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![The calcium-calmodulin-calcineurn-NFaT-DYRK1A pathway to human beta cell proliferation. Increases in intracellular calcium (Ca⁺⁺), induced, for example, by glucose, sulfonylureas and the glucagon-like peptide-1 (GLP-1) family of drugs, activate calmodulin (CAM), which in turn activates the calcineurins (CnA and CnB). CnA and CnB form a phosphatase complex, which de-phosphorylates a number of substrates, including the NFaT family of transcription factors that, in their phosphorylated state, are tethered to 14-3-3 scaffold proteins in the cytoplasm. De-phosphorylation by calcineurin allows these transcription factors to translocate into the nuclear compartment, where they bind to and activate promoters of cyclins E and A, and cyclin-dependent kinase 1 (CDK1), and repress promoters of the cell cycle inhibitor genes, CDKN2A, CDKN2B and CDKN1C, encoding p16INK4, p15INK4 and p57Kip2, respectively. Collectively these events result in cell cycle entry. The kinase DYRK1A serves as the normal termination mechanism in this process by re-phosphorylating NFaT members. This results in their return to the cytoplasm, and return to quiescence. Thus, DYRK1A is the ‘brake’ on cell cycle entry or proliferation. Harmine, INDY, 5-iodo-tubericidin (5-IT) and GNF4877 are all inhibitors of DYRK1A and, in essence, function by disabling the DYRK1A ‘brake’, permitting continued proliferation [14, 20, 21]. VDCC, voltage-dependent calcium channel. Figure adapted from [14]. This figure is available as part of a downloadable slideset](publication/325184287/figure/fig2/AS:941373360451585@1601452307147/The-calcium-calmodulin-calcineurn-NFaT-DYRK1A-pathway-to-human-beta-cell-proliferation.gif)
The calcium-calmodulin-calcineurn-NFaT-DYRK1A pathway to human beta cell proliferation. Increases in intracellular calcium (Ca⁺⁺), induced, for example, by glucose, sulfonylureas and the glucagon-like peptide-1 (GLP-1) family of drugs, activate calmodulin (CAM), which in turn activates the calcineurins (CnA and CnB). CnA and CnB form a phosphatase complex, which de-phosphorylates a number of substrates, including the NFaT family of transcription factors that, in their phosphorylated state, are tethered to 14-3-3 scaffold proteins in the cytoplasm. De-phosphorylation by calcineurin allows these transcription factors to translocate into the nuclear compartment, where they bind to and activate promoters of cyclins E and A, and cyclin-dependent kinase 1 (CDK1), and repress promoters of the cell cycle inhibitor genes, CDKN2A, CDKN2B and CDKN1C, encoding p16INK4, p15INK4 and p57Kip2, respectively. Collectively these events result in cell cycle entry. The kinase DYRK1A serves as the normal termination mechanism in this process by re-phosphorylating NFaT members. This results in their return to the cytoplasm, and return to quiescence. Thus, DYRK1A is the ‘brake’ on cell cycle entry or proliferation. Harmine, INDY, 5-iodo-tubericidin (5-IT) and GNF4877 are all inhibitors of DYRK1A and, in essence, function by disabling the DYRK1A ‘brake’, permitting continued proliferation [14, 20, 21]. VDCC, voltage-dependent calcium channel. Figure adapted from [14]. This figure is available as part of a downloadable slideset
Source publication
The numbers of insulin-secreting pancreatic beta cells are reduced in people with type 1 and type 2 diabetes. Driving beta cell regeneration in the pancreases of people with diabetes would be an attractive approach to reversing diabetes. While adult human beta cells have long been believed to be terminally differentiated and, therefore, irreversibl...
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Citations
... The dephosphorylation of the the nuclear factor of activated T cells (NFAT) family transcription factors by these phosphatases (CnA and CnB) results in NFAT translocation to the nucleus. In this case, NFAT activates the promoters of cyclins E and A, as well as cyclindependent kinase 1 (CDK1), while inhibiting the promoters of cell cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1C, resulting in cell cycle entrance and proliferation (47,48). ...
Background: Diabetes mellitus is a common metabolic disorder characterized by chronic high
blood sugar levels due to impaired insulin secretion or action. Existing diabetic medications
have limitations, including high costs and the risk of hypoglycemia. Aim: To overcome these
challenges, researchers are exploring advanced treatments, and one potential path is studying
plants and natural sources. Many plants include green tea (Camellia sinensis), rich in catechin
derivatives, particularly epigallocatechin-3-gallate (EGCG), have shown promising effect
because this agent may enhance beta cell proliferation, so it can produce dramatic response in
management of diabetes mellitus and it is expected to reduce complication of this disease.
