REVIEW URRENT C OPINION
A run on the biobank: what have we learned about type 1 diabetes from the nPOD tissue repository? John S. Kaddis a, Alberto Pugliese b, and Mark A. Atkinson c
Purpose of review Since the inaugural year of its biobank in 2007, the Network for Pancreatic Organ Donors with Diabetes program has provided 70 370 human samples to 127 investigators worldwide for projects focused on the pathogenesis of type 1 diabetes (T1D). The purpose of this review was to highlight major advances in our understanding of T1D using works that contain original data from experiments utilizing biospecimens provided by the Network for Pancreatic Organ Donors with Diabetes program. A total of 15 studies, published between 1 June 2013 and 31 December 2014, were selected using various search and filter strategies. Recent findings The type and frequency of B and/or T-cell immune markers in both the endocrine and exocrine compartments vary in T1D. Enterovirus signals have been identified as having new proteins in the extracellular matrix around infiltrated islets. Novel genes within human islet cell types have been shown to play a role in immunity, infiltration, inflammation, disease progression, cell mass and function. Various cytokines and a complement degradation product have also been detected in the blood or surrounding pancreatic ducts/vasculature. Summary These findings, from T1D donors across the disease spectrum, emphasize the notion that pathogenic heterogeneity is a hallmark of the disorder. Keywords atrophy, immunity, infiltration, pancreas, regeneration
INTRODUCTION Extensive efforts have been made in the last decade to expand the availability of human samples in type 1 diabetes (T1D) research to include not only peripheral blood collections [1–4] and isolated islets [5], but also relevant tissue specimens, such as those provided by the Belgium T1D registry and the Persistent Virus Infection in Diabetes Network. The impetus for this may, at least in part, be ascribed to the need to understand the causes of human T1D and its remarkable clinical heterogeneity [6]. This observation may explain to an extent why some preventive clinical trials or those seeking to delay T1D progression have not been effective on the basis of primary endpoint outcomes [7], despite the considerable immunological [8], genetic [9], and environmental [10] data that now exist. Many now consider the use of the human pancreata in T1D research as a gold standard of sorts, justified by new findings that drive our current understanding of T1D etiology [11] and a growing appreciation of the differences between humans and www.co-endocrinology.com
mouse models [12]. As such, a coordinated approach to the distribution of pancreas and related tissue samples, from deceased individuals in different stages of diabetes development, was launched in 2006 with JDRF support, through the introduction of the Network for Pancreatic Organ Donors with Diabetes (nPOD) biobank [13]. Samples from the pancreas, spleen, pancreatic and nonpancreatic lymph nodes, blood (whole blood, serum, and plasma), duodenum, and thymus are made available
a
Department of Information Sciences, City of Hope, Duarte, California, Diabetes Research Institute and Departments of Medicine, Microbiology and Immunology, University of Miami Miller School of Medicine, Miami and cDepartments of Pathology and Pediatrics, University of Florida, Gainesville, Florida, USA b
Correspondence to John S. Kaddis, PhD, City of Hope, Department of Information Sciences, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. Tel: +1 626 256 4673 ext. 83377; fax: +1 626 301 8802; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2015, 22:290–295 DOI:10.1097/MED.0000000000000171 Volume 22 Number 4 August 2015
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New findings in type 1 diabetes using nPOD samples Kaddis et al.
KEY POINTS Immunological irregularities in the exocrine compartment may play a role in the atrophy of T1D pancreata. A variety of immune-related molecules and cellular defects can be found in and around the human islet tissue of donors from different stages of T1D development. Barriers and pathways exist to protect human islets, but can be compromised in T1D pathogenesis. Pathogenic heterogeneity is a hallmark of T1D.
to investigators in whole or as slides from tissue blocks, minced tissue, cells, or nucleic acid extracts. Central characterization of these donors and biospecimens has been described elsewhere[13] and includes clinical and disease histories, autoantibody screening, tissue typing, laboratory testing, and histopathological examination. A collective of human samples from the same donor is crucial; for example, studies have noted differences in the behavior of genes involved in various pathways, depending on where the sample was taken (e.g. peripheral blood vs. pancreas) [14]. In total, 93 nPOD supported studies have been published in areas related to immunology, pathology, etiology, environment, novel biomarkers, b cell physiology, dysfunction, development, differentiation, and regeneration. What do these studies tell us about T1D that we did not know previously? Major findings from earlier studies have been summarized [15]. A review was undertaken, in light of new data, to answer this question using all T1D studies published within the last 18 months that included original experimental data from nPOD biobank donors [16 ,17 ,18,19 ,20,21,22 –27 ,28,29 ,30]. &
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EXOCRINE PANCREAS Perhaps amongst the most promising. . .and yet confusing notions emerging in T1D is the significance of pancreatic size. The pancreas has been shown to be anywhere from 24 to 48% smaller in T1D vs. control (i.e., nondiabetic) individuals. These observations have been borne out in pre [31], recent [32], and long-standing [33] T1D on the basis of volume [34] or weight [31], from both living [35] and deceased [36] individuals, in both children [37] and adults [38]. Data from type 2 diabetes (T2D) donors are mixed [35,38,39]. What could cause such dramatic atrophy of the organ? It is doubtful that loss of endocrine cells
plays a major role, as total b cell mass is estimated at 2% of mean pancreas weight [40]; however, insulitis-mediated lobular atrophy of acinar tissue has been observed [41], although the link between insulin secretion and exocrine atrophy is not well understood [36,42]. Nonetheless, these observations call into prominence pathogenic changes in the exocrine pancreas. Three recent studies are now shedding light on potential immunological abnormalities in the exocrine compartment that expand its role beyond that of digestion [43]. RodriguezCalvo et al. [16 ] found significantly elevated densities of CD8þ T cells, CD4þ T cells, and CD11cþ cells in exocrine pancreatic sections of deceased T1D donors compared with controls. These observations did not correlate with most of the clinical donor characteristics and were not statistically relevant in pre-T1D, i.e., autoantibody positive (AAbþ) diabetes-free, individuals. This raises the possibility that immune infiltrates in the exocrine pancreas may also be a feature of T1D pancreata and may be independent of autoimmunity against the islets. Interestingly, a study by Ye et al. that examined six T1D donors, five of the same used by Rodriguez-Calvo, found that the frequency of maternal microchimeric cells (MMc) was elevated across all T1D pancreas compartments, but particularly enriched in the b cell fraction [17 ]. Although there was no evidence that MMc act as immune effector cells (CD45þ MMc were not found), they may play a role in initiation of islet autoimmunity or early T1D initiation events. A third study by Rowe et al. showed that the complement system may also be important in the exocrine pancreas, as the degradation product c4d was found in the blood vessel endothelium and the extracellular matrix surrounding blood vessels and exocrine ducts [18]. A potential pathogenic role for c4d was never demonstrated, but may interact with or illicit an immune response, though this is highly speculative. These studies, taken together with others on exocrine insufficiency [44,45] and cytokines in the exocrine pancreas [46], all point to the diversity outside of the endocrine compartment in T1D. &
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ENDOCRINE PANCREAS New clues are also emerging from within, proximal, and distal to the human islet that implicate a number of factors in the pathogenesis of T1D.
