deficiency of these enzymes could contribute to increase levels of IAPP and other amyloidogenic-prone proteins in islets. Increased levels and altered degradation of misfolded proinsulin
Increased proinsulin synthesis upon metabolic demand is certainly one mechanism involved in increased abundance of misfolded proinsulin in islets. Altered proinsulin clearance can also play a major role in proinsulin misfolding. Several studies point to the ER-associated degradation (also known as ubiquitin-proteasome system) and autophagy as mechanisms for misfolded proinsulin removal ( for review see Ref. [13]).
Mechanisms of misfolded protein-induced toxicity in beta-cells Membrane permeability, ER stress and calpain-2 activation
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that may form in membranes and cause non-selective membrane permeability. In beta-cells from individuals with T2D, IAPP toxic oligomers are formed intracellularly and are found in intracellular membranes such as ER and secretory vesicles but also mitochondrial membranes [1], likely due to the close proximity of the ER and mitochondria at the mitochondria-associated membranes (MAM). Disruption of ER membrane in beta-cells may lead to ER stress, which is a characteristic of T2D [30,31]. Indeed, misfolded-prone IAPP induces apoptosis in part through the mechanism of ER stress in a beta-cell line and h-IAPP transgenic rodents [30,32]. Also, given that these toxic oligomers are known to act as non-selective ion channels, they likely contribute to aberrant cytosolic Ca2+ signaling [33]. The existence of this deleterious mechanism in humans was provided by the detection of cleaved alpha-spectrin, a target of calpain-2 in betacells of individuals with T2D [33]. In addition to the intracellular formation of IAPP toxic oligomers, the possibility that IAPP aggregates might propagate from islet cell to islet cell by a ‘prion-like mechanism’ has recently emerged [34], potentially also compromising plasma membranes. Disruption of the pathways of protein clearance
Amyloidogenic proteins are known to disrupt the pathways of protein clearance, further exacerbating accumulation of misfolded proteins. Indeed, increased expression of h-IAPP leads to an alteration of the ERAD/ubiquitinproteasome system as demonstrated by the accumulation of polyubiquitinated proteins [35]. This alteration is mediated by a deficit in UCH-L1, a deubiquitinating enzyme that allows ubiquitinated proteins to access the proteasome. Of interest, accumulation of polyubiquitinated proteins and UCH-L1 deficiency were both observed in the beta-cells of individuals with T2D [35]. Moreover, UCH-L1 downregulation enhances ER stress-induced beta-cell apoptosis [35,36], likely altering the beta-cell mass in T2D. The question arises whether a compromised ubiquitin/ proteasome pathway is compensated for by a sufficient increased flux through the autophagy/lysosomal pathway, to prevent the intracellular accumulation of misfolded proteins? To the contrary, increased expression of h-IAPP also impairs autophagy/lysosome-dependent degradation in beta-cells [37]. As a consequence of the failure in the degradation machinery, h-IAPP overload alters the clearance of damaged mitochondria through mitophagy, inducing oxidative stress and exacerbating ER stress in beta-cells [38]. Inflammation
Misfolded-prone IAPP may also induce islet inflammation and macrophage infiltration, pathological features of pancreatic islets in T2D [39]. Indeed, aggregates of IAPP activates macrophage IL1beta secretion by stimulating Current Opinion in Pharmacology 2018, 43:104–110
both the synthesis and processing of pro-IL1beta. The later may involve activation of the NLRP3 inflammasome, leading to pro-IL1beta cleavage by caspase-1 in bone marrow-derived macrophages [40]. In h-IAPP transgenic mice, aggregation of IAPP stimulates IL1beta secretion from resident islet macrophages, contributing to islet dysfunction [41,42]. In addition, amyloid deposits were found to reduce the levels of the natural IL1 receptor antagonist (IL1-Ra) in human islets [43], potentially exacerbating the toxicity imposed by IL1beta. A recent study also pointed to the receptor for advanced glycation endproducts (RAGE) as a mediator of h-IAPPinduced islet inflammation, via binding of IAPP toxic intermediates and fibrils [44].
Perspectives on targeting protein misfolding in type 2 diabetes Misfolded-prone IAPP exerts its toxicity by diverse overlapping mechanisms that share common signaling pahways, ultimately leading to beta-cell dysfunction and apoptosis (Figure 1). The knowledge on the mechanisms of IAPP-induced toxicity open new venues on how to target protein misfolding to protect islets in T2D. In this last section, recent emerging approaches for protecting beta-cells against misfolding protein-induced toxicity will be reviewed.