Thorough data searching from September 2021 to June 2023 was used to conduct this study.
The key terms diabetes mellitus, herbal treatment of diabetes, DYRK1A inhibitor,
Epigallocatechin-3-gallate, and beta cell proliferation were concomitantly searched in Google
Scholar, Web of Science, and PubMed in order to find relevant material. The publications that
are presented here were published between 2014 and 2023. Conclusion: Collectively EGCG
properties as a DYRK1A inhibitor may enhance β cell proliferation that is promising effects in
diabetes mellitus treatment
... DYRK1A inhibitors activate cell cycle progression through a family of transcription factors, the nuclear factor activated in T cells (NFaT) (Fig. 1). NFaTs are dephosphorylated by calcineurin to be able to translocate to the nucleus; then they bind to and transactivate, the cell cycle genes, CCNE, CCNA (encoding cyclins E and A), and CDK1, and repress the expression of the cell cycle inhibitors CDKN1C, CDKN2A, and CDKN2B [21], which encode the arresting proteins of G1 phase p57KIP2, p16INK4a, and p15INK4b, respectively [20]. ...
... Several studies suggest that NFaT is a reasonable target of β-cell proliferation. Moreover, calcineurin and NFaT signaling are conserved across rodents and humans [17], and DYRK1A inhibitors have provided the most widely replicated effects [21]. ...
... Collectively, is worth considering that DYRK1A is ubiquitous, thus adverse effects of its inhibitors affect many organs [21]. Harmine is able to inhibit MAOs and has been reported to have psychoactive effects (producing hallucination episodes) and to induce anxiety, tremor, convulsion, and ataxia [23]. ...
In both type 1 diabetes (T1D) and type 2 diabetes (T2D), there is a substantial β-cell mass loss. Residual β-cell mass is susceptible to cellular damage because of specific pancreatic β-cell characteristics. β cells have a low proliferation rate, being in human adults almost zero and a low antioxidant system that makes β cells susceptible to oxidative stress and increases their vulnerability to cell destruction. Different strategies have been addressed to preserve pancreatic β-cell residual mass and function in patients with diabetes. However, the effect of many compounds proposed in rodent models to trigger β-cell replication has different results in human β cells. In this review, scientific evidence of β-cell of two major regenerative approaches has been gathered. Regeneration proceedings for pancreatic β cells are promising and could improve β-cell proliferation capacity and contribute to the conservation of mature β-cell phenotypic characteristics. This evidence supports the notion that regenerative medicine could be a helpful strategy to yield amelioration of T1D and T2D pathogenesis.
... DYRK1A phosphorylates nuclear factor of activated T-cells transcription factors (NFATs) and keeps NFATs inactive in the cytoplasm. DYRK1A inactivation allows NFATs to be translocated to the nucleus, where they activate the expression of cell cycle entry-promoting genes: Forkhead Box M1 (FOXM1), cyclin E1, cyclin A2, and CDK1, and repress the expression of inhibitors, such as p57, p15, and p16 (Goodyer et al., 2012;Karakose et al., 2018). In parallel, DYRK1A inhibits beta cell proliferation by stabilizing the p27 inhibitor and the DREAM (dimerization partner, RB-like E2F and multi-vulval class B) protein complex (Abdolazimi et al., 2018), leading to an inhibition of cell cycle-promoting transcription factors, such as c-Myc, thereby maintaining cells in G0 phase (Sadasivam and DeCaprio, 2013). ...
... GABA acts through the binding to the GABA receptors on human beta cells, leading to an influx of Ca 2+ and activation of the Ca 2+dependent PI3K/Akt and CREB signaling pathways responsible for beta cell proliferation and survival . The signaling pathways involved in human beta cell proliferation have been described in more detail elsewhere (Shirakawa and Kulkarni, 2016;Karakose et al., 2018;Basile et al., 2019). ...