Immune attack What are the identities of innate and adaptive immune molecules that conspire to disrupt the function of the human islet and destroy the b cell?
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A great deal is known about B, T, and antigen presenting cells that will not be covered here [8]. What is striking is the specificity by which candidate pathogenic markers of islet immunity can now be identified. Arif et al. [19 ] classified two histological patterns of CD20þ B lymphocytes, based on the degree of islet infiltration in early onset T1D. The CD20 high population was termed hyperimmune, had statistically significantly higher numbers of CD4þ and CD8þ T cells per islet section, fewer insulin containing islets, and were obtained from younger donors; autoantibody and inflammatory cytokine differences were also found in the peripheral blood, but from a different cohort of recent T1D donors. Though b-cell function was not measured in this study, the data fit well with the concept of heterogeneity in disease progression, as has been recently demonstrated in a clinical study on the basis of c-peptide levels [47]. Likewise, RodriguezCalvo et al. [16 ] segregated T1D donors on the basis of tissue insulin staining and found differences in the CD8þ T cell islet infiltrate density. Interestingly, although the density of CD8þ T cells was increased in the islets of T1D donors with insulin vs. those without, there appeared to be no notable changes in the density of the two groups when looking at the corresponding exocrine tissue. Using some of those same donor samples, this group also demonstrated the specificity of autoreactive CD8þ T cells in the islet infiltrate [48]. Chen et al. [20] proceeded to examine the role of proinflammatory cytokines in the immune response. b cell specific overexpression of Interleukin-15 (IL-15) and its receptor, IL-15 receptor a (IL-15Ra), was induced in double transgenic mice and resulted in islet infiltration by T lymphocytes, B cells, and macrophages; loss of b cell insulin staining, hyperglycemia, and the development of the insulin autoantibody was also demonstrated. In human pancreatic tissue, IL-15 was statistically significantly elevated in T1D vs. control individuals, but not AAbþ T1D free donors. Although the elevation of IL-15Ra was not statistically significant, serum IL-15Ra was markedly increased, although this was taken from a different cohort of T1D donors. Remarkably, expression of IL-15 and IL-15Ra was previously shown to be induced through infection of human islets with an enterovirus [49], thus suggesting a potential role in disease pathogenesis. Given the prominence of these immune cells in T1D, two new studies have examined immune regulation. Gardner et al. [21] examined a subset of lymph node stromal cells capable of inactivating autoreactive CD4þ T cells that did not require regulatory T cells. Transfer of pancreatic antigen positive &
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extrathymic autoimmune regulator expressing cells (eTACs) from the spleen and lymph nodes of transgenic mice into a diabetic mouse model was shown to prevent CD4þ T-cell-mediated autoimmune diabetes. Although eTACs were also detected in pancreatic and nonpancreatic lymph nodes from nondiabetic individuals, much remains to be understood about their role in human T1D. Nonetheless, this potential player offers promising insights into self-tolerance. Similarly, Cheung et al. [22 ] looked at a T-cell costimulatory molecule capable of regulating the immune response. B7-H4 was moderately expressed in normal human islets, somewhat reduced in AAbþ diabetes-free individuals, and statistically significantly reduced in T1D donors; this pattern was also seen when colocalization with insulin staining was quantified. This study did not, however, include any direct examination of immune cells; nonetheless, these data identify a potential role for B7-H4 in T1D disease pathogenesis. These studies identify two new cell populations that potentially modulate immune response. &
Obstacles to infiltration Are there physical barriers that can shield the islet from domestic and foreign invaders? Studies are now pointing to the role of the extracellular matrix (ECM) as a potential barricade to unwanted cellular immigrants [50]. Bogdani et al. [23 ] showed that there were elevated levels of hyaluronan and hyaluronan-binding proteins, called hyaladherins, within and around islets from donors with less than 10 years of T1D. Hyaluronan was also significantly elevated around CD45þ immune cells of insulitic islets, thus demonstrating a possible involvement in lymphocytic adhesion, migration, and inflammation. These observations fit well with earlier studies showing that components of the basement membrane, a distinct form of the extracellular matrix that provides functional support and a delineating structure to tissues [51,52], could act as infiltration barriers [53,54]. In complementary work by Floyel et al. [24 ], it was demonstrated that cathepsin H levels were depressed in T1D donors. Cathepsins can play a role in antigen processing [55], but also have been shown to be important in leukocytic infiltration at the peri-islet basement membrane [54]. These studies suggest that there is a guarded border around the human islet that must be penetrated. Enzymatic degradation of ECM components has been proposed as a means of immune cell entry [53], but what can explain an enteroviral breach? Krogvold et al. [25 ] recently detected enteroviral RNA, enteroviral capsid protein 1, and hyperexpression of class I HLA from within the islets of recent &
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New findings in type 1 diabetes using nPOD samples Kaddis et al.
onset T1D donors. Likewise, Richardson et al. [56] detected enteroviral capsid protein 1 in cultured human cell lines, isolated human islets, and pancreas sections from T1D donors. Although the mechanism is not yet known, studies are showing some susceptibility of pancreatic endothelial cells to enteroviral infection [57], which would presumably occur before enteroviral penetration through the islet ECM.
