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Cited by 18Pancreatic function and diabetesMicroRNA in disease regulationDiabetes and associated disorders

β-Cell pre-mir-21 induces dysfunction and loss of cellular identity by targeting transforming growth factor beta 2 (Tgfb2) and Smad family member 2 (Smad2) mRNAs

Open access
Ibrahim, Sara, Johnson, Macey, Stephens, Clarissa Hernandez, Xu, Jerry, Moore, Rachel, Mariani, Andrea, Contreras, Christopher, Syed, Farooq +3 more·2021·Molecular Metabolism
DOI 10.1016/j.molmet.2021.101289PMC PMC8361274
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Abstract

OBJECTIVE: β-cell microRNA-21 (miR-21) is increased by islet inflammatory stress but it decreases glucose-stimulated insulin secretion (GSIS). Thus, we sought to define the effects of miR-21 on β-cell function using in vitro and in vivo systems. METHODS: We developed a tetracycline-on system of pre-miR-21 induction in clonal β-cells and human islets, along with transgenic zebrafish and mouse models of β-cell-specific pre-miR-21 overexpression. RESULTS: β-cell miR-21 induction markedly reduced GSIS and led to reductions in transcription factors associated with β-cell identity and increased markers of dedifferentiation, which led us to hypothesize that miR-21 induces β-cell dysfunction by loss of cell identity. In silico analysis identified transforming growth factor-beta 2 (Tgfb2) and Smad family member 2 (Smad2) mRNAs as predicted miR-21 targets associated with the maintenance of β-cell identity. Tgfb2 and Smad2 were confirmed as direct miR-21 targets through RT-PCR, immunoblot, pulldown, and luciferase assays. In vivo zebrafish and mouse models exhibited glucose intolerance, decreased peak GSIS, decreased expression of β-cell identity markers, increased insulin and glucagon co-staining cells, and reduced Tgfb2 and Smad2 expression. CONCLUSIONS: These findings implicate miR-21-mediated reduction of mRNAs specifying β-cell identity as a contributor to β-cell dysfunction by the loss of cellular differentiation.

AI snapshot

Written from the paper’s full text.

TL;DR

β-cell pre-miR-21 induction reduces glucose-stimulated insulin secretion and β-cell identity markers while increasing dedifferentiation/progenitor markers, in part by directly targeting Tgfb2 and Smad2 mRNAs. Zebrafish, mouse, and human islet models show miR-21 overexpression causes glucose intolerance/hyperglycemia, reduced Tgfb2/Smad2, and loss of β-cell identity.

Key findings

  • In INS1-miR-21 cells, doxycycline-induced miR-21 reduced baseline and glucose-stimulated insulin secretion, decreased Rab37 granule staining, and increased the proinsulin-to-insulin ratio; it decreased Mafa, Nkx6.1, Ins1, Ins2, Neurod1, and Glut2 mRNAs and MafA protein, while increasing Ngn3, Nanog, L-Myc, and Aldh1a3.
  • Tgfb2 and Smad2 were confirmed as direct miR-21 targets: transcripts and proteins decreased after miR-21 induction, biotinylated miR-21 pulldown enriched Tgfb2 and Smad2 mRNAs, and luciferase activity was reduced with wild-type 3′UTRs but not with mutated binding sites for Tgfb2 (positions 1281–1289) or Smad2 (positions 8900–8908).
  • miR-21 inhibition blocked IL1β-induced Aldh1a3 and increased Tgfb2, Smad2, Pdx1, and Ins1 mRNAs; Tgfb2 overexpression in INS1-miR-21 cells decreased Ngn3, Nanog, and L-myc and increased Pdx1, Ins1, Ins2, and Neurod1.
  • In vivo, Tg(HS:βmiR-21) zebrafish showed hyperglycemia, fewer insulin+ cells, more insulin+glucagon+ cells, decreased Nkx6.1 and Tgfb2 staining, and reduced MafA, Pdx1, Tgfb2, and Smad2 mRNAs; Tg(βmiR-21) mice showed mild glucose intolerance without insulin tolerance differences, decreased peak insulin secretion, decreased β-cell mass, increased insulin+glucagon+ cells, increased glucagon+ area, decreased insulin+ area, reduced Tgfb2, Smad2, MafA, Pdx1, Glut2, Pcsk1, and Pcsk2, and increased Aldh1a3. Human islets transduced with miR-21 showed increased ALDH1A3 and decreased PDX1, TGFB2, and SMAD2 (n = 6).

