Alterations in Beta Cell Identity in Type 1 and Type 2 Diabetes
Purpose of Review
To discuss the current understanding of “β cell identity” and factors underlying altered identity of pancreatic β cells in diabetes, especially in humans.
Altered identity of β cells due to dedifferentiation and/or transdifferentiation has been proposed as a mechanism of loss of β cells in diabetes. In dedifferentiation, β cells do not undergo apoptosis; rather, they lose their identity and function. Dedifferentiation is well characterized by the decrease in expression of key β cell markers such as genes encoding major transcription factors, e.g., MafA, NeuroD1, Nkx6.1, and Foxo1, and an increase in atypical or “disallowed” genes for β cells such as lactate dehydrogenase, monocarboxylate transporter MCT1, or progenitor cell genes (Neurog3, Pax4, or Sox9). Moreover, altered identity of mature β cells in diabetes also involves transdifferentiation of β cells into other islet hormone producing cells. For example, overexpression of α cell specific transcription factor Arx or ablation of Pdx1 resulted in an increase of α cell numbers and a decrease in β cell numbers in rodents. The frequency of α-β double-positive cells was also prominent in human subjects with T2D. These altered identities of β cells likely serve as a compensatory response to enhance function/expand cell numbers and may also camouflage/protect cells from ongoing stress. However, it is equally likely that this may be a reflection of new cell formation as a frank regenerative response to ongoing tissue injury. Physiologically, all these responses are complementary.
In diabetes, (1) endocrine identity recapitulates the less mature/less-differentiated fetal/neonatal cell type, possibly representing an adaptive mechanism; (2) residual β cells may be altered in their subtype proportions or other molecular features; (3) in humans, “altered identity” is a preferable term to dedifferentiation as their cellular fate (differentiated cells losing identity or progenitors becoming more differentiated) is unclear as yet.
Keywordsβ Cell Dedifferentiation Transdifferentiation Type 1 diabetes Type 2 diabetes Pancreas
Both classic forms of diabetes mellitus are characterized by the inability of pancreatic β cells to meet the demand of insulin secretion due to either a nearly complete loss (type 1 diabetes [T1D]) or a deficit of functional β cells in the setting of peripheral insulin resistance (type 2 diabetes [T2D]). The deficit in β cell mass (~ 90% in long-standing T1D , ~ 65% in long-standing T2D ) has long been proposed to be a consequence of β cell death. However, this principle has recently been challenged by studies mainly performed in animal models, with the suggestion that, rather than β cell death, the deficit in β cell mass is due to β cell dedifferentiation or transdifferentiation [3••, 4].
Functional β cell mass refers to adequate numbers of appropriately functioning β cells; a deficit in either number or function/identity can therefore lead to a diminution of “functional β cell mass” [5, 6]. Altered β cell identity, rather than β cell apoptosis, in the setting of chronic hyperglycemia was first reported in Sprague-Dawley rats . Subsequently, others reported a loss of mature β cell identity accompanied by dedifferentiation in the diabetic state [3, 8••, 9••, 10••]. Upon dedifferentiation, β cells regress to a less mature or even precursor-like state, leading to a loss of key components responsible for optimal performance, most notably in terms of insulin secretion. However, there is ambiguity in defining “dedifferentiation,” as altered β cell identity can also be explained as “β cell degranulation,” where insulin granules are depleted due to metabolic stresses [9••, 11]. Emerging evidence also suggests that phenotypic alterations of β cells can promote transdifferentiation to other pancreatic endocrine cell types (mainly α cells and δ cells), a phenomenon that has been observed in both diabetic animals and human subjects [4, 9••, 10••, 12, 13]. Regardless of how β cell dedifferentiation is defined, its importance in diabetes research stems from the direct implications for β cell function, turnover, and regeneration. In this review, we will discuss the characteristics of human pancreatic β cells, the concept of “β cell identity-crisis,” and the factors underlying the altered identity of β cells in diabetes.
Fetal Development of Human Endocrine Pancreas: the Transcriptional Roadmap of Human β Cell Differentiation
The organogenesis of human pancreas involves regulation at the level of gene transcription to furnish mature pancreatic cells. Originating from a pool of apparently identical progenitor cells, the mature pancreas comprises endocrine, exocrine, and ductal cell types that collectively synthesize and secrete the hormones and enzymes required for nutritional homeostasis . The endocrine compartment (Islets of Langerhans) further differentiates into five cell types (α, β, δ, PP, ϵ) that have obvious similarities in expression of common genes and ability to secrete hormones . In comparison to rodent pancreas, the knowledge of gene expression profiles during early human pancreas development is limited. However, several studies suggest the involvement of conserved genetic regulatory networks and transcription factors [14, 15, 16].