Cellular regeneration Can the human islet fight back, or be coached to do so, against damage sustained during a recent or historic attack? New molecules are being identified that may play a role in islet cell proliferation, differentiation, and/or function. Grzesik et al. [26 ] found that 12-lipoxygenase (12-LO) was elevated in AAbþ diabetes-free, T1D, and T2D donor islet tissue, but absent from control individuals. 12-LO was colocalized to cells with low levels of pancreatic polypeptide (PPLOW) and high levels of vimentin, but not found in macrophages, endothelial cells, PPHIGH cells, cells expressing insulin or glucagon, or in long duration T1D donors without detectable b cells. Although it remains to be seen whether these PPLOW vimentin high cells represent de-differentiated b cells in humans, an association has been made in mouse models [58,59], and so further work will be needed to determine if 12-LO can be targeted as a means to preserve b cell loss in diabetes. Zhao et al. [27 ] focused on the modulation of cyclic adenosine monophosphate levels in the b cell, from rat and human islets, to promote replication. Phosphodiesterase inhibitors, in an adenosine signallingdependent manner, were shown to promote, and a2-adrenergic agonists, shown to suppress, b cell replication. In human pancreatic tissue, b cells were found to express catechol-O-methyltransferase, which degrades norepinephrine, a suppressor of cyclic adenosine monophosphate synthesis and b cell replication, via activation of a2-adrenergic receptors. Interestingly, a role for adenosine signaling is now emerging in the pathogenesis of diabetes and cellular regeneration of b cells [60]. In a related study, Yip et al. [28] looked at the role of the adenosine A1 receptor (Adora1) expression in a cells in the context of T1D pathogenesis. Using pancreatic tissue and RNA samples, gene and protein expression of Adora1 was shown to be gradually reduced in a cells of NOD mice and from both AAbþ diabetes-free and T1D donors. Loss or reduced Adora1 expression has been proposed to lead to uncontrolled glucagon secretion. This observation raises the possibility that dysfunction or loss of a cells plays a role in T1D pathogenesis. Next, Piran et al. [29 ] used a &
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pharmacological agent to induce a to d cell transdifferentiation in both mice and human T1D donor samples. This novel mechanism provides a means by which, if partially reversible, b cells can be regenerated. Nonetheless, the potential for human islet transdifferentiation by some pathogenic process has not been well established, and an over-abundance of d and/or somatostatin positive cells will need to be formally demonstrated in T1D. Finally, Kavishwar and Moore [30] developed an antibody that uniquely targeted cholesterol-stabilized sphingomyelin patches on the surface of b cells and demonstrated the utility of it as a functional biomarker. Using a diabetic mouse model and human pancreatic tissue samples from control and T1D donors, various histological staining patterns were used to show the specificity of this antibody. Many other groups are also seeking to identify b cell biomarkers [61], as the monitoring of islet cell health and disease progression are of critical clinical importance [62].
CONCLUSION Pathogenic heterogeneity in the human pancreas of T1D donors has been convincingly demonstrated. The exocrine and endocrine compartments can come under attack by a variety of immune-related molecules. Cellular defects can be found that accompany the disease, from both new onset and long-term T1D individuals. Protective barriers in and around human islets exist, but can be compromised by agents and mechanisms not yet fully understood. Promising pathways have been identified that may preserve b cell loss or induce replication. Lessons in disease pathogenesis can be used in the aid and design of the next generation of therapeutics. Acknowledgements Irina Kusmartseva performed the analysis of distribution numbers cited in the abstract, Catherine S. Kaddis abstracted nPOD case ID numbers from the reviewed studies and reviewed the manuscript, and Patrick Allen Rowe gathered supplemental information for one of the articles reviewed. This review was assembled using research performed with the support of nPOD, a collaborative type 1 diabetes research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/for-partners/npod-partners. The authors regret that they could not reference the recent and excellent work of many colleagues whose contributions included topics covered in this review. Financial support and sponsorship The Network for Pancreatic Organ Donors with Diabetes (nPOD) program was sponsored by the Juvenile Diabetes
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Research Foundation (JDRF; grant numbers 25-2013268, 25-2012-380, and 25-2007-874 to M.A.A., including subcontracts to A.P. and J.S.K.). Conflicts of interest M.A.A. and A.P. serve as executive directors of the nPOD program, and J.S.K. directs its data management core. The reviewed studies all included tissues provided by nPOD. nPOD is a peer-reviewed, but open-access, tissue bank open to investigation, including requests for tissues, by any qualified investigator. The authors declare that there are no other conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Beck RW, Tamborlane WV, Bergenstal RM, et al. The T1D Exchange Clinic Registry. J Clin Endocrinol Metab 2012; 97:4383–4389. 2. Skyler JS, Greenbaum CJ, Lachin JM, et al. Type 1 Diabetes TrialNet: an international collaborative clinical trials network. Ann N Y Acad Sci 2008; 1150:14–24. 3. Rich SS, Akolkar B, Concannon P, et al. Overview of the type I diabetes genetics consortium. Genes Immun 2009; 10:S1–S4. 4. Group TS. The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Ann N Y Acad Sci 2008; 1150:1–13. 5. Kaddis JS, Olack BJ, Sowinski J, et al. Human pancreatic islets and diabetes research. JAMA 2009; 301:1580–1587. 6. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet 2014; 383:69–82. 7. Herold KC, Vignali DAA, Cooke A, Bluestone JA. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 2013; 13:243–256. 8. Roep BO, Tree TIM. Immune modulation in humans: implications for type 1 diabetes mellitus. Nat Rev Endocrinol 2014; 10:229–242. 9. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009; 360:1646–1654. 