Targeting IAPP processing and oligomerization
Only few approaches were identified to specifically interfere with IAPP processing and/or toxic intermediates formation. The glucagon-like peptide 1 (GLP-1) receptor agonist, exenatide, was shown to restore processing of proIAPP in human islets, thereby reducing toxic IAPP oligomer formation and beta-cell toxicity [45], suggesting that a current T2D therapy could improve IAPP processing to protect beta-cells. Supporting the pathological relevance of toxic IAPP oligomers in T2D, autoantibodies which specifically recognize these assemblies were exclusively identified in the serum of T2D patients and were shown to reduce apoptosis induced by these oligomers [46]. A recent study identified RAGE as a new mediator of IAPPinduced toxicity. RAGE selectively binds toxic intermediates, but not non toxic forms of h-IAPP; and inhibition of this interaction in vivo protects h-IAPP transgenic mice from IAPP aggregation, loss of beta-cell function and area, thereby improving glucose tolerance [44]. The transmembrane protein Bri2 was also identified as an endogenous inhibitor of IAPP aggregation and toxicity in human beta-cells, revealing another potential target in T2D [47]. As a novel concept to consider, extracellular vesicles (EV) from healthy human islets, but not from T2D, limit IAPP amyloid formation, suggesting that EV lipids and/or proteins might also play a key role in IAPP aggregation [48]. www.sciencedirect.com
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Figure 1 Insulin resistance, aging, low beta-cell mass
Aging
Increased IAPP synthesis
Decreased IAPP degradation
IAPP misfolding and aggregation
Formation of toxic oligomers
Aberrant Ca2+ release
Inflammation
Alteration of ubiquitin/proteasome system
ER stress
Calpain hyperactivation
Disruption of autophagy/lysosomal pathway
Disruption of mitophagy
Oxidative stress
Beta-cell dysfunction and apoptosis Current Opinion in Pharmacology
Mechanisms favouring the formation of IAPP toxic oligomers and their deleterious consequences for beta-cells. Under conditions of insulin resistance, aging or low beta-cell mass, the burden of insulin and IAPP synthesis is increased in beta-cells. Under conditions of altered protein degradation, as occurs in aging, IAPP is not properly degraded. Both increase in IAPP synthesis and decrease in IAPP degradation favor the accumulation of IAPP, that when reaching a critical threshold, leads to the formation of toxic oligomers in beta-cells. These toxic oligomers activate several stress pathways such as ER stress, calpain activation, inflammation, and disrupt the main pathways of protein clearance, further enhancing IAPP accumulation as a negative circle. Ultimately these stress pathways alter beta-cell function and survival. The red stars indicate promising targets of intervention (described in the literature) to protect beta-cells from IAPP toxicity.
Targeting chaperones
Treatment with molecular chaperone Glucose-regulated protein 78 kDa (GRP78, also known as BiP) and protein disulfide isomerase (PDI), or chemical chaperones taurine-conjugated ursodeoxycholic acid (TUDCA) or 4phenylbutyrate (PBA) alleviates h-IAPP-induced ER stress and ameliorates beta-cell function in vitro [49] and ex vivo [50]. PBA also prevents amyloid formation, inflammation and ameliorates beta-cell viability in hIAPP transgenic mice [51].
content and prevent apoptosis in islets isolated from hIAPP transgenic rats [22]. In addition, administration of an enhancer of autophagy, trehalose, ameliorates the glucose profile in h-IAPP transgenic mice [23]. Stimulation of autophagy with rapamycin in the Akita mouse, model of diabetes characterized by proinsulin misfolding, attenuates beta-cell apoptosis and delays diabetes [52], further supporting the important role of autophagy to protect beta-cells against misfolded proteins.
Targeting misfolded protein degradation
Targeting misfolded proteins-induced ER stress, oxidative stress and inflammation
Since autophagy deficiency could be a risk factor in the pathogenesis of T2D associated with h-IAPP oligomer formation in humans, autophagy activation could potentially prevent beta-cell demise. Indeed, rapamycin, an enhancer of autophagy, decreases IAPP cellular content in human islets [22]. Besides rapamycin, the FDAapproved compounds amiodarone and trifluoperazine, identified to stimulate autophagy, decrease IAPP cellular
Deletion of the ER stress marker CCAAT/enhancerbinding protein homologous protein (CHOP) was shown to delay beta-cell loss and diabetes onset in h-IAPP transgenic mice [53], demonstrating that targeting ER stress could be an interesting approach to protect betacells from misfolding IAPP. However, deletion of CHOP does not fully prevent IAPP-induced diabetes [53], suggesting that other deleterious mechanisms are
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involved in h-IAPP-induced stress. A recent study reveals that suppression of calpain hyperactivation with calpastatin overexpression is remarkably protective against beta-cell dysfunction and loss, thereby preventing diabetes in h-IAPP transgenic mice [54]. Suppression of calpain hyperactivation attenuates ER stress, oxidative stress but also the defect in the autophagy/lysosomal pathway in beta-cells from h-IAPP transgenic mice [54], establishing the suppression of calpain hyperactivation as a potentially efficient disease-modifying strategy in T2D. As IAPP toxicity also includes a pro-inflammatory response in islets, strategies aimed to alleviate inflammation may be of interest to protect beta-cells. Recently, the human serum C4b-binding protein (C4BP) was shown to inhibit IAPP-mediated inflammasome activation and IL1beta production, proposing C4BP as an extracellular chaperone to limit the pro-inflammatory effects of h-IAPP [55]. In addition, use of IL1-Ra also improves glucose tolerance and reduces islet inflammatory response in hIAPP transgenic mice [41].
de la Sante´ et de la Recherche Me´dicale’ (INSERM, Paris, France) and from the ‘Socie´te´ Francophone du Diabe`te’ (SFD, Paris, France). We apologize to the many authors whose work could not be cited owing to space restrictions.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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Targeting IAPP-induced apoptosis
Another way to protect beta-cells from misfolded/aggregated proteins may be to interfere downstream of the converging signaling pathways engaged by protein misfolding: on apoptosis. Indeed, overexpression of apoptosis repressor with caspase recruitment domain (ARC) diminishes IAPP-induced apoptosis via a decrease in cJun N-terminal kinase (JNK) activation, thereby preserving beta-cell integrity in h-IAPP transgenic mice [56]. Deletion of Fas, a transmembrane receptor protein involved in the extrinsic apoptotic pathway, also protects beta-cells from h-IAPP-induced apoptosis [57].
Conclusion T2D is on the rise worldwide. While the current available therapies tend to mitigate hyperglycemia, drug development efforts should now focus on disease-modifying strategies with the goal to target the underlying cause of T2D. Among them targeting protein misfolding appears to be a promising avenue of therapeutic investigation, but requires to be led further at preclinical stage. Additionnaly, given the multiple stress pathways involved in misfolded protein-induced beta-cell demise (Figure 1), there is a need to target proximal cause of betacell dysfunction and apoptosis, or to envision a combination therapy to protect beta-cells in T2D.