The pancreas originates from two primary diverticula of the primitive gut at 26-day post-conception (dpc; ~ 6-week gestation) . After gastrulation, the earliest event leading to pancreas development is exclusion of sonic hedgehog (SHH) signaling from the dorsal endoderm where it is in contact with the notochord , which allows expression of the key transcription factor pancreatic and duodenal homeobox factor 1 (PDX1) [18, 19]. The gut epithelium evaginates into the surrounding mesoderm-derived mesenchymal tissue from the dorsal and ventral pancreatic buds, which at Carnegie stage 13 (CS13, ~ 6.5-week gestation) in humans is marked by the transcription factors SRY (sex determining region Y)-box 9 (SOX9), PDX1, and GATA binding protein 4 (GATA4) [14, 15]. The buds expand, branch, and fuse, and, by CS15 (~ 7.5-week gestation), gut rotation brings the buds together on either side of the portal vein [14, 20], the ventral portion giving rise to the lower head of the pancreas and the dorsal portion giving rise to the body, tail, and upper head portion of pancreas. Between CS15 and CS19, the central duct-like structure (“trunks”) contains a pool of multipotent progenitor cells that express more SOX9/NKX6.1 but less GATA4, whereas the more peripheral clustered cells (“tips”) are triple-positive (SOX9/GATA4/NKX6.1) . By CS19 (~ 9-week gestation), the pancreatic progenitor cells become more differentiated, with segregation of acinar and endocrine precursors.
Endocrine pancreas formation requires the transient activation of Neurogenin3 (NEUROG3), as NEUROG3+ cells generate the five endocrine cell subtypes. NEUROG3 expression increases rapidly during late embryogenesis and is closely linked to the appearance of fetal insulin (CS20–21) (~ 9–10-week gestation) . Fetal β cells demonstrate a unique transcription factor signature (for example, loss of SOX9) with subsequent detection of nuclear NKX2.2, NKX6.1, PDX1, FOXA2, ISL1, and insulin . Co-expression of several hormones is notable amongst endocrine cells in the developing human pancreas. Polyhormonal cells are typically present either as single cells or in small clusters in the acinar parenchyma, suggesting that these cells represent newly forming islets [21, 22, 23].
Formation of secretory granules with an increase in insulin content occurs in β cells at ~ 10–14-week gestation , a concept supported by the expression of more differentiated β cell markers (PC1/3, IAPP) in virtually all β cells at 12–14 weeks of development [15, 25]. Data from previous studies suggests that large islets of mixed types (akin to adult islets) are formed only after 21-week gestation  and are accompanied by increased numbers of β cells, produced by β cell proliferation, thereby increasing the β/α and β/δ cell ratios . After birth, the human pancreatic β cell proliferation index is highest during the first 2 years, gradually decreasing until, after the age of 3–5 years, replication of existing β cells is negligible in most cases .
Postnatal Distribution and Identity of Mature β Cells
To study β cell dedifferentiation, it is important to understand how pancreatic β cells are organized in the complex cytoarchitecture of an islet (reviewed in ). Detailed quantitative studies have revealed that human pancreatic islets consist of ~ 60% insulin-producing β cells and 30% glucagon-producing α cells, the remaining 10% consisting of δ cells (somatostatin), γ cells (PP) and ϵ cells (ghrelin) [29, 30, 31] randomly distributed throughout the islet [32, 33]. Exactly how this architecture affects cell-to-cell interactions leading to regulated and concerted hormonal secretion remains to be determined; however, a modified core-mantle structure of the human islet has been proposed where, in small human islets (40–60 μm in diameter), β cells are in the core position surrounded by α cells in the mantle position, with a more complex intermingled arrangement found in larger islets . Similar studies also reported that β cells are contiguously arranged either into smaller clusters surrounded by non-β cells or along invaginations of the exterior surface of the islet [35, 36]. An alternative arrangement of β cells in human islets has also been described with β cells intermingling freely (without clustering) with other endocrine cells . The unique topological arrangements of β cells (especially β-β cell contacts) in human islets has measurable consequences in terms of islet function [37, 38]. In addition to intra-islet connections, individual human β cells and larger aggregates of cells (in association with the mesenchymal protein vimentin) can form within the ductal epithelium and migrate during gestation, suggesting that β cells are capable of remodeling . In humans, β cells harbor connexin-36 (Cx36) gap junctions that create channel coupling between β cells, and which correlate with insulin secretion, suggesting the dependence of functional identity of human β cells on gap junction coupling .
A β cell is classically defined by its function: synthesizing, sorting, and secreting insulin. However, the hallmark of a mature β cell involves a more complex cellular identity with finely tuned coupling to the prevailing glucose level. Ultrastructurally, β cells are marked by the presence of electron dense-core insulin granules with a clear peripheral mantle (size, ~ 300 nm and number, ~ 10,000 per β cell). The presence or absence of fully processed proinsulin molecules in these dense-core granules depends on the maturity of the β cell [41, 42, 43]. As previously noted, the fate of islet endocrine cells is decided by the ON/OFF switch and concerted activities of key transcription factors during development; mature β cells are also distinct in terms of expression of certain genes and transcription factors. Single-cell analyses that have revealed the transcriptional program of human pancreatic endocrine cells depicted genes (for example, PAX4, PDX1, MAFA, MAFB, DLK1, SIX2/3, ID1, IAPP, UCN3, OLIG1) that are highly or exclusively expressed in human β cells ( [44••] and reviewed in ). Expression of certain genes has revealed notable cell-type and species differences. For example, in humans, MAFB expression has been detected in adult α and β cells [44••, 46••], whereas MafB and MafA expressions become restricted to α and β cells, respectively, in the mouse [47, 48]. In addition, SIX2 and SIX3, two recently identified transcription factors reported in human β cells [46••, 49, 50••], have been shown to enhance insulin content and secretion in immature β cells, suggesting their crucial role in human β cell maturation .