10. Knip M, Simell O. Environmental triggers of type 1 diabetes. Cold Spring Harb Perspect Med 2012; 2:a007690. 11. Morgan NG, Leete P, Foulis AK, Richardson SJ. Islet inflammation in human type 1 diabetes mellitus. IUBMB Life 2014; 66:723–734. 12. In’t Veld P. Insulitis in human type 1 diabetes: a comparison between patients and animal models. Semin Immunopathol 2014; 36:569–579. 13. Campbell-Thompson M, Wasserfall C, Kaddis J, et al. Network for Pancreatic Organ Donors with Diabetes (nPOD): developing a tissue biobank for type 1 diabetes. Diabetes/Metab Res Rev 2012; 28:608–617. 14. Planas R, Pujol-Borrell R, Vives-Pi M. Global gene expression changes in type 1 diabetes: insights into autoimmune response in the target organ and in the periphery. Immunol Lett 2010; 133:55–61. 15. Pugliese A, Yang M, Kusmarteva I, et al. The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatr Diabetes 2014; 15:1–9. 16. Rodriguez-Calvo T, Ekwall O, Amirian N, et al. Increased immune cell infiltra& tion of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes 2014; 63:3880–3890. An important demonstration of the role of the exocrine pancreas in disease pathogenesis. 17. Ye J, Vives-Pi M, Gillespie KM. Maternal microchimerism: increased in the & insulin positive compartment of type 1 diabetes pancreas but not in infiltrating immune cells or replicating islet cells. PLoS One 2014; 9:e86985. An important study that shows the ability of maternally transferred cells to affect T1D. 18. Rowe P, Wasserfall C, Croker B, et al. Increased complement activation in human type 1 diabetes pancreata. Diabetes Care 2013; 36:3815–3817. 19. Arif S, Leete P, Nguyen V, et al. Blood and islet phenotypes indicate & immunological heterogeneity in type 1 diabetes. Diabetes 2014; 63:3835–3845. A very interesting study that shows two distinct populations of T1D donors that correlated with potentially different disease progression groups. 20. Chen J, Feigenbaum L, Awasthi P, et al. Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Ralpha. Proc Natl Acad Sci USA 2013; 110:13534–13539.
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21. Gardner JM, Metzger TC, McMahon EJ, et al. Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4(þ) T cells. Immunity 2013; 39:560–572. 22. Cheung SS, Ou D, Metzger DL, et al. B7-H4 expression in normal and & diseased human islet beta cells. Pancreas 2014; 43:128–134. A new cosignaling molecule was identified as important in T1D. 23. Bogdani M, Johnson PY, Potter-Perigo S, et al. Hyaluronan and hyaluronan& binding proteins accumulate in both human type 1 diabetic islets and lymphoid tissues and associate with inflammatory cells in insulitis. Diabetes 2014; 63:2727–2743. An altered ECM environment was detected in T1D donors. 24. Floyel T, Brorsson C, Nielsen LB, et al. CTSH regulates beta-cell function and & disease progression in newly diagnosed type 1 diabetes patients. Proc Natl Acad Sci USA 2014; 111:10305–10310. Demonstrated that cathepsin H levels were depressed in T1D donors. 25. Krogvold L, Edwin B, Buanes T, et al. Detection of a low-grade enteroviral & infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes 2015; 64:1682–1687. Detected enterovirus signals in human pancreatic tissue biopsies using a variety of methods. 26. Grzesik WJ, Nadler JL, Machida Y, et al. Expression pattern of 12-lipoxy& genases in human islets with type 1 diabetes and type 2 diabetes. J Clin Endocrinol Metab 2014. Showed two distinct populations of PP cells, with one being associated with diabetes. 27. Zhao Z, Low YS, Armstrong NA, et al. Repurposing cAMP-modulating & medications to promote beta-cell replication. Mol Endocrinol 2014; 28:1682–1697. Modulation of cAMP resulted in increased replicative potential. 28. Yip L, Taylor C, Whiting CC, Fathman CG. Diminished adenosine A1 receptor expression in pancreatic alpha-cells may contribute to the pathology of type 1 diabetes. Diabetes 2013; 62:4208–4219. 29. Piran R, Lee SH, Li CR, et al. Pharmacological induction of pancreatic islet cell & transdifferentiation: relevance to type I diabetes. Cell Death Dis 2014; 5:e1357. Showed alpha to delta transdifferentiation was possible using only 1 pharmacological agent. 30. Kavishwar A, Moore A. Sphingomyelin patches on pancreatic beta-cells are indicative of insulin secretory capacity. J Histochem Cytochem 2013; 61:910–919. 31. Campbell-Thompson M, Wasserfall C, Montgomery EL, et al. PAncreas organ weight in individuals with disease-associated autoantibodies at risk for type 1 diabetes. JAMA 2012; 308:2337–2339. 32. Gaglia JL, Guimaraes AR, Harisinghani M, et al. Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. J Clin Investig 2011; 121:442–445. 33. Williams AJK, Chau W, Callaway MP, Dayan CM. Magnetic resonance imaging: a reliable method for measuring pancreatic volume in type 1 diabetes. Diabetic Med 2007; 24:35–40. 34. Williams AJK, Thrower SL, Sequeiros IM, et al. Pancreatic volume is reduced in adult patients with recently diagnosed type 1 diabetes. J Clin Endocrinol Metab 2012; 97:E2109–E2113. 35. Fonseca V, Berger LA, Beckett AG, Dandona P. Size of pancreas in diabetes mellitus: a study based on ultrasound. Br Med J 1985; 291:1240–1241. 36. Lo¨hr M, Klo¨ppel G. Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia 1987; 30:757–762. 37. Altobelli E, Blasetti A, Verrotti A, et al. Size of pancreas in children and adolescents with type I (insulin-dependent) diabetes. J Clin Ultrasound 1998; 26:391–395. 38. Goda K, Sasaki E, Nagata K, et al. Pancreatic volume in type 1 und type 2 diabetes mellitus. Acta Diabetol 2001; 38:145–149. 39. Gilbeau JP, Poncelet V, Libon E, et al. The density, contour, and thickness of the pancreas in diabetics: CT findings in 57 patients. Am J Roentgenol 1992; 159:527–531. 40. In’t Veld P, Marichal M. Microscopic anatomy of the human islet of langerhans. In: Islam MS, editor. The islets of Langerhans. Springer Netherlands: Berlin; 2010. pp. 1–19. 41. Foulis AK, Stewart JA. The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue. Diabetologia 1984; 26:456–461. 42. Czako L, Hegyi P, Rakonczay Z Jr, et al. Interactions between the endocrine and exocrine pancreas and their clinical relevance. Pancreatology 2009; 9:351–359. 43. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut 2005; 54:1–28. 44. Philippe MF, Benabadji S, Barbot-Trystram L, et al. Pancreatic volume and endocrine and exocrine functions in patients with diabetes. Pancreas 2011; 40:359–363. 