Conflict of interest statement Nothing declared.
Acknowledgements A sincere thank you to Peter C. Butler (UCLA, Los Angeles, CA, USA) for his comments and corrections that greatly improved the manuscript. This work was supported by grants to S.C. obtained from the ‘Institut National Current Opinion in Pharmacology 2018, 43:104–110
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46. Bram Y, Frydman-Marom A, Yanai I, Gilead S, Shaltiel-Karyo R, Amdursky N, Gazit E: Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetesassociated specific antibodies. Sci Rep 2014, 4:4267. 47. Oskarsson ME, Hermansson E, Wang Y, Welsh N, Presto J, Johansson J, Westermark GT: BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proc Natl Acad Sci U S A 2018, 115:E2752E2761. In this article, the authors identified the integral membrane protein 2B (Bri2), and in particular its BRICHOS domain as an efficient inhibitor of IAPP fibril formation. BRICHOS pocesses an antiamyloid chaperone activity that appears to be involved in protection of human beta-cells from cellular stress 48. Ribeiro D, Horvath I, Heath N, Hicks R, Forslow A, Wittung Stafshede P: Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation. Proc Natl Acad Sci U S A 2017, 114:11127-11132. This paper points to a novel concept that extracellular vesicles (Evs) released by healthy islet cells may prevent IAPP aggregation, revealing the existence of a potential tissue-specific control mechanism. 49. Cadavez L, Montane J, Alcarraz-Vizan G, Visa M, Vidal-Fabrega L, Servitja JM, Novials A: Chaperones ameliorate beta cell dysfunction associated with human islet amyloid polypeptide overexpression. PLoS One 2014, 9:e101797. 50. Montane J, de Pablo S, Obach M, Cadavez L, Castano C, AlcarrazVizan G, Visa M, Rodriguez-Comas J, Parrizas M, Servitja JM et al.: Protein disulfide isomerase ameliorates beta-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide. Mol Cell Endocrinol 2016, 420:57-65. 51. Montane J, de Pablo S, Castano C, Rodriguez-Comas J, Cadavez L, Obach M, Visa M, Alcarraz-Vizan G, SanchezMartinez M, Nonell-Canals A et al.: Amyloid-induced beta-cell dysfunction and islet inflammation are ameliorated by 4phenylbutyrate (PBA) treatment. FASEB J 2017, 31:5296-5306.
proinsulin mutant in parallel with restoration of wild-type insulin secretion. Diabetes 2017, 66:741-753. 53. Gurlo T, Rivera JF, Butler AE, Cory M, Hoang J, Costes S, Butler PC: CHOP contributes to, but is not the only mediator of, IAPP induced beta-cell apoptosis. Mol Endocrinol 2016, 30:446454. In this article, the authors report that deletion of CHOP, a mediator of ER stress, delays but does not prevent h-IAPP-induced beta-cell loss and diabetes in transgenic mice. This study therefore suggests that additional stress pathways are involved in h-IAPP toxicity 54. Gurlo T, Costes S, Hoang JD, Rivera JF, Butler AE, Butler PC: b-Cell-specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity. JCI Insight 2016, 1:e89590. This study reveals that overexpression of calpastatin is remarkably protective against h-IAPP-induced diabetes in transgenic mice. It points to calpain activation as a proximal event involved in h-IAPP-induced toxicity. 55. Kulak K, Westermark GT, Papac-Milicevic N, Renstrom E, Blom AM, King BC: The human serum protein C4b-binding protein inhibits pancreatic IAPP-induced inflammasome activation. Diabetologia 2017, 60:1522-1533. 56. Templin AT, Samarasekera T, Meier DT, Hogan MF, Mellati M, Crow MT, Kitsis RN, Zraika S, Hull RL, Kahn SE: Apoptosis repressor with caspase recruitment domain ameliorates amyloid-induced beta-cell apoptosis and JNK pathway activation. Diabetes 2017, 66:2636-2645. In this paper, the authors demonstrated that ARC is a physiological regulator of amyloid-prone IAPP toxicity in beta-cells. Increasing its expression inhibits islet amyloid-induced apoptosis without altering amyloid formation. 57. Park YJ, Lee S, Kieffer TJ, Warnock GL, Safikhan N, Speck M, Hao Z, Woo M, Marzban L: Deletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide. Diabetologia 2012, 55:1035-1047.
52. Cunningham CN, He K, Arunagiri A, Paton AW, Paton JC, Arvan P, Tsai B: Chaperone-driven degradation of a misfolded
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ScienceDirect Targeting protein misfolding to protect pancreatic beta-cells in type 2 diabetes Safia Costes The islet in type 2 diabetes is characterized by beta-cell dysfunction and deficit, increased beta-cell apoptosis and amyloid deposits that derived from islet amyloid polypeptide (IAPP). In species such as humans that are vulnerable to developing type 2 diabetes, IAPP has the propensity to form toxic oligomers that contribute to beta-cell dysfunction and apoptosis, defining type 2 diabetes as a protein misfolding disorder. In this report, we review mechanisms known to contribute to protein misfolding and formation of toxic oligomers, and the deleterious consequences of these oligomers on beta-cell function and survival. Finally, we will consider approaches to prevent protein misfolding and formation of toxic oligomers as potential novel therapeutic targets for type 2 diabetes and other protein misfolding diseases. Address IGF, CNRS, INSERM, University of Montpellier, Montpellier, France Corresponding author: Costes, Safia ([email protected])
Current Opinion in Pharmacology 2018, 43:104–110 This review comes from a themed issue on Endocrine & metabolic diseases Edited by James Bowe and Shanta Persaud
https://doi.org/10.1016/j.coph.2018.08.016 1471-4892/ã 2018 Elsevier Ltd. All rights reserved.