Heterogeneity of β cells has recently received increasing attention, as emerging evidence (mainly from rodent studies) suggests that β cells pass through different maturation states in adult islets [52•, 53••]. During development, distinct subpopulations of β cells have been observed [54, 55•]. In adult human islets, marker analysis coupled with single-cell RNA sequencing (scRNA-seq) revealed two surface markers, ST8SIA1 and CD9, that discriminated four distinct human β cell subpopulations (β1–4), each expressing common β cell markers but displaying differences in insulin secretion rates and gene expression profiles [56••]. It is however uncertain whether in adults these subsets are proportionally stable or whether they can interconvert. A population of β cells has been shown to develop during the progression of T1D in non-obese diabetic (NOD) mice which have characteristics of immature proliferation, reduced insulin granule content, and reduced functional capacity with relative resistance to cell death . In T2D, three distinct subpopulations of β cells were identified, shifting in number with age or BMI [58••], suggesting a possible correlation of β cell heterogeneity and dysfunction in diabetes and aging, due partly to altered phenotypes of human β cells in islets. Apart from the molecular heterogeneity, functional heterogeneity within the β cell population also exists which might offer advantages for the ability of β cells to respond robustly to different physiological conditions. For example, by utilizing a set of novel techniques, insulin secretion responses were found to be orchestrated by two populations of β cells in rodents: the hub cells, which function as pacemakers to control the insulin secretion dynamics, and the follower cells that respond to hub cell signaling cues [59••]. More detailed molecular characterizations of subgroups of β cells are required to determine their biological significance, function, ontogeny, and involvement in disease. The main challenge in this regard is the high donor-to-donor variation identified by single-cell studies [46, 52•, 58••]; however, a recently developed single-cell heterogeneity analysis algorithm (RePACT) might help to resolve these issues and to identify β cell specific disease genes [60•].
β Cell turnover is a critical factor for maintaining functional β cell mass in health. Postnatal β cell mass is dynamic and maintained by the balance of cell birth/renewal (by replication of pre-existing differentiated β cells and by neogenesis or differentiation from progenitor cells) and cell death (usually by apoptosis) [27, 61]. Though adult β cells are largely in a quiescent state (evidenced by a very low frequency of proliferation) , β cell mass demonstrates a degree of plasticity, expanding in response to metabolic demands associated with the insulin resistance of pregnancy  and obesity . The establishment of β cell mass during childhood likely plays a crucial role in successful or failed adaptation to increased β cell metabolic workload demand, a key factor for the onset of T2D [63, 64].
Dedifferentiation of Pancreatic β Cells—Altered Identity
Transdifferentiation of Pancreatic β Cells—Altered Identity Continued
Transdifferentiation refers to the process, whereby a mature endocrine cell transforms into another cell type without reverting backwards towards a more primitive progenitor-like state. Only a few examples of transdifferentiation of human cells have been reported to date, and those require forced expression of transcription factors or miRNAs for the conversion of human fibroblasts into neurons, hematopoetic progenitors, or brown fat cells  or of human liver cells into β cells . Even though mature human β cells are considered as “non-switching” in terms of their hormone production, spontaneous conversion of human β cells into glucagon producing α cells has been reported during islet cell reaggregration in vitro . These results are consistent with other reports where, in both T1D and T2D, β cells transdifferentiated into α cells in humans [10, 72] or into δ cells in rats  and mice .
Various mouse models of diabetes have also revealed that a percentage of existing β cells can adopt the mature identity of glucagon-producing α cells under hyperglycemic conditions [3, 12]. While it has not been firmly established, it appears that loss of β cell mass/function is the driving force towards this seemingly counterintuitive change. Insulin may be required to maintain β cell identity, a reduction in insulin release in the local islet environment potentially having an impact upon the identity of endocrine cells. Inappropriately increased α cell function and consequent hyperglucagonemia has long been recognized as a contributor to hyperglycemia in diabetic patients, via stimulation of hepatic glucose production ; therefore, stringent control over β to α-transdifferentiation (by minimizing β cell plasticity) might be helpful in preventing the progression of diabetes. Transdifferentiation of pancreatic α to β cells has also been reported in a mouse model where overexpression of PAX4  or deletion of Arx [76, 77] in α cells resulted in loss of α cells through transdifferentiation to β cells. These data suggest potential new avenues for restoration of β cell mass in diabetes, not only by providing alternative sources of β cells, but also by reducing α cell mass, and thus potentially restoring the insulin-glucagon balance, which is perturbed in diabetes [78, 79]. Apart from α to β transdifferentiation, the regenerative process of endocrine pancreas also includes transdifferentiation of pancreatic ductal cells to endocrine β cells in rodents. By utilizing a genetic lineage-tracing approach (a mouse model used to trace the ductal specific human carbonic anhydrase-II (CA-II)-positive cells in which the CA-II promoter is conjugated with the Cre-Loxp system) showed that CA-II-positive cells merged with β cells in the adult pancreas and ligated duct, suggesting a potential transdifferentiation of ductal cells to generate new islets . Moreover, the existence of rat and human pancreatic progenitor cells in the duct and their differentiation potentials has also been reported [81, 82]. The regenerative capacity of endocrine pancreas from ductal sources is also supported by our recent report showing an increased proliferation of the pancreatic duct gland (PDG) compartment in humans with T1D [83•].