45. Larger E, Philippe MF, Barbot-Trystram L, et al. Pancreatic exocrine function in patients with diabetes. 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New findings in type 1 diabetes using nPOD samples Kaddis et al. 47. Oram RA, McDonald TJ, Shields BM, et al. Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors. Diabetes Care 2015; 38:323–328. 48. Coppieters KT, Dotta F, Amirian N, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 2012; 209:51–60. 49. Ylipaasto P, Kutlu B, Rasilainen S, et al. Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets. Diabetologia 2005; 48:1510–1522. 50. Bogdani M, Korpos E, Simeonovic C, et al. Extracellular matrix components in the pathogenesis of type 1 diabetes. Curr Diab Rep 2014; 14: 1–11. 51. Kragl M, Lammert E. Basement membrane in pancreatic islet function. In: Islam MS, editor. The islets of Langerhans. Springer Netherlands: Dordrecht; 2010. pp. 217–234. 52. LeBleu VS, MacDonald B, Kalluri R. Structure and function of basement membranes. Exp Biol Med 2007; 232:1121–1129. 53. Simeonovic CJ, Ziolkowski A, Wu Z, et al. Heparanase and autoimmune diabetes. Frontiers Immunol 2013; 4:471. 54. Korpos E´, Kadri N, Kappelhoff R, et al. The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. Diabetes 2013; 62:531–542.
55. Kim A, Sadegh-Nasseri S. Determinants of immunodominance for CD4 T cells. Curr Opin Immunol 2015; 34:9–15. 56. Richardson SJ, Leete P, Dhayal S, et al. Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas. Diabetologia 2014; 57:392–401. 57. Zanone MM, Favaro E, Ferioli E, et al. Human pancreatic islet endothelial cells express coxsackievirus and adenovirus receptor and are activated by coxsackie B virus infection. FASEB J 2007; 21:3308–3317. 58. Talchai C, Xuan S, Lin HV, et al. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 2012; 150:1223–1234. 59. El-Gohary Y, Tulachan S, Wiersch J, et al. A smad signaling network regulates islet cell proliferation. Diabetes 2014; 63:224–236. 60. Antonioli L, Blandizzi C, Csoka B, et al. Adenosine signalling in diabetes mellitus[mdash]pathophysiology and therapeutic considerations. Nat Rev Endocrinol 2015; 11:228–241. 61. Lindskog C, Korsgren O, Ponten F, et al. Novel pancreatic beta cell-specific proteins: antibody-based proteomics for identification of new biomarker candidates. J Proteomics 2012; 75:2611–2620. 62. Lebastchi J, Herold KC. Immunologic and Metabolic Biomarkers of (-Cell Destruction in the Diagnosis of Type 1 Diabetes. Cold Spring Harb Perspect Med 2012; 2:a007708.
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A run on the biobank: what have we learned about type 1 diabetes from the nPOD tissue repository? John S. Kaddis a, Alberto Pugliese b, and Mark A. Atkinson c
Purpose of review Since the inaugural year of its biobank in 2007, the Network for Pancreatic Organ Donors with Diabetes program has provided 70 370 human samples to 127 investigators worldwide for projects focused on the pathogenesis of type 1 diabetes (T1D). The purpose of this review was to highlight major advances in our understanding of T1D using works that contain original data from experiments utilizing biospecimens provided by the Network for Pancreatic Organ Donors with Diabetes program. A total of 15 studies, published between 1 June 2013 and 31 December 2014, were selected using various search and filter strategies. Recent findings The type and frequency of B and/or T-cell immune markers in both the endocrine and exocrine compartments vary in T1D. Enterovirus signals have been identified as having new proteins in the extracellular matrix around infiltrated islets. Novel genes within human islet cell types have been shown to play a role in immunity, infiltration, inflammation, disease progression, cell mass and function. Various cytokines and a complement degradation product have also been detected in the blood or surrounding pancreatic ducts/vasculature. Summary These findings, from T1D donors across the disease spectrum, emphasize the notion that pathogenic heterogeneity is a hallmark of the disorder. Keywords atrophy, immunity, infiltration, pancreas, regeneration
INTRODUCTION Extensive efforts have been made in the last decade to expand the availability of human samples in type 1 diabetes (T1D) research to include not only peripheral blood collections [1–4] and isolated islets [5], but also relevant tissue specimens, such as those provided by the Belgium T1D registry and the Persistent Virus Infection in Diabetes Network. The impetus for this may, at least in part, be ascribed to the need to understand the causes of human T1D and its remarkable clinical heterogeneity [6]. This observation may explain to an extent why some preventive clinical trials or those seeking to delay T1D progression have not been effective on the basis of primary endpoint outcomes [7], despite the considerable immunological [8], genetic [9], and environmental [10] data that now exist. Many now consider the use of the human pancreata in T1D research as a gold standard of sorts, justified by new findings that drive our current understanding of T1D etiology [11] and a growing appreciation of the differences between humans and www.co-endocrinology.com
mouse models [12]. As such, a coordinated approach to the distribution of pancreas and related tissue samples, from deceased individuals in different stages of diabetes development, was launched in 2006 with JDRF support, through the introduction of the Network for Pancreatic Organ Donors with Diabetes (nPOD) biobank [13]. Samples from the pancreas, spleen, pancreatic and nonpancreatic lymph nodes, blood (whole blood, serum, and plasma), duodenum, and thymus are made available
a
Department of Information Sciences, City of Hope, Duarte, California, Diabetes Research Institute and Departments of Medicine, Microbiology and Immunology, University of Miami Miller School of Medicine, Miami and cDepartments of Pathology and Pediatrics, University of Florida, Gainesville, Florida, USA b
Correspondence to John S. Kaddis, PhD, City of Hope, Department of Information Sciences, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. Tel: +1 626 256 4673 ext. 83377; fax: +1 626 301 8802; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2015, 22:290–295 DOI:10.1097/MED.0000000000000171 Volume 22 Number 4 August 2015
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New findings in type 1 diabetes using nPOD samples Kaddis et al.