Methods

  • Lentiviral tetracycline/doxycycline-inducible pre-miR-21 was expressed in INS1 823/13 cells and human islets, with scrambled controls; 48 h 5 μg/ml doxycycline was used for induction. Cells were also treated with miR-21 LNA inhibitor, IL-1β (5 ng/ml), or a Tgfb2 overexpression vector.
  • In silico miR-21 target prediction was overlapped with human islet mRNAs downregulated in inflammatory stress or diabetes. RNA sequencing, qRT-PCR, immunoblot, biotinylated miRNA pulldown, luciferase 3′UTR assays, static GSIS/perifusion, and immunofluorescence were used.
  • Zebrafish Tg(hs:CS-βmiR-21) were crossed with Tg(ins:Cre)s924 for heat-shock-inducible β-cell miR-21; Tg(βmiR-21) mice were generated from Tg(CAG-Z-miR-21-EGFP) × Ins1tm1(CreERT2)Thor and treated with 1 mg/day tamoxifen for 6 days. IPGTTs, IPITTs, islet isolation, and histology were performed; statistics used t-tests, Kolmogorov–Smirnov tests, or one-way ANOVA with Tukey’s post-test, with p ≤ 0.05 significant.

Limitations

  • The paper states variability in observed impacts of miR-21 and TGFB/Smad signaling within and across systems, especially human islets, where one donor did not show an effect of miR-21 on β-cell identity, consistent with heterogeneity in human disease.
  • The paper states that INS1 GSIS was not normalized for differences in cell death; prior mimic experiments with larger apoptosis showed higher baseline insulin secretion, whereas the lentiviral model with more physiologic miR-21 increases reduced both baseline and stimulated GSIS.
  • The paper notes model differences: zebrafish had higher β-cell miR-21 induction than mice, and miR-21 induction occurred 3 days post fertilization in zebrafish versus 8 weeks after birth in mice, which could affect β-cell fate. Zebrafish immunostaining was limited by available antibodies, and Smad2 antibodies were not available for zebrafish immunofluorescence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.molmet.2021.101289

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

19 of 23 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    miRNA mimic transfection leads to supraphysiologic increases in miRNAs.

    “Because miRNA mimic transfection leads to supraphysiologic increases in miRNAs [34], we generated a tetracycline-on, doxycycline dependent system of lentiviral pre-miR-21 (hereafter referred to as miR-21) induction to define the effect of smaller fold increases in β-cell miR-21 (Figure 1A).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Thomson, 2011, Experimental strategies for microRNA target identification, Nucleic Acids Research source
  • Premisecitation

    Overexpression of miR-21-5p has a negative effect on glucose-stimulated insulin secretion (GSIS).

    “Using RNA duplexes or mimic transfection, several groups have also shown a negative effect of miR-21-5p overexpression on GSIS [6, 7]”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [6] Sims, 2017, MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells, Diabetologia source
    • cites [7] Bravo-Egana, 2012, Inflammation-mediated regulation of MicroRNA expression in transplanted pancreatic islets, Journal of Transplant source

      Results §3.4 reports that miR-21 mimic overexpression reduced Pclo mRNA in MIN6 cells. The Discussion (§4) proposes that this could impair insulin exocytosis, but the paper does not report a glucose-stimulated insulin secretion measurement or demonstrate the claimed effect on GSIS. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Tgfb2 has been shown to play an important role in β-cell identity and function.

    “Specifically, Tgfb2 has been shown to play an important role in β-cell identity and function [14].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Brown, 2010, Emerging roles for the TGFbeta family in pancreatic beta-cell homeostasis, Trends in Endocrinology and Metabolism source

      The TGFβ section reports that TGFβ2 increased insulin secretion from adult rat islets in vitro, supporting a role in β-cell function under that condition. The TGFβ family signaling section discusses possible roles for family members in cell-fate specification, but does not establish a role for TGFβ2 specifically in β-cell identity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    β-cell miR-21-5p is increased in models of inflammation and diabetes.

    “This work has identified that β-cell miR-21-5p is increased in models of inflammation and diabetes [[6], [7], [8], [9], [10]].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [6] Sims, 2017, MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells, Diabetologia source
    • cites [7] Bravo-Egana, 2012, Inflammation-mediated regulation of MicroRNA expression in transplanted pancreatic islets, Journal of Transplant source

      Results §3.4 reports that cytokine treatment increased miR-21 expression in insulin-secreting MIN6 cells, supporting the inflammation-model portion. The paper does not establish increased β-cell miR-21 in a diabetes model, and these passages identify miR-21 rather than specifically miR-21-5p. No page number is available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [8] Meng, 2007, MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer, Gastroenterology source

      The Results and Discussion report increased miR-21 in hepatocellular cancer cells and tumors, not in β-cells. Searches for β-cells, inflammation, diabetes, and miR-21-5p found no passage addressing the claimed models. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    The use of miRNA mimics can saturate RISC complexes and displace other endogenous miRNAs, causing disproportionately increased binding with lower affinity targets.