Decreased number and function of beta cells are a key aspect of diabetes mellitus (diabetes), a disease that remains an onerous global health problem. Means of restoring beta cell mass are urgently being sought as a potential cure for diabetes. Several strategies, such as de novo beta cell derivation via pluripotent stem cell differentiation or mature somatic cell transdifferentiation, have yielded promising results. Beta cell expansion is another promising strategy, rendered challenging by the very low proliferative capacity of beta cells. Many effective mitogens have been identified in rodents, but the vast majority do not have similar mitogenic effects in human beta cells. Extensive research has led to the identification of several human beta cell mitogens, but their efficacy and specificity remain insufficient. An approach based on the simultaneous application of several mitogens has recently emerged and can yield human beta cell proliferation rates of up to 8%. Here, we discuss recent advances in restoration of the beta cell population, focusing on mitogen synergy, and the contribution of RNA-sequencing (RNA-seq) to accelerating the elucidation of signaling pathways in proliferating beta cells and the discovery of novel mitogens. Together, these approaches have taken beta cell research up a level, bringing us closer to a cure for diabetes.
... Traditional disease models postulated that beta cells were fully depleted at the time of clinical presentation, but more recent findings support the notion that even in advanced disease states, it is possible that residual reservoirs of insulinproducing beta cell mass could persist [11,23] and might have the potential to re-gain function, even post-diagnosis [24]. The replicative quiescence of adult beta cells is thought to result from several interrelated mechanisms, including the functional potential of cell cycle regulators and epigenetic factors [25], but nevertheless there may be opportunities to intervene and restore or enhance their regenerative potential [12,25,26]. For example, enhancement of beta cell proliferation and regeneration has been achieved through pharmacological targeting of pathways such as the glucagon-like peptide-1 receptor (GLP-1R) and TGF-β family members [27]. ...
... Traditional disease models postulated that beta cells were fully depleted at the time of clinical presentation, but more recent findings support the notion that even in advanced disease states, it is possible that residual reservoirs of insulinproducing beta cell mass could persist [11,23] and might have the potential to re-gain function, even post-diagnosis [24]. The replicative quiescence of adult beta cells is thought to result from several interrelated mechanisms, including the functional potential of cell cycle regulators and epigenetic factors [25], but nevertheless there may be opportunities to intervene and restore or enhance their regenerative potential [12,25,26]. For example, enhancement of beta cell proliferation and regeneration has been achieved through pharmacological targeting of pathways such as the glucagon-like peptide-1 receptor (GLP-1R) and TGF-β family members [27]. ...
... DYRK1A inhibitors are thought to work by reversing the inhibitory effect of DYRK1A on the nuclear factor activated in T cells (NFAT) family of transcription factors, which are required for cell cycle activation in beta cells. Exposure to DYRK1A inhibitors on their own increases beta cell proliferation to~1-3% [25]; although the effect size is small, it is sufficient to improve glucose tolerance in immunodeficient mice transplanted with human islets [18,25]. These proproliferative effects can be enhanced in combination with GLP-1R agonists, stimulating up to 6% of beta cells to proliferate [28]. ...
Type 1 diabetes results from defects in immune self-tolerance that lead to inflammatory infiltrate in pancreatic islets, beta cell dysfunction and T cell-mediated killing of beta cells. Although therapies that broadly inhibit immunity show promise to mitigate autoinflammatory damage caused by effector T cells, these are unlikely to permanently reset tolerance or promote regeneration of the already diminished pool of beta cells. An emerging concept is that certain populations of immune cells may have the capacity to both promote tolerance and support the restoration of beta cells by supporting proliferation, differentiation and/or regeneration. Here we will highlight three immune cell types—macrophages, regulatory T cells and innate lymphoid cells—for which there is evidence of dual roles of immune regulation and tissue regeneration. We explore how findings in this area from other fields might be extrapolated to type 1 diabetes and highlight recent discoveries in the context of type 1 diabetes. We also discuss technological advances that are supporting this area of research and contextualise new therapeutic avenues to consider for type 1 diabetes.
Graphical abstract
... Stimulation of β-cell regeneration Stimulation of β-cell regeneration with small molecules has emerged as a promising therapeutic strategy against diabetes [1][2][3][4]. Even though endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass and actually cure diabetes, the known chemical compounds that promote regeneration or expansion of endogenous β-cells still have inadequate potency for clinical application. ...
The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes β-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small–molecule–induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.
... Regeneration of β-cell is another process that may account for recovery β-cell mass after remission, and some drugs have been reported to have such proliferative effects. However, evidence of β-cell replication or proliferation is lacking in adult humans [108,200,201]. ...
Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of β-cell dysfunction and recovery in T2DM are discussed in the context of abnormal hepatic lipid metabolism and cardiovascular health. (i) In normal health, continuous exposure of the pancreas to nutrient stimulus increases the demand on β-cells. In the long term, this will not only stress β-cells and decrease their insulin secretory capacity, but also will blunt the cellular response to insulin. (ii) At the pre-diabetes stage, β-cells compensate for insulin resistance through hypersecretion of insulin. This increases the metabolic burden on the stressed β-cells and changes hepatic lipoprotein metabolism and adipose tissue function. (iii) If this lipotoxic hyperinsulinemic environment is not removed, β-cells start to lose function, and CVD risk rises due to lower lipoprotein clearance. (iv) Once developed, T2DM can be reversed by weight loss, a process described recently as remission. However, the precise mechanism(s) by which calorie restriction causes normalization of lipoprotein metabolism and restores β-cell function are not fully established. Understanding the pathophysiological and molecular basis of β-cell failure and recovery during remission is critical to reduce β-cell burden and loss of function. The aim of this review is to highlight the link between lipoprotein export and lipid-driven β-cell dysfunction in T2DM and how this is related to cardiovascular health. A second aim is to understand the mechanisms of β-cell recovery after weight loss, and to explore new areas of research for developing more targeted future therapies to prevent T2DM and the associated CVD events.
... [13] Efek lain yang tidak kalah penting adalah kemampuan harmine untuk mengembalikan massa sel β pankreas mendekati normal (Gambar 1d). [13,25] Penelitian yang dilakukan oleh Dirice dkk juga menunjukkan hasil yang serupa. [18] Ditambah lagi, harmine adalah molekul pertama yang terbukti mampu menginduksi proliferasi sel islet manusia yang ditransplantasikan pada mencit. ...
Background: Type 1 and 2 diabetes mellitus (DM) is a chronic metabolic disease most commonly affects millions of people worldwide. Despite the differences in pathogenesis, both share one thing in common - that is the drastic depletion in the number of pancreatic β cells. Unfortunately, physiological proliferation of β cells has come to a halt starting from the first year of neonatal. To overcome this problem, researchers have been searching for molecules with the ability to induce β cells proliferation. Upon extensive screening, only harmine was proven to be the most potent β cells proliferation inducer. Furthermore, combination of harmine with TGFβSF inhibitor was found to boost harmine’s effectivity even more. Another development was also made to improve harmine’s selectivity by incorporating 1-hydroxymethyl group. Objective: Evaluate the potency of 1-hydroxymethyl harmine-TGFβSF inhibitor as a novel therapy for DM. Method: A systematic literature study was conducted with the database from Pubmed, Google Scholar, ScienceDirect, and Proquest for articles published within 2015-2019. Discussion: This literature review yields result that harmine-TGFβSF inhibitor is proven to induce β cells proliferation up to 18%/day or equal to 18 times the normal cell proliferation rate during embryogenesis. Moreover, incorporating 1-hydroxymethyl group into harmine is proven not only to improve selectivity but also lessen the toxicity, making 1-hydroxymethyl harmine safe as a novel therapy for diabetes. Conclusion: 1-hydroxymethyl harmine-TGFβSF inhibitor display promising potential as a novel therapy for all type of diabetes patients. Keywords: diabetes mellitus, harmine, TGFβSF inhibitor, β cell proliferation Latar Belakang: Diabetes Melitus (DM) tipe 1 maupun tipe 2 merupakan penyakit metabolik kronis yang paling banyak ditemukan di seluruh dunia. Walaupun memiliki proses patogenesis yang berbeda, namun kedua tipe DM ini ternyata memiliki kesamaan, yaitu terjadinya penurunan kuantitas sel β pankreas. Sayangnya, kemampuan regenerasi sel β pankreas manusia telah terhenti semenjak tahun pertama masa neonatal. Untuk menangani permasalahan tersebut, para peneliti menemukan sebuah molekul bernama harmine yang terbukti efektif menginisiasi proses regenerasi sel β pankreas. Selanjutnya, untuk meningkatkan efektifitas dari harmine agar lebih baik lagi, peneliti kemudian mengkombinasikan harmine dengan TGFβSF inhibitor. Sedangkan, untuk meningkatkan selektivitas dari harmine, peneliti menambahkan gugus 1-hidroksimetil pada molekul tersebut. Tujuan: Evaluasi potensi 1-hydroxymethyl harmine-TGFβSF inhibitor sebagai terapi utama bagi semua penderita DM. Metode: Penelitian dilakukan dengan melakukan tinjauan pustaka dari beberapa database jurnal, yakni PubMed, Google Scholar, ScienceDirect dan ProQuest dengan kriteria literatur dipublikasikan dalam kurun waktu 2015-2019. Pembahasan: Studi literatur ini menunjukan bahwa harmine-TGFβSF inhibitor telah terbukti mampu meningkatkan proliferasi sel β pankreas manusia hingga mencapai 18%/hari atau setara dengan 18 kali kecepatan embriogenesis pada sel normal. Selain itu, penambahan gugus 1-hidroksimetil pada harmine juga telah terbukti tidak hanya mampu meningkatkan selektivitas dari molekul tersebut, tetapi juga mampu menurunkan efek toksisitasnya, sehingga aman digunakan sebagai terapi anti-diabetes terbaru. Kesimpulan: 1-hydroxymethyl harmine-TGFβSF inhibitor memiliki potensi yang menjanjikan untuk menjadi terapi baru bagi semua tipe penderita DM. Kata Kunci: diabetes mellitus, harmine, proliferasi sel β, TGFβSF inhibitor