Altered Identity of Pancreatic β Cells in Humans with T1D and T2D—Are β Cells Hidden or Camouflaged?
Circumstantial evidence of an altered β cell phenotype in clinical diabetes was revealed by the observation of co-localization of insulin with glucagon or vimentin (a mesenchymal marker) in a distinct subset of cells in human pancreas sections from subjects with T2D [84, 85]. Likewise, a significant increase in bihormonal insulin+/glucagon+ and NKX6.1+/amyloid+/glucagon+ cells was found upon analysis of mature β cell markers (e.g., MAFA, FOXO1, NKX6.1) in T2D human and nonhuman primate pancreas ; a greater frequency of Nkx6.1+ glucagon+ insulin− cells was found in islet amyloid-positive regions.
An altered phenotype in islets from subjects with T2D was observed with an ~ 3-fold increase in the number of pancreatic islet cells (insulin−/synaptophysin+/ALDH1A3+ cells) that no longer expressed any of the major pancreatic hormones, yet retained endocrine features, thus implying dedifferentiation of β cells in T2D . Moreover, in T2D, human β cells were found to express gastrin (an embryonic pancreas marker), a phenotype that resolved upon glucose normalization, suggesting reversible β cell reprogramming in T2D [55, 86].
We first reported an increased frequency of endocrine cells that express no known islet hormones but do express the endocrine marker chromograninA (chromogranin A-positive hormone-negative [CPHN cells]) in humans with T1D [87••, 88] and T2D [8••, 89••] (Fig. 1b). CPHN cells occurred within established islets but were most frequently found as scattered cells, either singly or in small clusters in the exocrine pancreas. Despite the lack of expression of any endocrine hormones in CPHN cells in T1D, the presence of β cell–specific transcription factors (for example, NKX6.1 and NKX2.2) found mainly in the scattered or single cells suggested that those cells represent a pool of “hidden β cells” [87••]. While it is potentially plausible that these cells were formerly β cells that have undergone dedifferentiation or transdifferentiation, this is less likely given their distribution and increased frequency as scattered cells in exocrine pancreas in the setting of diabetes; it is therefore possible that they represent partially differentiated, newly formed endocrine cells. In support of this, we further reported abundant scattered CPHN cells in the exocrine compartment of human fetal and neonatal pancreas [8••], the highest frequency being in fetal pancreas compared to neonatal , potentially suggesting that the increased frequency of CPHN cells containing the β cell–specific transcription factors NKX6.1 or NKX2.2 in both T1D and T2D may be indicative of attempted β cell regeneration.
This conclusion is consistent with previous findings where pancreatic β cell regeneration in humans with recent-onset T1D was reported [91, 92]. Moreover, persistent residual β cell function in patients with recent-onset or, in some cases, very long-standing T1D has been reported [93, 94, 95], with measurable levels of C-peptide detected in serum of donors with long-standing T1D [96•, 97••]. To date, it has not been possible to trace the β cell lineage in those individuals to determine if their residual β cells had (1) dedifferentiated, evaded immune attack, and then redifferentiated again (perhaps once insulin therapy had been initiated) ; (2) transdifferentiated from other endocrine cells; or (3) are newly generated β cells in a transition state towards maturity. Whether due to loss of identity or attempted regeneration, the altered endocrine phenotype in T1D/T2D likely reflects an adaptive response (either to camouflage the endocrine cells from potential destruction or to expand/regenerate).
One approach to establish the sequence of events leading to defective β cell function and mass in diabetes is to evaluate the pancreas from prediabetic individuals. However, there was no change in the frequency of CPHN cells in pancreas from nondiabetic autoantibody-positive brain dead organ donors (unpublished data); however, most of these donors had a single autoantibody to a T1D autoantigen, which is associated with low risk of progression to clinical diabetes in living subjects, and they did not have evidence of insulitis or beta cell destruction. Perhaps it would be more instructive to study pancreas from double or triple antibody-positive prediabetic donors to elucidate the pattern of endocrine cell identity alterations in incipient diabetes; these donors are, however, quite rare [99••].