KEY POINTS Immunological irregularities in the exocrine compartment may play a role in the atrophy of T1D pancreata. A variety of immune-related molecules and cellular defects can be found in and around the human islet tissue of donors from different stages of T1D development. Barriers and pathways exist to protect human islets, but can be compromised in T1D pathogenesis. Pathogenic heterogeneity is a hallmark of T1D.
to investigators in whole or as slides from tissue blocks, minced tissue, cells, or nucleic acid extracts. Central characterization of these donors and biospecimens has been described elsewhere[13] and includes clinical and disease histories, autoantibody screening, tissue typing, laboratory testing, and histopathological examination. A collective of human samples from the same donor is crucial; for example, studies have noted differences in the behavior of genes involved in various pathways, depending on where the sample was taken (e.g. peripheral blood vs. pancreas) [14]. In total, 93 nPOD supported studies have been published in areas related to immunology, pathology, etiology, environment, novel biomarkers, b cell physiology, dysfunction, development, differentiation, and regeneration. What do these studies tell us about T1D that we did not know previously? Major findings from earlier studies have been summarized [15]. A review was undertaken, in light of new data, to answer this question using all T1D studies published within the last 18 months that included original experimental data from nPOD biobank donors [16 ,17 ,18,19 ,20,21,22 –27 ,28,29 ,30]. &
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EXOCRINE PANCREAS Perhaps amongst the most promising. . .and yet confusing notions emerging in T1D is the significance of pancreatic size. The pancreas has been shown to be anywhere from 24 to 48% smaller in T1D vs. control (i.e., nondiabetic) individuals. These observations have been borne out in pre [31], recent [32], and long-standing [33] T1D on the basis of volume [34] or weight [31], from both living [35] and deceased [36] individuals, in both children [37] and adults [38]. Data from type 2 diabetes (T2D) donors are mixed [35,38,39]. What could cause such dramatic atrophy of the organ? It is doubtful that loss of endocrine cells
plays a major role, as total b cell mass is estimated at 2% of mean pancreas weight [40]; however, insulitis-mediated lobular atrophy of acinar tissue has been observed [41], although the link between insulin secretion and exocrine atrophy is not well understood [36,42]. Nonetheless, these observations call into prominence pathogenic changes in the exocrine pancreas. Three recent studies are now shedding light on potential immunological abnormalities in the exocrine compartment that expand its role beyond that of digestion [43]. RodriguezCalvo et al. [16 ] found significantly elevated densities of CD8þ T cells, CD4þ T cells, and CD11cþ cells in exocrine pancreatic sections of deceased T1D donors compared with controls. These observations did not correlate with most of the clinical donor characteristics and were not statistically relevant in pre-T1D, i.e., autoantibody positive (AAbþ) diabetes-free, individuals. This raises the possibility that immune infiltrates in the exocrine pancreas may also be a feature of T1D pancreata and may be independent of autoimmunity against the islets. Interestingly, a study by Ye et al. that examined six T1D donors, five of the same used by Rodriguez-Calvo, found that the frequency of maternal microchimeric cells (MMc) was elevated across all T1D pancreas compartments, but particularly enriched in the b cell fraction [17 ]. Although there was no evidence that MMc act as immune effector cells (CD45þ MMc were not found), they may play a role in initiation of islet autoimmunity or early T1D initiation events. A third study by Rowe et al. showed that the complement system may also be important in the exocrine pancreas, as the degradation product c4d was found in the blood vessel endothelium and the extracellular matrix surrounding blood vessels and exocrine ducts [18]. A potential pathogenic role for c4d was never demonstrated, but may interact with or illicit an immune response, though this is highly speculative. These studies, taken together with others on exocrine insufficiency [44,45] and cytokines in the exocrine pancreas [46], all point to the diversity outside of the endocrine compartment in T1D. &
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ENDOCRINE PANCREAS New clues are also emerging from within, proximal, and distal to the human islet that implicate a number of factors in the pathogenesis of T1D.
Immune attack What are the identities of innate and adaptive immune molecules that conspire to disrupt the function of the human islet and destroy the b cell?