... The double knockout between HL-1 and TNF points further into better understanding about depths of bimodal outcome of cytokine TNF-α and regulation of Nrf2/Keap1 pathway The nuclear erythroid-2 like factor-2 (Nrf2) is continuously ubiquitinated via Kelch-like ECH-associated protein 1 (Keap1), under normal conditions, followed by its degradation in the proteosome. Inactivation of Keap1 and phosphorylation of Nrf2 takes place in oxidative stress conditions, where phosphorylated Nrf2 is accumulated in the nucleus, followed by its binding to ARE sites, further activating several genes, like detoxifying enzymes, antioxidants and transport molecules [39,40]. It is therefore better understood that why Nrf2 is suggested to be suitable in controlling ROS/TNF signaling and these are also essential to activate protective Nrf2 pathway. ...
In spite of much awareness, diabetes mellitus continues to remain one of major reasons for mortality and morbidity rate all over the globe. Free radicals cause oxidative stress which is responsible for causing diabetes. The recent advancements in elucidation of ARE/keap1/Nrf2 pathway can help in better understanding of diabetes mellitus. Various clinical trials and animal studies have shown the promising effect of Nrf2 pathway in reversing diabetes by counteracting with the oxidative stress produced. The gene is known to dissociate from Keap1 on coming in contact with such stresses to show preventive and prognosis effect. The Nrf2 gene has been marked as a molecular player in dealing with wide intracellular as well as extracellular cellular interactions in different diseases. The regulation of this gene gives some transcription factor that contain antioxidant response elements (ARE) in their promoter region and thus are responsible for encoding certain proteins involved in regulation of metabolic and detoxifying enzymes.
... Genetic silencing of TBK1 in these β-cells led to increased proliferation and reduced expression of β-cell markers consistent with the predicted inverse relation between proliferative capacity and β-cell maturity 9,26 . Thus, it is likely that in physiological conditions, TBK1 acts as one of the proliferation, not functional, barriers of β-cells, which might help to explain the replicationquiescent, not function-quiescent, state of non-diabetic adult β-cells 4,5,[53][54][55][56][57][58] . ...
Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells.
... In addition to our work on NKX6.1 and PDX-1 as upstream inducers of islet cell proliferation [7][8][9][10][11][12][13], other signaling pathways that have been identified with potential for activating human β-cell proliferation include the PDGF pathway [20], signaling by TGF-β family members [13,21,22], and glucose-regulated activation of proliferation mediated by ChREBP and MYC [17,23]. Pathways that regulate translocation of the NFAT transcription factor have also received attention stemming from early studies showing that conditional ablation of NFAT caused a reduction of β-cell mass in mouse models [24][25][26]. ...
A key event in the development of both major forms of diabetes is the loss of functional pancreatic islet β-cell mass. Strategies aimed at enhancing β-cell regeneration have long been pursued, but methods for reliably inducing human β-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor NKX6.1 stimulates β-cell proliferation, while also enhancing GSIS and providing protection against β-cell cytotoxicity through induction of the VGF prohormone. We developed an NKX6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation, but not expression of NKX6.1 or VGF, suggesting an alternative mechanism of action. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human β-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. GNF-9228 stimulates proliferation via a mechanism distinct from recently emergent DYRK1A inhibitors, as it is unaffected by DYRK1A overexpression and does not activate NFAT translocation. In conclusion, we have identified a small molecule with pleiotropic positive effects on islet biology, including stimulation of human β-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.