Introduction: type 2 diabetes as a protein misfolding disease The islet in type 2 diabetes (T2D) is characterized by beta-cell deficit and dysfunction, increased beta-cell apoptosis and amyloid deposits composed of islet amyloid polypeptide (IAPP), a protein co-expressed and secreted with insulin by pancreatic beta-cells. IAPP and other amyloidogenic proteins have the propensity to misfold and form membrane-permeant toxic oligomers [1]. Protein misfolding diseases are typically manifest in ordinarily long-lived cells such as neurons and pancreatic beta-cells, initially leading to cellular dysfunction and eventually cell loss. Examples of protein misfolding disorders include Alzheimer’s disease, Motor neuron disease, Parkinson’s disease and T2D. In this Current Opinion in Pharmacology 2018, 43:104–110
review, we will mainly discuss the mechanisms involved in misfolding, aggregation and toxicity of IAPP. IAPP is one of the most aggregate-prone protein of all amyloidogenic proteins, and while its aggregation properties have been extensively investigated in vitro by structural biologists, the potential inhibition of IAPP aggregation as a therapeutic target has largely been neglected by the diabetes field. Therefore strategies that inhibit formation and alleviate toxicity of oligomers of misfolded amyloidogenic proteins represent a promising avenue for novel therapeutic targets in T2D. The two principal client proteins of the ER secretory pathway in pancreatic beta-cells are insulin and IAPP. The burden of protein synthesis, folding and processing of these client proteins is increased with insulin resistance and/or a decreased beta-cell number. The former is a known risk factor for T2D and, given the increased risk of low birth weight with subsequent T2D, it is likely that an innate low beta-cell mass is also a risk factor for T2D [2]. Experimentally, beta-cell dysfunction and death may be induced by increasing the expression of IAPP per beta-cell either by manipulating the gene dosage or insulin sensitivity [3,4]. These experimental models reveal that even in healthy beta-cells, if a critical threshold of expression rate of an aggregate-prone protein is exceeded, toxic oligomers may form and further compromise the capacity of the cell to eliminate misfolded proteins by the degradative pathways introducing a negative cycle. It is therefore logical that formation of toxic protein oligomers in betacells can be avoided indirectly by enhancing insulin sensitivity, or directly, by strategies that suppress misfolding and formation of toxic protein oligomers. The deleterious actions of protein misfolding and toxic oligomers might also be selectively suppressed as a third therapeutic approach.
Islet misfolding-prone proteins Islet amyloid polypeptide
IAPP is a 37–amino acid peptide that is coexpressed and cosecreted with insulin by pancreatic beta-cells. Because of an amyloid-prone sequence (aa 20–29), IAPP has the propensity to form amyloid fibrils in species at risk of spontaneously developing diabetes (e.g. nonhuman primates, cats and humans) [2]. Indeed, more than 90% of individuals with T2D have IAPP deposits in pancreatic islets [5,6]. A missense mutation in the IAPP gene (S20G) that increases IAPP amyloidogenicity [7] is associated with beta-cell dysfunction and early onset T2D [8], www.sciencedirect.com
Protein misfolding in pancreatic beta-cells Costes 105
further supporting a role of IAPP misfolding in the development of T2D. In contrast, in rodents, the propensity of IAPP to misfold and aggregate is decreased by three proline substitutions in the amyloidogenic sequence, and rodents do not spontaneously develop T2D [9]. However, transgenic expression of human-IAPP (h-IAPP) in rodents has induced diabetes and recapitulated islet pathology that is comparable to that in humans with T2D [2,9,10]. IAPP forms aggregates of different sizes and properties ranging from small oligomers, larger soluble oligomers, protofibers and large amyloid fibrils [2]. The nature of toxic aggregates and the mechanisms of toxicity are still subject of debate [9,11] but it is now generally accepted that the most toxic form of protein aggregates of amyloidogenic proteins, including IAPP, are small oligomers such as hexamer with a cylindrical barrel structure that has been termed a cylindrin [12]. Proinsulin
Proinsulin, the precursor of insulin, is also prone to misfold in beta-cells. Proinsulin misfolding occurs in the ER in consequence of disordered post-translational processing with mispaired disulfide bonds, including both intramolecular and intermolecular disulfide mispairing [13]. The link between proinsulin misfolding and diabetes progression is supported by genetic studies of patients with mutant INS geneinduced Diabetes of Youth (MIDY), where all MIDY alleles encode a misfolded proinsulin [14]. Misfolded proteins known from neurodegenerative disorders
Other amyloid-prone proteins have been found to misfold and aggregate in beta-cells in T2D. Aggregated amyloid beta and hyperphosphorylated Tau, biological markers in Alzheimer’s disease, were detected in the pancreatic islets of humans with T2D [15]. In addition, the levels alpha-synuclein, an amyloidogenic protein that accumulates in brain in Parkinson’s disease, were increased in islets of T2D patients [16]. These findings highlight the closely shared molecular pathology between neurodegenerative disorders and T2D.