Whilst the evidence reported in the literature from numerous sources supports the concept that dedifferentiation or transdifferentiation of β cells does occur in T1D and T2D, one critical question is to what extent? We found ~ 3% increase in Ins+/Glu+ bihormonal cells in the pancreas in subjects with T2D with a further increase to about 16% in incretin-treated individuals with T2D . This ~ 3–4% frequency in T2D was later confirmed [10••]. To address the quantitative contribution of altered β cell identity to the β cell deficit, we studied the frequency of polyhormonal cells and determined that changes of β cell identity that have been ascribed to loss of differentiation in T2D could only account for approximately 2% of β cell loss (Fig. 1c) [89••]. In addition, our data revealed an increased frequency of polyhormonal cells (Ins+/hormone cocktail+ cells) in lean subjects with T2D [89••]. Given that human pancreas, obtained at the time of surgery or at post-mortem, is by definition a single timepoint for any given individual, it is not possible to definitively determine the evolution and fate of those “camouflaged” Ins+ β cells in humans with T2D.
Mechanisms Involved in β Cell Dedifferentiation in T1D and T2D
Drivers of altered identity of β cells in T1D and T2D
Cellular and physiological modulators
Altered identity of β cells in
Most relevant references
Possibly linked,(no direct evidence)
Possibly linked (no direct evidence)
Beta cell heterogenity
Possibly linked (no direct evidence)
Protein misfolding/ER stress
Islet-derived proinflammatory mediators might induce β cell dedifferentiation in human T1D, as the islet micoenvironment has also been reported to be the generator of proinsulin targeting CD4 T cells in humans with T1D . Such impaired “self-maintenance” of pancreatic β cells has also been observed in T2D, where cytokines and chemokines (secreted by β cells) recruit macrophages by inducing stress signaling in islets , and this may ultimately play a role in “inflammation-induced dedifferentiation” in T2D [102••]. The molecular mechanism of such β cell decompensation is not known, however though, factors such as microRNAs  or virus-like infection (enteroviral infection)  might be key regulators of this process.
Extensive animal and in vitro studies have implicated glucotoxicity and dysregulation of downstream pathways as being involved in β cell dedifferentiation. Cellular events, like hyperglycemia-induced alterations of β cell–specific gene expression (for example, downregulation of β cell–enriched genes and upregulation of β cell “forbidden” genes) (extensively reviewed in [112••]), might lead to the altered phenotypic and functional changes that are the hallmarks of a dedifferentiated β cell. Despite the fact that high glucose levels, as well as the duration of hyperglycemia, are two major upstream regulators of β cell dedifferentiation, our experimental data has demonstrated that the increase in both CPHN cells and polyhormonal endocrine cells in the human IAPP-transgenic (HIP) rat (a model of T2D) is already present by 2–3 months of age, thereby preceding diabetes onset, elevations in glucose, or any measurable loss of β cell mass . This implies that β cell stressors, in the HIP rat consequent upon IAPP mis-folding and cell dysfunction induced by IAPP-derived toxic oligomers, provoke the alteration in β cell identity and the increase in CPHN cells, rather than the hyperglycemia that develops only from the age of 5 months in this model . Peptide-based analyses of epitope targeting by either CD4 or CD8 T cells revealed a plausible role of IAPP as an autoantigen in the pathophysiology of T1D both in humans and in a non-obese diabetic (NOD) mouse model of spontaneous autoimmune diabetes [114, 115, 116, 117]. Recently, histological studies on pancreas from subjects with recent onset T1D have revealed that amyloidosis is also present in T1D [118, 119•].
Endoplasmic reticulum (ER) stress with inadequate induction of an adaptive unfolded protein response (UPR) might be a key driver of β cell dedifferentiation. β Cells are extremely dependent on their ER to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Altered metabolic states, for example in obesity, result in decreased insulin sensitivity in the skeletal muscle, liver, and adipose tissues that is counteracted by a compensatory increase in insulin secretion by β cells through an increase in both β cell function and mass . For insulin translation and folding, β cells rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress . A recent study demonstrated that targeted deletion of ATF4 (the main transcriptional regulator of UPR) in β cells in Akita mice (Akita/βATF4KO) leads to the increase in number of glucagon, somatostatin, or pancreatic polypeptide-positive cells in islets, suggesting increased β cell dedifferentiation . Therefore, the fine-tuning of this adaptive UPR is vital for the preservation of the β cell differentiated phenotype and failure of this process is associated with the progression to diabetes and altered β cell differentiation [109, 110].
Epigenetic regulation of pancreatic β cell identity could also play a crucial role in maintaining β cell plasticity. For example, the α cell–specific DNA-binding protein Arx must be repressed to prevent β- to α-transdifferentiation in a mouse model . Arx silencing in β cells is accomplished, at least in part, by binding of the transcription factor Nkx2.2 to the Arx promoter, followed by recruitment of DNA methyltransferase Dnmt3, increased DNA (CpG) methylation, and finally binding of MeCP2, a DNA-binding protein, to the promoter region of Arx in βcells to establish and maintain a fully repressed state [104••, 123]. Recently, unbiased epigenome mapping and single-cell RNA sequencing (ScRNA-Seq) have revealed that the β cell–specific chromatin regulatory system, Polycomb (Eed/PRC2), is necessary for maintenance of global silencing and terminal differentiation of β cells in the mouse [105•]. Therefore, as observed in rodent models of diabetes , it is likely that epigenetic dysregulation similarly contributes to β cell dedifferentiation in humans with T1D or T2D [106•].