    “The use of miRNA mimics can saturate RISC complexes and displace other endogenous miRNAs, causing disproportionately increased binding with lower affinity targets that may not be as dramatically impacted by lower level increases in the miRNA of interest [34].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Thomson, 2011, Experimental strategies for microRNA target identification, Nucleic Acids Research source
  • Classified as probably not a substantial claim. 11
  • May combine two claims. 18

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    β-cell dedifferentiation, loss of identity, or reversion to a progenitor-like state is a compensatory response to islet inflammatory stress, with evidence in models of T1D and T2D.

    “Recent data have identified β-cell dedifferentiation, loss of identity, or reversion to a progenitor-like state, as a compensatory response to islet inflammatory stress, with evidence of β-cell dedifferentiation in models of T1D and T2D [35].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] Remedi, 2016, Pancreatic β-cell identity in diabetes, Diabetes obesity metabol source

      In “Is it a change in β-cell fate in diabetes?” (page unavailable), the paper describes loss of β-cell identity and reversion to progenitor-like cells, and reports evidence in type 2 diabetes. The Concluding remarks (page unavailable) propose dedifferentiation as a possible protective response to metabolic stress, not specifically islet inflammatory stress. The paper says dedifferentiation may occur in type 1 diabetes, but the cited passages do not establish evidence in a type 1 diabetes model. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Tgfb2 is a member of the TGF-β superfamily that signals through Smad transcription factors.

    “Tgfb2 is a member of the TGF-β superfamily of proteins that is involved in diverse roles across different cell types by signaling through a group of transcription factors called Smads [13].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Xiao, 2013, TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation, Diabetes source

      The introductory passage (page unavailable) says TGFβ superfamily signaling has diverse roles across cell types and can activate Smad transcription factors. The References list names TGF-β2 as an isoform, but the paper does not specifically describe Tgfb2 signaling through Smads; that part is inferred from its discussion of the broader family. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prior studies have linked loss of β-cell identity and dedifferentiation to β-cell dysfunction in models of insulin resistance and reduced islet mass.

    “Prior studies have linked loss of β-cell identity and dedifferentiation to β-cell dysfunction in models of insulin resistance and reduced islet mass [38, 40].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [38] Poitout, 2002, Minireview: secondary beta-cell failure in type 2 diabetes–a convergence of glucotoxicity and lipotoxicity, Endocrinology source
    • cites [40] Szabat, 2012, Maintenance of β-cell maturity and plasticity in the adult pancreas: developmental biology concepts in adult physiology, Diabetes source

      The section “Active Maintenance of β-Cell Function: Evidence from Conditional Mutants and Human Genetics” (page unavailable) links impaired β-cell function to loss of identity markers after Pdx1 deletion and reports a 40% loss of β-cell mass. It does not establish this link in models of insulin resistance or models defined by pre-existing reduced islet mass; its discussion of lineage confusion is also more specific than a general finding of dedifferentiation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mimic transfection yields overexpression of the predicted sense strand (5p strand) of the miRNA, while in vivo induction of pre-miRNA transcripts could lead to differential effects owing to activities of the antisense strand of the miRNA duplex.

    “Furthermore, mimic transfection yields overexpression of the predicted sense strand (5p strand) of the miRNA, while in vivo induction of pre-miRNA transcripts could lead to differential effects owing to activities of the antisense strand of the miRNA duplex [34].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Thomson, 2011, Experimental strategies for microRNA target identification, Nucleic Acids Research source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Combined pharmacological inhibition of human β-cell DYRK1A and the TGF-β superfamily did not lead to a dedifferentiated phenotype.

    “By contrast, combined pharmacological inhibition of human β-cell DYRK1A and the TGF-β superfamily did not lead to a dedifferentiated phenotype [48].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Wang, 2019, Combined inhibition of DYRK1A, SMAD, and trithorax pathways synergizes to induce robust replication in adult human beta cells, Cell Metabolism source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The TGF-β signaling pathway has been implicated in the development of the endocrine pancreas, β-cell development, and postnatal β-cell identity and function.

    “This signaling pathway has also been implicated in the development of the endocrine pancreas [13], β-cell development, and postnatal β-cell identity and function [14].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Xiao, 2013, TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation, Diabetes source

      The paper’s introductory passage (labeled Abstract in our copy; page unavailable) links TGF-β signaling to embryonic endocrine-cell differentiation and maturation, and discusses its effects on β-cell insulin release and proliferation. The Discussion also addresses adult β-cell homeostasis. Neither passage establishes a role in maintaining postnatal β-cell identity, so that part of the claim is unsupported. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [14] Brown, 2010, Emerging roles for the TGFbeta family in pancreatic beta-cell homeostasis, Trends in Endocrinology and Metabolism source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent study identified gene signature profile changes in murine embryonic β-cells and adult β-cells following STZ treatment to identify β-cell dedifferentiation and dysfunction markers using single-cell RNA-seq.