Mechanisms involved in protein misfolding in islets in type 2 diabetes Exceeding the threshold of misfoded-prone proteins in beta-cells is an important determinant of aggregation and toxicity. The threshold can be outreached by several processes such as increased production rate, defective chaperone activity in the ER, naturally acquired or transmitted mutations and defective clearance of misfolded/ aggregated proteins. Increased IAPP production
IAPP is assembled in the ER as an 89-amino acid preproIAPP, and then enzymatically processed to its mature 37-amino acid form within the secretory pathway. Processed IAPP is stored with insulin in the secretory vesicles. The ER www.sciencedirect.com
and the secretory vesicles provide a protective microenvironment (pH, zinc) and chaperones to favor appropriate folding and maturation of IAPP ( for review see Ref. [2]), but disturbance of this microenvironment is likely to favor IAPP aggregation. In the context of high insulin demand such as insulin resistance, not only insulin but also IAPP production is increased [3,17,18]. Insulin resistance plays thus a key role in IAPP misfolding and aggregation since it leads to an increased IAPP production that, when reaching a certain threshold, will favor its aggregation. This negative circle involved in IAPP production may be further accentuated by the increased transcriptional expression of IAPP mediated by Thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor induced by high glucose in beta-cells [19]. Altered degradation of IAPP
In long-lived secretory cells, such as beta-cells, that bear a high burden of protein synthesis and folding, the removal of misfolded proteins is also particularly important. The autophagy/lysosomal pathway plays a key role in clearance of misfolded proteins, damaged organelles and oligomerization-prone proteins. Autophagy is crucial for betacell homeostasis under high-fat diet conditions [20,21]. But most importantly, autophagy is a major pathway for IAPP degradation [22], and lack of beta-cell autophagy leads to an accumulation of IAPP toxic oligomers in transgenic mouse beta-cells [22–24]. Evidence of altered autophagy and accumulation of intracellular IAPP toxic oligomers in beta-cells of humans with T2D [1,25], further suggest that defective autophagy/lysosomal system contributes to IAPP aggregation in T2D. In addition to autophagy, IAPP may also be degraded by enzymes such as neprilysin [26,27], matrix metalloproteinase-9 [28] and insulin-degrading enzyme [29]. Whereas their exact contribution in IAPP degradation remains to be clarified, deficiency of these enzymes could contribute to increase levels of IAPP and other amyloidogenic-prone proteins in islets. Increased levels and altered degradation of misfolded proinsulin
Increased proinsulin synthesis upon metabolic demand is certainly one mechanism involved in increased abundance of misfolded proinsulin in islets. Altered proinsulin clearance can also play a major role in proinsulin misfolding. Several studies point to the ER-associated degradation (also known as ubiquitin-proteasome system) and autophagy as mechanisms for misfolded proinsulin removal ( for review see Ref. [13]).
Mechanisms of misfolded protein-induced toxicity in beta-cells Membrane permeability, ER stress and calpain-2 activation
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that may form in membranes and cause non-selective membrane permeability. In beta-cells from individuals with T2D, IAPP toxic oligomers are formed intracellularly and are found in intracellular membranes such as ER and secretory vesicles but also mitochondrial membranes [1], likely due to the close proximity of the ER and mitochondria at the mitochondria-associated membranes (MAM). Disruption of ER membrane in beta-cells may lead to ER stress, which is a characteristic of T2D [30,31]. Indeed, misfolded-prone IAPP induces apoptosis in part through the mechanism of ER stress in a beta-cell line and h-IAPP transgenic rodents [30,32]. Also, given that these toxic oligomers are known to act as non-selective ion channels, they likely contribute to aberrant cytosolic Ca2+ signaling [33]. The existence of this deleterious mechanism in humans was provided by the detection of cleaved alpha-spectrin, a target of calpain-2 in betacells of individuals with T2D [33]. In addition to the intracellular formation of IAPP toxic oligomers, the possibility that IAPP aggregates might propagate from islet cell to islet cell by a ‘prion-like mechanism’ has recently emerged [34], potentially also compromising plasma membranes. Disruption of the pathways of protein clearance
Amyloidogenic proteins are known to disrupt the pathways of protein clearance, further exacerbating accumulation of misfolded proteins. Indeed, increased expression of h-IAPP leads to an alteration of the ERAD/ubiquitinproteasome system as demonstrated by the accumulation of polyubiquitinated proteins [35]. This alteration is mediated by a deficit in UCH-L1, a deubiquitinating enzyme that allows ubiquitinated proteins to access the proteasome. Of interest, accumulation of polyubiquitinated proteins and UCH-L1 deficiency were both observed in the beta-cells of individuals with T2D [35]. Moreover, UCH-L1 downregulation enhances ER stress-induced beta-cell apoptosis [35,36], likely altering the beta-cell mass in T2D. The question arises whether a compromised ubiquitin/ proteasome pathway is compensated for by a sufficient increased flux through the autophagy/lysosomal pathway, to prevent the intracellular accumulation of misfolded proteins? To the contrary, increased expression of h-IAPP also impairs autophagy/lysosome-dependent degradation in beta-cells [37]. As a consequence of the failure in the degradation machinery, h-IAPP overload alters the clearance of damaged mitochondria through mitophagy, inducing oxidative stress and exacerbating ER stress in beta-cells [38]. Inflammation
Misfolded-prone IAPP may also induce islet inflammation and macrophage infiltration, pathological features of pancreatic islets in T2D [39]. Indeed, aggregates of IAPP activates macrophage IL1beta secretion by stimulating Current Opinion in Pharmacology 2018, 43:104–110
both the synthesis and processing of pro-IL1beta. The later may involve activation of the NLRP3 inflammasome, leading to pro-IL1beta cleavage by caspase-1 in bone marrow-derived macrophages [40]. In h-IAPP transgenic mice, aggregation of IAPP stimulates IL1beta secretion from resident islet macrophages, contributing to islet dysfunction [41,42]. In addition, amyloid deposits were found to reduce the levels of the natural IL1 receptor antagonist (IL1-Ra) in human islets [43], potentially exacerbating the toxicity imposed by IL1beta. A recent study also pointed to the receptor for advanced glycation endproducts (RAGE) as a mediator of h-IAPPinduced islet inflammation, via binding of IAPP toxic intermediates and fibrils [44].