Concluding Remarks and Future Perspectives
Pancreatic β cell dedifferentiation encompasses both a loss of one or more elements that are present in a mature functional β cell (this occurring for a multitude of reasons, including cellular stress or senescence) and a regression back towards a more primitive state, such as the pluripotent progenitor cell from whence it came.
Emerging evidence suggests that altered β cell identity in humans with T1D and T2D contributes to impaired β cell function in diabetes; however, the exact mechanisms are not known. Such cellular adoption of a resting or dedifferentiated state for a subset of pancreatic β cells might be a natural phenomenon that temporarily allows interruption of regular cellular function, serving as a protective mechanism to circumvent damage or death.
In order to derive benefits from the inherent plasticity of pancreatic β cells in humans with T1D or T2D, future research should aim to enhance our understanding of some key questions. Firstly, the extent of altered β cell identity in humans with prediabetes is yet to be determined, and this knowledge would be instructive in characterizing β cell dedifferentiation in humans. Secondly, it is imperative to identify key regulatory molecules and molecular markers of β cell dedifferentiation in humans (possibly by using laser capture microdissection of the altered β cell followed by single-cell RNA-seq). Thirdly, it is crucial to understand how the expression of chromograninA remains unaltered in the dedifferentiated β cell, given that insulin and chromograninA reside in the same dense-core granules of the β cell. Finally, effective re-differentiation mechanisms directed towards “altered state” pancreatic β cells should be explored, as identifying ways to inhibit or reverse these stages could substantially enhance the scope for developing novel therapies for restoration of β cell function in diabetes.
Open Access funding provided by the Qatar National Library.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 3.•• Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012;150(6):1223–34. https://doi.org/10.1016/j.cell.2012.07.029. This is the first report where β cell dedifferentiation was proposed as an alternative mechanism in animal model of T2D. CrossRefPubMedPubMedCentralGoogle Scholar
- 8.•• Butler AE, Dhawan S, Hoang J, Cory M, Zeng K, Fritsch H, et al. Beta-cell deficit in obese type 2 diabetes, a minor role of beta-cell dedifferentiation and degranulation. J Clin Endocrinol Metab. 2016;101(2):523–32. https://doi.org/10.1210/jc.2015-3566. This report demonstrated that dedifferentiated β cells played minor role in β cell deficit in human with T2D. CrossRefPubMedGoogle Scholar
- 9.•• Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. Evidence of beta-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1044–54. https://doi.org/10.1210/jc.2015-2860. Evidence of β cell dedifferentiation and trasdifferentiation in human with T2D. CrossRefPubMedGoogle Scholar
- 10.•• Spijker HS, Song H, Ellenbroek JH, Roefs MM, Engelse MA, Bos E, et al. Loss of beta-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes. 2015;64(8):2928–38. https://doi.org/10.2337/db14-1752. This report revealed a possible association of toxic islet amyloid polypeptide (IAPP) in β cell dedifferentiation in human with T2D. CrossRefPubMedGoogle Scholar
- 22.Jensen J, Heller RS, Funder-Nielsen T, Pedersen EE, Lindsell C, Weinmaster G, et al. Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes. 2000;49(2):163–76.CrossRefGoogle Scholar
- 31.Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, et al. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem : official journal of the Histochemistry Society. 2005;53(9):1087–97. https://doi.org/10.1369/jhc.5C6684.2005.CrossRefGoogle Scholar
- 44.•• Xin Y, Kim J, Okamoto H, Ni M, Wei Y, Adler C, et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab. 2016;24(4):608–15. https://doi.org/10.1016/j.cmet.2016.08.018. By using single-cell RNA sequencing this report demonstrated the cell type–specific genes and pathways that are altered in human with T2D. CrossRefPubMedGoogle Scholar
- 46.•• Segerstolpe A, Palasantza A, Eliasson P, Andersson EM, Andreasson AC, Sun X, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 2016;24(4):593–607. https://doi.org/10.1016/j.cmet.2016.08.020. This study demonstrated the comparison of single-cell transcriptomes between healthy and T2D human subjects. CrossRefPubMedPubMedCentralGoogle Scholar
- 50.•• Lawlor N, George J, Bolisetty M, Kursawe R, Sun L, Sivakamasundari V, et al. Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes. Genome Res. 2017;27(2):208–22. https://doi.org/10.1101/gr.212720.116. This study revealed (in single cell level) genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. CrossRefPubMedPubMedCentralGoogle Scholar