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A great deal is known about B, T, and antigen presenting cells that will not be covered here [8]. What is striking is the specificity by which candidate pathogenic markers of islet immunity can now be identified. Arif et al. [19 ] classified two histological patterns of CD20þ B lymphocytes, based on the degree of islet infiltration in early onset T1D. The CD20 high population was termed hyperimmune, had statistically significantly higher numbers of CD4þ and CD8þ T cells per islet section, fewer insulin containing islets, and were obtained from younger donors; autoantibody and inflammatory cytokine differences were also found in the peripheral blood, but from a different cohort of recent T1D donors. Though b-cell function was not measured in this study, the data fit well with the concept of heterogeneity in disease progression, as has been recently demonstrated in a clinical study on the basis of c-peptide levels [47]. Likewise, RodriguezCalvo et al. [16 ] segregated T1D donors on the basis of tissue insulin staining and found differences in the CD8þ T cell islet infiltrate density. Interestingly, although the density of CD8þ T cells was increased in the islets of T1D donors with insulin vs. those without, there appeared to be no notable changes in the density of the two groups when looking at the corresponding exocrine tissue. Using some of those same donor samples, this group also demonstrated the specificity of autoreactive CD8þ T cells in the islet infiltrate [48]. Chen et al. [20] proceeded to examine the role of proinflammatory cytokines in the immune response. b cell specific overexpression of Interleukin-15 (IL-15) and its receptor, IL-15 receptor a (IL-15Ra), was induced in double transgenic mice and resulted in islet infiltration by T lymphocytes, B cells, and macrophages; loss of b cell insulin staining, hyperglycemia, and the development of the insulin autoantibody was also demonstrated. In human pancreatic tissue, IL-15 was statistically significantly elevated in T1D vs. control individuals, but not AAbþ T1D free donors. Although the elevation of IL-15Ra was not statistically significant, serum IL-15Ra was markedly increased, although this was taken from a different cohort of T1D donors. Remarkably, expression of IL-15 and IL-15Ra was previously shown to be induced through infection of human islets with an enterovirus [49], thus suggesting a potential role in disease pathogenesis. Given the prominence of these immune cells in T1D, two new studies have examined immune regulation. Gardner et al. [21] examined a subset of lymph node stromal cells capable of inactivating autoreactive CD4þ T cells that did not require regulatory T cells. Transfer of pancreatic antigen positive &
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extrathymic autoimmune regulator expressing cells (eTACs) from the spleen and lymph nodes of transgenic mice into a diabetic mouse model was shown to prevent CD4þ T-cell-mediated autoimmune diabetes. Although eTACs were also detected in pancreatic and nonpancreatic lymph nodes from nondiabetic individuals, much remains to be understood about their role in human T1D. Nonetheless, this potential player offers promising insights into self-tolerance. Similarly, Cheung et al. [22 ] looked at a T-cell costimulatory molecule capable of regulating the immune response. B7-H4 was moderately expressed in normal human islets, somewhat reduced in AAbþ diabetes-free individuals, and statistically significantly reduced in T1D donors; this pattern was also seen when colocalization with insulin staining was quantified. This study did not, however, include any direct examination of immune cells; nonetheless, these data identify a potential role for B7-H4 in T1D disease pathogenesis. These studies identify two new cell populations that potentially modulate immune response. &
Obstacles to infiltration Are there physical barriers that can shield the islet from domestic and foreign invaders? Studies are now pointing to the role of the extracellular matrix (ECM) as a potential barricade to unwanted cellular immigrants [50]. Bogdani et al. [23 ] showed that there were elevated levels of hyaluronan and hyaluronan-binding proteins, called hyaladherins, within and around islets from donors with less than 10 years of T1D. Hyaluronan was also significantly elevated around CD45þ immune cells of insulitic islets, thus demonstrating a possible involvement in lymphocytic adhesion, migration, and inflammation. These observations fit well with earlier studies showing that components of the basement membrane, a distinct form of the extracellular matrix that provides functional support and a delineating structure to tissues [51,52], could act as infiltration barriers [53,54]. In complementary work by Floyel et al. [24 ], it was demonstrated that cathepsin H levels were depressed in T1D donors. Cathepsins can play a role in antigen processing [55], but also have been shown to be important in leukocytic infiltration at the peri-islet basement membrane [54]. These studies suggest that there is a guarded border around the human islet that must be penetrated. Enzymatic degradation of ECM components has been proposed as a means of immune cell entry [53], but what can explain an enteroviral breach? Krogvold et al. [25 ] recently detected enteroviral RNA, enteroviral capsid protein 1, and hyperexpression of class I HLA from within the islets of recent &
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New findings in type 1 diabetes using nPOD samples Kaddis et al.
onset T1D donors. Likewise, Richardson et al. [56] detected enteroviral capsid protein 1 in cultured human cell lines, isolated human islets, and pancreas sections from T1D donors. Although the mechanism is not yet known, studies are showing some susceptibility of pancreatic endothelial cells to enteroviral infection [57], which would presumably occur before enteroviral penetration through the islet ECM.
Cellular regeneration Can the human islet fight back, or be coached to do so, against damage sustained during a recent or historic attack? New molecules are being identified that may play a role in islet cell proliferation, differentiation, and/or function. Grzesik et al. [26 ] found that 12-lipoxygenase (12-LO) was elevated in AAbþ diabetes-free, T1D, and T2D donor islet tissue, but absent from control individuals. 12-LO was colocalized to cells with low levels of pancreatic polypeptide (PPLOW) and high levels of vimentin, but not found in macrophages, endothelial cells, PPHIGH cells, cells expressing insulin or glucagon, or in long duration T1D donors without detectable b cells. Although it remains to be seen whether these PPLOW vimentin high cells represent de-differentiated b cells in humans, an association has been made in mouse models [58,59], and so further work will be needed to determine if 12-LO can be targeted as a means to preserve b cell loss in diabetes. Zhao et al. [27 ] focused on the modulation of cyclic adenosine monophosphate levels in the b cell, from rat and human islets, to promote replication. Phosphodiesterase inhibitors, in an adenosine signallingdependent manner, were shown to promote, and a2-adrenergic agonists, shown to suppress, b cell replication. In human pancreatic tissue, b cells were found to express catechol-O-methyltransferase, which degrades norepinephrine, a suppressor of cyclic adenosine monophosphate synthesis and b cell replication, via activation of a2-adrenergic receptors. Interestingly, a role for adenosine signaling is now emerging in the pathogenesis of diabetes and cellular regeneration of b cells [60]. In a related study, Yip et al. [28] looked at the role of the adenosine A1 receptor (Adora1) expression in a cells in the context of T1D pathogenesis. Using pancreatic tissue and RNA samples, gene and protein expression of Adora1 was shown to be gradually reduced in a cells of NOD mice and from both AAbþ diabetes-free and T1D donors. Loss or reduced Adora1 expression has been proposed to lead to uncontrolled glucagon secretion. This observation raises the possibility that dysfunction or loss of a cells plays a role in T1D pathogenesis. Next, Piran et al. [29 ] used a &
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pharmacological agent to induce a to d cell transdifferentiation in both mice and human T1D donor samples. This novel mechanism provides a means by which, if partially reversible, b cells can be regenerated. Nonetheless, the potential for human islet transdifferentiation by some pathogenic process has not been well established, and an over-abundance of d and/or somatostatin positive cells will need to be formally demonstrated in T1D. Finally, Kavishwar and Moore [30] developed an antibody that uniquely targeted cholesterol-stabilized sphingomyelin patches on the surface of b cells and demonstrated the utility of it as a functional biomarker. Using a diabetic mouse model and human pancreatic tissue samples from control and T1D donors, various histological staining patterns were used to show the specificity of this antibody. Many other groups are also seeking to identify b cell biomarkers [61], as the monitoring of islet cell health and disease progression are of critical clinical importance [62].