Perspectives on targeting protein misfolding in type 2 diabetes Misfolded-prone IAPP exerts its toxicity by diverse overlapping mechanisms that share common signaling pahways, ultimately leading to beta-cell dysfunction and apoptosis (Figure 1). The knowledge on the mechanisms of IAPP-induced toxicity open new venues on how to target protein misfolding to protect islets in T2D. In this last section, recent emerging approaches for protecting beta-cells against misfolding protein-induced toxicity will be reviewed.
Targeting IAPP processing and oligomerization
Only few approaches were identified to specifically interfere with IAPP processing and/or toxic intermediates formation. The glucagon-like peptide 1 (GLP-1) receptor agonist, exenatide, was shown to restore processing of proIAPP in human islets, thereby reducing toxic IAPP oligomer formation and beta-cell toxicity [45], suggesting that a current T2D therapy could improve IAPP processing to protect beta-cells. Supporting the pathological relevance of toxic IAPP oligomers in T2D, autoantibodies which specifically recognize these assemblies were exclusively identified in the serum of T2D patients and were shown to reduce apoptosis induced by these oligomers [46]. A recent study identified RAGE as a new mediator of IAPPinduced toxicity. RAGE selectively binds toxic intermediates, but not non toxic forms of h-IAPP; and inhibition of this interaction in vivo protects h-IAPP transgenic mice from IAPP aggregation, loss of beta-cell function and area, thereby improving glucose tolerance [44]. The transmembrane protein Bri2 was also identified as an endogenous inhibitor of IAPP aggregation and toxicity in human beta-cells, revealing another potential target in T2D [47]. As a novel concept to consider, extracellular vesicles (EV) from healthy human islets, but not from T2D, limit IAPP amyloid formation, suggesting that EV lipids and/or proteins might also play a key role in IAPP aggregation [48]. www.sciencedirect.com
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Figure 1 Insulin resistance, aging, low beta-cell mass
Aging
Increased IAPP synthesis
Decreased IAPP degradation
IAPP misfolding and aggregation
Formation of toxic oligomers
Aberrant Ca2+ release
Inflammation
Alteration of ubiquitin/proteasome system
ER stress
Calpain hyperactivation
Disruption of autophagy/lysosomal pathway
Disruption of mitophagy
Oxidative stress
Beta-cell dysfunction and apoptosis Current Opinion in Pharmacology
Mechanisms favouring the formation of IAPP toxic oligomers and their deleterious consequences for beta-cells. Under conditions of insulin resistance, aging or low beta-cell mass, the burden of insulin and IAPP synthesis is increased in beta-cells. Under conditions of altered protein degradation, as occurs in aging, IAPP is not properly degraded. Both increase in IAPP synthesis and decrease in IAPP degradation favor the accumulation of IAPP, that when reaching a critical threshold, leads to the formation of toxic oligomers in beta-cells. These toxic oligomers activate several stress pathways such as ER stress, calpain activation, inflammation, and disrupt the main pathways of protein clearance, further enhancing IAPP accumulation as a negative circle. Ultimately these stress pathways alter beta-cell function and survival. The red stars indicate promising targets of intervention (described in the literature) to protect beta-cells from IAPP toxicity.
Targeting chaperones
Treatment with molecular chaperone Glucose-regulated protein 78 kDa (GRP78, also known as BiP) and protein disulfide isomerase (PDI), or chemical chaperones taurine-conjugated ursodeoxycholic acid (TUDCA) or 4phenylbutyrate (PBA) alleviates h-IAPP-induced ER stress and ameliorates beta-cell function in vitro [49] and ex vivo [50]. PBA also prevents amyloid formation, inflammation and ameliorates beta-cell viability in hIAPP transgenic mice [51].
content and prevent apoptosis in islets isolated from hIAPP transgenic rats [22]. In addition, administration of an enhancer of autophagy, trehalose, ameliorates the glucose profile in h-IAPP transgenic mice [23]. Stimulation of autophagy with rapamycin in the Akita mouse, model of diabetes characterized by proinsulin misfolding, attenuates beta-cell apoptosis and delays diabetes [52], further supporting the important role of autophagy to protect beta-cells against misfolded proteins.
Targeting misfolded protein degradation
Targeting misfolded proteins-induced ER stress, oxidative stress and inflammation
Since autophagy deficiency could be a risk factor in the pathogenesis of T2D associated with h-IAPP oligomer formation in humans, autophagy activation could potentially prevent beta-cell demise. Indeed, rapamycin, an enhancer of autophagy, decreases IAPP cellular content in human islets [22]. Besides rapamycin, the FDAapproved compounds amiodarone and trifluoperazine, identified to stimulate autophagy, decrease IAPP cellular
Deletion of the ER stress marker CCAAT/enhancerbinding protein homologous protein (CHOP) was shown to delay beta-cell loss and diabetes onset in h-IAPP transgenic mice [53], demonstrating that targeting ER stress could be an interesting approach to protect betacells from misfolding IAPP. However, deletion of CHOP does not fully prevent IAPP-induced diabetes [53], suggesting that other deleterious mechanisms are
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involved in h-IAPP-induced stress. A recent study reveals that suppression of calpain hyperactivation with calpastatin overexpression is remarkably protective against beta-cell dysfunction and loss, thereby preventing diabetes in h-IAPP transgenic mice [54]. Suppression of calpain hyperactivation attenuates ER stress, oxidative stress but also the defect in the autophagy/lysosomal pathway in beta-cells from h-IAPP transgenic mice [54], establishing the suppression of calpain hyperactivation as a potentially efficient disease-modifying strategy in T2D. As IAPP toxicity also includes a pro-inflammatory response in islets, strategies aimed to alleviate inflammation may be of interest to protect beta-cells. Recently, the human serum C4b-binding protein (C4BP) was shown to inhibit IAPP-mediated inflammasome activation and IL1beta production, proposing C4BP as an extracellular chaperone to limit the pro-inflammatory effects of h-IAPP [55]. In addition, use of IL1-Ra also improves glucose tolerance and reduces islet inflammatory response in hIAPP transgenic mice [41].