- 53.•• Bader E, Migliorini A, Gegg M, Moruzzi N, Gerdes J, Roscioni SS, et al. Identification of proliferative and mature beta-cells in the islets of Langerhans. Nature. 2016;535(7612):430–4. https://doi.org/10.1038/nature18624. This report demostrated a new technique to identify proliferative beta cells in adult islets. CrossRefPubMedGoogle Scholar
- 55.• Rodnoi P, Rajkumar M, Moin ASM, Georgia SK, Butler AE, Dhawan S. Neuropeptide Y expression marks partially differentiated β cells in mice and humans. JCI insight. 2017;2(12):e94005. https://doi.org/10.1172/jci.insight.94005. This report highlighted the contribution of neuropeptide Y (NPY) in the regulation of β cell differentiation. CrossRefPubMedCentralGoogle Scholar
- 58.•• Wang YJ, Golson ML, Schug J, Traum D, Liu C, Vivek K, et al. Single-cell mass cytometry analysis of the human endocrine pancreas. Cell Metab. 2016;24(4):616–26. https://doi.org/10.1016/j.cmet.2016.09.007. Analysis of human beta cells at single-cell level. CrossRefPubMedPubMedCentralGoogle Scholar
- 59.•• Johnston NR, Mitchell RK, Haythorne E, Pessoa MP, Semplici F, Ferrer J, et al. Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab. 2016;24(3):389–401. https://doi.org/10.1016/j.cmet.2016.06.020. Elucidation of the mechanism of functional heterogenity of beta cells. CrossRefPubMedPubMedCentralGoogle Scholar
- 60.• Fang Z, Weng C, Li H, Tao R, Mai W, Liu X, et al. Single-cell heterogeneity analysis and CRISPR screen identify key β-cell-specific disease genes. Cell Rep. 2019;26(11):3132–44.e7. https://doi.org/10.1016/j.celrep.2019.02.043. This report descrived a new algorithm to interepret the single-cell heterogenity analysis of different subpopulations of beta cells. CrossRefPubMedPubMedCentralGoogle Scholar
- 68.Kluth O, Mirhashemi F, Scherneck S, Kaiser D, Kluge R, Neschen S, et al. Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure. Diabetologia. 2011;54(3):605–16. https://doi.org/10.1007/s00125-010-1973-8.CrossRefPubMedGoogle Scholar
- 69.Jurgens CA, Toukatly MN, Fligner CL, Udayasankar J, Subramanian SL, Zraika S, et al. Beta-cell loss and beta-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol. 2011;178(6):2632–40. https://doi.org/10.1016/j.ajpath.2011.02.036.CrossRefPubMedPubMedCentralGoogle Scholar
- 71.Sapir T, Shternhall K, Meivar-Levy I, Blumenfeld T, Cohen H, Skutelsky E, et al. Cell-replacement therapy for diabetes: generating functional insulin-producing tissue from adult human liver cells. Proc Natl Acad Sci U S A. 2005;102(22):7964–9. https://doi.org/10.1073/pnas.0405277102.CrossRefPubMedPubMedCentralGoogle Scholar
- 75.Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell. 2009;138(3):449–62. https://doi.org/10.1016/j.cell.2009.05.035.CrossRefPubMedPubMedCentralGoogle Scholar
- 76.Courtney M, Gjernes E, Druelle N, Ravaud C, Vieira A, Ben-Othman N, et al. The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. PLoS Genet. 2013;9(10):e1003934. https://doi.org/10.1371/journal.pgen.1003934.CrossRefPubMedPubMedCentralGoogle Scholar
- 83.• Moin AS, Butler PC, Butler AE. Increased proliferation of the pancreatic duct gland compartment in type 1 diabetes. J Clin Endocrinol Metab. 2017;102(1):200–9. https://doi.org/10.1210/jc.2016-3001. This study demonstrated pancreatic duct gland compartment (PDG) as a potential source of pancreatic endocrine cell regeneration in type 1 diabetes. CrossRefPubMedGoogle Scholar
- 85.Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62(7):2595–604. https://doi.org/10.2337/db12-1686.CrossRefPubMedPubMedCentralGoogle Scholar
- 87.•• Md Moin AS, Dhawan S, Shieh C, Butler PC, Cory M, Butler AE. Increased hormone-negative endocrine cells in the pancreas in type 1 diabetes. J Clin Endocrinol Metab. 2016;101(9):3487–96. https://doi.org/10.1210/jc.2016-1350. This study demonstrated the altered β cell identity in human with T1D. CrossRefPubMedPubMedCentralGoogle Scholar
- 89.•• Md Moin AS, Dhawan S, Cory M, Butler PC, Rizza RA, Butler AE. Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes. J Clin Endocrinol Metab. 2016;101(10):3628–36. https://doi.org/10.1210/jc.2016-2496. This study revealed the increased frequency of altered β cells in lean human with T2D and that alteration prceeded the onset of T2D in a diabetic animal model. CrossRefPubMedGoogle Scholar
- 90.• Moin ASM, Montemurro C, Zeng K, Cory M, Nguyen M, Kulkarni S, et al. Characterization of non-hormone expressing endocrine cells in fetal and infant human pancreas. Front Endocrinol (Lausanne). 2018;9:791. https://doi.org/10.3389/fendo.2018.00791. This report showed the frequency of altered β cells in fetal and infant human pancreas. CrossRefGoogle Scholar
- 93.Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). The DCCT Research Group. J Clin Endocrinol Metab 1987;65(1):30–6. doi: https://doi.org/10.1210/jcem-65-1-30.