CONCLUSION Pathogenic heterogeneity in the human pancreas of T1D donors has been convincingly demonstrated. The exocrine and endocrine compartments can come under attack by a variety of immune-related molecules. Cellular defects can be found that accompany the disease, from both new onset and long-term T1D individuals. Protective barriers in and around human islets exist, but can be compromised by agents and mechanisms not yet fully understood. Promising pathways have been identified that may preserve b cell loss or induce replication. Lessons in disease pathogenesis can be used in the aid and design of the next generation of therapeutics. Acknowledgements Irina Kusmartseva performed the analysis of distribution numbers cited in the abstract, Catherine S. Kaddis abstracted nPOD case ID numbers from the reviewed studies and reviewed the manuscript, and Patrick Allen Rowe gathered supplemental information for one of the articles reviewed. This review was assembled using research performed with the support of nPOD, a collaborative type 1 diabetes research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/for-partners/npod-partners. The authors regret that they could not reference the recent and excellent work of many colleagues whose contributions included topics covered in this review. Financial support and sponsorship The Network for Pancreatic Organ Donors with Diabetes (nPOD) program was sponsored by the Juvenile Diabetes
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Research Foundation (JDRF; grant numbers 25-2013268, 25-2012-380, and 25-2007-874 to M.A.A., including subcontracts to A.P. and J.S.K.). Conflicts of interest M.A.A. and A.P. serve as executive directors of the nPOD program, and J.S.K. directs its data management core. The reviewed studies all included tissues provided by nPOD. nPOD is a peer-reviewed, but open-access, tissue bank open to investigation, including requests for tissues, by any qualified investigator. The authors declare that there are no other conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Beck RW, Tamborlane WV, Bergenstal RM, et al. The T1D Exchange Clinic Registry. J Clin Endocrinol Metab 2012; 97:4383–4389. 2. Skyler JS, Greenbaum CJ, Lachin JM, et al. Type 1 Diabetes TrialNet: an international collaborative clinical trials network. Ann N Y Acad Sci 2008; 1150:14–24. 3. Rich SS, Akolkar B, Concannon P, et al. Overview of the type I diabetes genetics consortium. Genes Immun 2009; 10:S1–S4. 4. Group TS. The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Ann N Y Acad Sci 2008; 1150:1–13. 5. Kaddis JS, Olack BJ, Sowinski J, et al. Human pancreatic islets and diabetes research. JAMA 2009; 301:1580–1587. 6. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet 2014; 383:69–82. 7. Herold KC, Vignali DAA, Cooke A, Bluestone JA. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 2013; 13:243–256. 8. Roep BO, Tree TIM. Immune modulation in humans: implications for type 1 diabetes mellitus. Nat Rev Endocrinol 2014; 10:229–242. 9. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009; 360:1646–1654. 10. Knip M, Simell O. Environmental triggers of type 1 diabetes. Cold Spring Harb Perspect Med 2012; 2:a007690. 11. Morgan NG, Leete P, Foulis AK, Richardson SJ. Islet inflammation in human type 1 diabetes mellitus. IUBMB Life 2014; 66:723–734. 12. In’t Veld P. Insulitis in human type 1 diabetes: a comparison between patients and animal models. Semin Immunopathol 2014; 36:569–579. 13. Campbell-Thompson M, Wasserfall C, Kaddis J, et al. Network for Pancreatic Organ Donors with Diabetes (nPOD): developing a tissue biobank for type 1 diabetes. Diabetes/Metab Res Rev 2012; 28:608–617. 14. Planas R, Pujol-Borrell R, Vives-Pi M. Global gene expression changes in type 1 diabetes: insights into autoimmune response in the target organ and in the periphery. Immunol Lett 2010; 133:55–61. 15. Pugliese A, Yang M, Kusmarteva I, et al. The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatr Diabetes 2014; 15:1–9. 16. Rodriguez-Calvo T, Ekwall O, Amirian N, et al. Increased immune cell infiltra& tion of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes 2014; 63:3880–3890. An important demonstration of the role of the exocrine pancreas in disease pathogenesis. 17. Ye J, Vives-Pi M, Gillespie KM. Maternal microchimerism: increased in the & insulin positive compartment of type 1 diabetes pancreas but not in infiltrating immune cells or replicating islet cells. PLoS One 2014; 9:e86985. An important study that shows the ability of maternally transferred cells to affect T1D. 18. Rowe P, Wasserfall C, Croker B, et al. Increased complement activation in human type 1 diabetes pancreata. Diabetes Care 2013; 36:3815–3817. 19. Arif S, Leete P, Nguyen V, et al. Blood and islet phenotypes indicate & immunological heterogeneity in type 1 diabetes. Diabetes 2014; 63:3835–3845. A very interesting study that shows two distinct populations of T1D donors that correlated with potentially different disease progression groups. 20. Chen J, Feigenbaum L, Awasthi P, et al. Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Ralpha. Proc Natl Acad Sci USA 2013; 110:13534–13539.
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Krogvold L, Edwin B, Buanes T, et al. Detection of a low-grade enteroviral & infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes 2015; 64:1682–1687. Detected enterovirus signals in human pancreatic tissue biopsies using a variety of methods. 26. Grzesik WJ, Nadler JL, Machida Y, et al. Expression pattern of 12-lipoxy& genases in human islets with type 1 diabetes and type 2 diabetes. J Clin Endocrinol Metab 2014. Showed two distinct populations of PP cells, with one being associated with diabetes. 27. Zhao Z, Low YS, Armstrong NA, et al. Repurposing cAMP-modulating & medications to promote beta-cell replication. Mol Endocrinol 2014; 28:1682–1697. Modulation of cAMP resulted in increased replicative potential. 28. Yip L, Taylor C, Whiting CC, Fathman CG. Diminished adenosine A1 receptor expression in pancreatic alpha-cells may contribute to the pathology of type 1 diabetes. Diabetes 2013; 62:4208–4219. 29. 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