de la Sante´ et de la Recherche Me´dicale’ (INSERM, Paris, France) and from the ‘Socie´te´ Francophone du Diabe`te’ (SFD, Paris, France). We apologize to the many authors whose work could not be cited owing to space restrictions.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Gurlo T, Ryazantsev S, Huang CJ, Yeh MW, Reber HA, Hines OJ, O’Brien TD, Glabe CG, Butler PC: Evidence for proteotoxicity in beta cells in type 2 diabetes: toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway. Am J Pathol 2010, 176:861-869.
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Costes S, Langen R, Gurlo T, Matveyenko AV, Butler PC: b-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes 2013, 62:327-335.
3.
Couce M, Kane LA, O’Brien TD, Charlesworth J, Soeller W, McNeish J, Kreutter D, Roche P, Butler PC: Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction. Diabetes 1996, 45:1094-1101.
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Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC: Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci U S A 1996, 93:7283-7288.
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Clark A, Wells CA, Buley ID, Cruickshank JK, Vanhegan RI, Matthews DR, Cooper GJ, Holman RR, Turner RC: Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 1988, 9:151-159.
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Jurgens CA, Toukatly MN, Fligner CL, Udayasankar J, Subramanian SL, Zraika S, Aston-Mourney K, Carr DB, Westermark P, Westermark GT et al.: b-Cell loss and beta-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol 2011, 178:2632-2640.
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Meier DT, Entrup L, Templin AT, Hogan MF, Mellati M, Zraika S, Hull RL, Kahn SE: The S20G substitution in hIAPP is more amyloidogenic and cytotoxic than wild-type hIAPP in mouse islets. Diabetologia 2016, 59:2166-2171.
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9.
Haataja L, Gurlo T, Huang CJ, Butler PC: Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev 2008, 29:303-316.
Targeting IAPP-induced apoptosis
Another way to protect beta-cells from misfolded/aggregated proteins may be to interfere downstream of the converging signaling pathways engaged by protein misfolding: on apoptosis. Indeed, overexpression of apoptosis repressor with caspase recruitment domain (ARC) diminishes IAPP-induced apoptosis via a decrease in cJun N-terminal kinase (JNK) activation, thereby preserving beta-cell integrity in h-IAPP transgenic mice [56]. Deletion of Fas, a transmembrane receptor protein involved in the extrinsic apoptotic pathway, also protects beta-cells from h-IAPP-induced apoptosis [57].
Conclusion T2D is on the rise worldwide. While the current available therapies tend to mitigate hyperglycemia, drug development efforts should now focus on disease-modifying strategies with the goal to target the underlying cause of T2D. Among them targeting protein misfolding appears to be a promising avenue of therapeutic investigation, but requires to be led further at preclinical stage. Additionnaly, given the multiple stress pathways involved in misfolded protein-induced beta-cell demise (Figure 1), there is a need to target proximal cause of betacell dysfunction and apoptosis, or to envision a combination therapy to protect beta-cells in T2D.
Conflict of interest statement Nothing declared.
Acknowledgements A sincere thank you to Peter C. Butler (UCLA, Los Angeles, CA, USA) for his comments and corrections that greatly improved the manuscript. This work was supported by grants to S.C. obtained from the ‘Institut National Current Opinion in Pharmacology 2018, 43:104–110
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proteins by human islet amyloid polypeptide. Am J Physiol Endocrinol Metab 2007, 293:E1656-1662. 33. Huang CJ, Gurlo T, Haataja L, Costes S, Daval M, Ryazantsev S, Wu X, Butler AE, Butler PC: Calcium-activated calpain-2 is a mediator of beta cell dysfunction and apoptosis in type 2 diabetes. J Biol Chem 2010, 285:339-348. 34. Mukherjee A, Morales-Scheihing D, Salvadores N, Moreno Gonzalez I, Gonzalez C, Taylor-Presse K, Mendez N, Shahnawaz M, Gaber AO, Sabek OM et al.: Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism. J Exp Med 2017, 214:2591-2610. In this paper, the authors suggest for the first time that IAPP aggregates could be transmissible through a similar mechanism by which prions are transmitted in prion diseases, propagating protein misfolding and aggregation. This study raises new questions about transmission of the pathology from cell to cell or from islet to islet during the progression of type 2 diabetes. 35. Costes S, Huang CJ, Gurlo T, Daval M, Matveyenko AV, Rizza RA, Butler AE, Butler PC: b-Cell dysfunctional ERAD/ubiquitin/ proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency. Diabetes 2011, 60:227-238. 36. Costes S, Gurlo T, Rivera JF, Butler PC: UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in betacells: evidence of interplay between the ubiquitin/proteasome system and autophagy. Autophagy 2014, 10:1004-1014. 37. Rivera JF, Gurlo T, Daval M, Huang CJ, Matveyenko AV, Butler PC, Costes S: Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic beta-cells: protective role of p62positive cytoplasmic inclusions. Cell Death Differ 2011, 18:415426. 38. Hernandez MG, Aguilar AG, Burillo J, Oca RG, Manca MA, Novials A, Alcarraz-Vizan G, Guillen C, Benito M: Pancreatic beta cells overexpressing hIAPP impaired mitophagy and unbalanced mitochondrial dynamics. Cell Death Dis 2018, 9:481. 