- 94.Sørensen JS, Johannesen J, Pociot F, Kristensen K, Thomsen J, Hertel NT, et al. Residual β-cell function 3-6 years after onset of type 1 diabetes reduces risk of severe hypoglycemia in children and adolescents. Diabetes Care. 2013;36(11):3454–9. https://doi.org/10.2337/dc13-0418.CrossRefPubMedPubMedCentralGoogle Scholar
- 96.• Sims EK, Bahnson HT, Nyalwidhe J, Haataja L, Davis AK, Speake C, et al. Proinsulin secretion is a persistent feature of type 1 diabetes. Diabetes Care. 2019;42(2):258–64. https://doi.org/10.2337/dc17-2625. This report highlighted the functional β cell mass in long-standing T1D. CrossRefPubMedGoogle Scholar
- 97.•• Wasserfall C, Nick HS, Campbell-Thompson M, Beachy D, Haataja L, Kusmartseva I, et al. Persistence of pancreatic insulin mRNA expression and proinsulin protein in type 1 diabetes pancreata. Cell Metab. 2017;26(3):568–75.e3. https://doi.org/10.1016/j.cmet.2017.08.013. This report demonstrated the functional capacity of residual β cells in T1D. CrossRefPubMedPubMedCentralGoogle Scholar
- 99.•• Burke GW, Posgai AL, Wasserfall CH, Atkinson MA, Pugliese A. Raising awareness: the need to promote allocation of pancreata from rare nondiabetic donors with pancreatic islet autoimmunity to type 1 diabetes research. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2017;17(1):306–7. https://doi.org/10.1111/ajt.13983. This report focuses the importance of pancreatic organ donation to study the pathogenisis of T1D. CrossRefGoogle Scholar
- 102.•• Nordmann TM, Dror E, Schulze F, Traub S, Berishvili E, Barbieux C, et al. The role of inflammation in beta-cell dedifferentiation. Sci Rep. 2017;7(1):6285. https://doi.org/10.1038/s41598-017-06731-w. This report demonstrated that inflammation causes β cell dedifferentiation in vitro. CrossRefPubMedPubMedCentralGoogle Scholar
- 104.•• Dhawan S, Georgia S, Tschen SI, Fan G, Bhushan A. Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell. 2011;20(4):419–29. https://doi.org/10.1016/j.devcel.2011.03.012. This report described the importance of epigenetic modifications in maintenance of beta cell identity. CrossRefPubMedPubMedCentralGoogle Scholar
- 105.• Lu TT, Heyne S, Dror E, Casas E, Leonhardt L, Boenke T, et al. The polycomb-dependent epigenome controls beta cell dysfunction, dedifferentiation, and diabetes. Cell Metab. 2018;27(6):1294–308.e7. https://doi.org/10.1016/j.cmet.2018.04.013. A new proposed mechanism of epigenetic regulation pancreatic beta cell biology. CrossRefPubMedPubMedCentralGoogle Scholar
- 106.• Davegårdh C, García-Calzón S, Bacos K, Ling C. DNA methylation in the pathogenesis of type 2 diabetes in humans. Mol Metab. 2018;14:12–25. https://doi.org/10.1016/j.molmet.2018.01.022. This study demonstrated the role of epigenetics in the pathogenesis of T2D. CrossRefPubMedPubMedCentralGoogle Scholar
- 109.Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR. Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in β-cell gene expression and progression to diabetes. Diabetes. 2013;62(5):1557–68. https://doi.org/10.2337/db12-0701.CrossRefPubMedPubMedCentralGoogle Scholar
- 112.•• Bensellam M, Jonas JC, Laybutt DR. Mechanisms of beta-cell dedifferentiation in diabetes: recent findings and future research directions. J Endocrinol. 2018;236(2):R109–r43. https://doi.org/10.1530/joe-17-0516. An integrative review on β cell dedifferentiation and factors associated with that phenomenon. CrossRefPubMedGoogle Scholar
- 115.Standifer NE, Ouyang Q, Panagiotopoulos C, Verchere CB, Tan R, Greenbaum CJ, et al. Identification of Novel HLA-A*0201-restricted epitopes in recent-onset type 1 diabetic subjects and antibody-positive relatives. Diabetes. 2006;55(11):3061–7. https://doi.org/10.2337/db06-0066.CrossRefPubMedGoogle Scholar
- 116.Baker RL, Delong T, Barbour G, Bradley B, Nakayama M, Haskins K. Cutting edge: CD4 T cells reactive to an islet amyloid polypeptide peptide accumulate in the pancreas and contribute to disease pathogenesis in nonobese diabetic mice. J Immunol. 2013;191(8):3990–4. https://doi.org/10.4049/jimmunol.1301480.CrossRefPubMedGoogle Scholar
- 119.• Westermark GT, Krogvold L, Dahl-Jørgensen K, Ludvigsson J. Islet amyloid in recent-onset type 1 diabetes-the DiViD study. Ups J Med Sci. 2017;122(3):201–3. https://doi.org/10.1080/03009734.2017.1359219. This report described amyloidosis of islets in patients with T1D. CrossRefPubMedPubMedCentralGoogle Scholar
- 122.Courtney M, Gjernes E, Druelle N, Ravaud C, Vieira A, Ben-Othman N, et al. The inactivation of Arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells. PLoS Genet. 2013;9(10):e1003934. https://doi.org/10.1371/journal.pgen.1003934.CrossRefPubMedPubMedCentralGoogle Scholar
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