39. Donath MY, Boni-Schnetzler M, Ellingsgaard H, Halban PA, Ehses JA: Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol Metab 2010, 21:261-267. 40. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z et al.: Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 2010, 11:897-904. 41. Westwell-Roper CY, Chehroudi CA, Denroche HC, Courtade JA, Ehses JA, Verchere CB: IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice. Diabetologia 2015, 58:575-585. 42. Westwell-Roper CY, Ehses JA, Verchere CB: Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta-cell dysfunction. Diabetes 2014, 63:1698-1711. 43. Hui Q, Asadi A, Park YJ, Kieffer TJ, Ao Z, Warnock GL, Marzban L: Amyloid formation disrupts the balance between interleukin1beta and interleukin-1 receptor antagonist in human islets. Mol Metab 2017, 6:833-844. 44. Abedini A, Cao P, Plesner A, Zhang J, He M, Derk J, Patil SA, Rosario R, Lonier J, Song F et al.: RAGE binds preamyloid IAPP intermediates and mediates pancreatic beta cell proteotoxicity. J Clin Invest 2018, 128:682-698. In this article, the authors identify the receptor for advanced glycation endproducts (RAGE) as a new mediator of IAPP-induced toxicity, via binding of toxic intermediates of h-IAPP.In vivo inhibition of this binding in h-IAPP transgenic mice remarkably preserves beta-cell function and area. 45. Park YJ, Ao Z, Kieffer TJ, Chen H, Safikhan N, Thompson DM, Meloche M, Warnock GL, Marzban L: The glucagon-like peptide1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation. Diabetologia 2013, 56:508-519. Current Opinion in Pharmacology 2018, 43:104–110
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46. Bram Y, Frydman-Marom A, Yanai I, Gilead S, Shaltiel-Karyo R, Amdursky N, Gazit E: Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetesassociated specific antibodies. Sci Rep 2014, 4:4267. 47. Oskarsson ME, Hermansson E, Wang Y, Welsh N, Presto J, Johansson J, Westermark GT: BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. Proc Natl Acad Sci U S A 2018, 115:E2752E2761. In this article, the authors identified the integral membrane protein 2B (Bri2), and in particular its BRICHOS domain as an efficient inhibitor of IAPP fibril formation. BRICHOS pocesses an antiamyloid chaperone activity that appears to be involved in protection of human beta-cells from cellular stress 48. Ribeiro D, Horvath I, Heath N, Hicks R, Forslow A, Wittung Stafshede P: Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation. Proc Natl Acad Sci U S A 2017, 114:11127-11132. This paper points to a novel concept that extracellular vesicles (Evs) released by healthy islet cells may prevent IAPP aggregation, revealing the existence of a potential tissue-specific control mechanism. 49. Cadavez L, Montane J, Alcarraz-Vizan G, Visa M, Vidal-Fabrega L, Servitja JM, Novials A: Chaperones ameliorate beta cell dysfunction associated with human islet amyloid polypeptide overexpression. PLoS One 2014, 9:e101797. 50. Montane J, de Pablo S, Obach M, Cadavez L, Castano C, AlcarrazVizan G, Visa M, Rodriguez-Comas J, Parrizas M, Servitja JM et al.: Protein disulfide isomerase ameliorates beta-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide. Mol Cell Endocrinol 2016, 420:57-65. 51. Montane J, de Pablo S, Castano C, Rodriguez-Comas J, Cadavez L, Obach M, Visa M, Alcarraz-Vizan G, SanchezMartinez M, Nonell-Canals A et al.: Amyloid-induced beta-cell dysfunction and islet inflammation are ameliorated by 4phenylbutyrate (PBA) treatment. FASEB J 2017, 31:5296-5306.
proinsulin mutant in parallel with restoration of wild-type insulin secretion. Diabetes 2017, 66:741-753. 53. Gurlo T, Rivera JF, Butler AE, Cory M, Hoang J, Costes S, Butler PC: CHOP contributes to, but is not the only mediator of, IAPP induced beta-cell apoptosis. Mol Endocrinol 2016, 30:446454. In this article, the authors report that deletion of CHOP, a mediator of ER stress, delays but does not prevent h-IAPP-induced beta-cell loss and diabetes in transgenic mice. This study therefore suggests that additional stress pathways are involved in h-IAPP toxicity 54. Gurlo T, Costes S, Hoang JD, Rivera JF, Butler AE, Butler PC: b-Cell-specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity. JCI Insight 2016, 1:e89590. This study reveals that overexpression of calpastatin is remarkably protective against h-IAPP-induced diabetes in transgenic mice. It points to calpain activation as a proximal event involved in h-IAPP-induced toxicity. 55. Kulak K, Westermark GT, Papac-Milicevic N, Renstrom E, Blom AM, King BC: The human serum protein C4b-binding protein inhibits pancreatic IAPP-induced inflammasome activation. Diabetologia 2017, 60:1522-1533. 56. Templin AT, Samarasekera T, Meier DT, Hogan MF, Mellati M, Crow MT, Kitsis RN, Zraika S, Hull RL, Kahn SE: Apoptosis repressor with caspase recruitment domain ameliorates amyloid-induced beta-cell apoptosis and JNK pathway activation. Diabetes 2017, 66:2636-2645. In this paper, the authors demonstrated that ARC is a physiological regulator of amyloid-prone IAPP toxicity in beta-cells. Increasing its expression inhibits islet amyloid-induced apoptosis without altering amyloid formation. 57. Park YJ, Lee S, Kieffer TJ, Warnock GL, Safikhan N, Speck M, Hao Z, Woo M, Marzban L: Deletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide. Diabetologia 2012, 55:1035-1047.
52. Cunningham CN, He K, Arunagiri A, Paton AW, Paton JC, Arvan P, Tsai B: Chaperone-driven degradation of a misfolded
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