    “A recent study identified gene signature profile changes in murine embryonic β-cells and adult β-cells following STZ treatment to identify β-cell dedifferentiation and dysfunction markers using single-cell RNA-seq [45].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Sachs, 2020, Targeted pharmacological therapy restores β-cell function for diabetes remission, Nature Metabolism source

      The Articles (pp. 6, 8) report scRNA-seq comparisons of β-cells from STZ-treated and healthy mice and identify markers of dysfunction and dedifferentiation. The paper also compares those cells with embryonic β-cells from a reference dataset (Articles, pp. 8–9), but it does not describe the embryonic cells as having received STZ treatment. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reduced prohormone processing enzyme expression has been described in models of islet dedifferentiation.

    “Additionally, reduced prohormone processing enzyme expression has also been described in models of islet dedifferentiation, a phenotype observed in our models, with an increase in proinsulin relative to insulin staining, and decreased expression of processing enzymes [44].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Talchai, 2012, Pancreatic β-cell dedifferentiation as a mechanism of diabetic β-cell failure, Cell source

  • May combine two claims.

    Findingown data

    Cytokine treatment increased Aldh1a3 expression in INS1 cells, and miR-21 inhibitor pretreatment abrogated this cytokine-induced increase.

    “Consistent with a role for miR-21 in cytokine-induced β-cell dysfunction and loss of identity, treatment with cytokines increased Aldh1a3 expression, but pretreatment with miR-21 inhibitors abrogated these cytokine-induced increases (Figure 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-21 induction in INS1 β-cells reduced insulin secretion at baseline and in response to high glucose.

    “Compared to INS1-scramble cells, INS1-miR-21 cells exhibited a pronounced reduction in insulin secretion at baseline and a response to high glucose (Figure 1D).”
    • Also stated in: § Results · plain
      “β-cell miR-21 induction markedly reduced GSIS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tgfb2 and Smad2 mRNAs were significantly enriched in biotinylated miR-21 pulldown compared to control, suggesting direct binding to miR-21-5p and -3p respectively.

    “Compared to control pull-downs, Tgfb2 and Smad2 mRNAs were significantly enriched within the biotinylated miR-21 pulldown, suggesting direct binding to miR-21-5p and -3p, respectively (Figure 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Our models exhibit an increase in proinsulin relative to insulin staining and decreased expression of processing enzymes.

    “Additionally, reduced prohormone processing enzyme expression has also been described in models of islet dedifferentiation, a phenotype observed in our models, with an increase in proinsulin relative to insulin staining, and decreased expression of processing enzymes [44].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the present study, baseline and stimulated GSIS were both reduced in concert.

    “In contrast, in the present study, baseline and stimulated GSIS were both reduced in concert.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both zebrafish and mouse models of islet miR-21 induction displayed reduced expression of transcription factors specifying β-cell identity and in insulin+ cells, with increases in double positive insulin+ and glucagon+ islet cells, and hyperglycemia or glucose intolerance.

    “Both zebrafish and mouse models of islet miR-21 induction displayed reduced expression of transcription factors specifying β-cell identity and in insulin+ cells, with increases in double positive insulin+ and glucagon+ islet cells, and hyperglycemia or glucose intolerance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Islets from donor 4 did not exhibit changes in Aldh1a3, Pdx1 or Mafa mRNAs despite successful miR-21 overexpression.

    “Islets from one donor (donor 4) did not exhibit changes in Aldh1a3, Pdx1 or, Mafa mRNAs, despite successful overexpression of miR-21.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Islet inflammatory stress increases islet miR-21 expression and is associated with altered β-cell identity.

    “Islet inflammatory stress increases islet miR-21 expression and is associated with the altered β-cell identity [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Poitout, 2002, Minireview: secondary beta-cell failure in type 2 diabetes–a convergence of glucotoxicity and lipotoxicity, Endocrinology source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Recent data have identified reversion to a progenitor-like state as a compensatory response to islet inflammatory stress, with evidence of β-cell dedifferentiation in models of T1D.

    “Recent data have also identified this reversion to a progenitor-like state, as a compensatory response to islet inflammatory stress, with evidence of β-cell dedifferentiation in models of T1D [[38], [40]].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [[38], [40]]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Increased β-cell miR-21 has a conserved role in loss of β-cell identity, suggesting that this pathway could be an important physiologic response to islet inflammation.

    “This allowed for the usage of multiple model systems in vitro and in vivo to validate a conserved role of increased β-cell miR-21 in loss of β-cell identity, suggesting that this pathway could be an important physiologic response to islet inflammation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The phenotypes observed in zebrafish, mouse, and human islets are homologous manifestations of the same conserved biological process (loss of β-cell identity) rather than species-specific or model-specific artifacts.

  • May combine two claims.

    Interpretationown data

    The inclusion of multiple model systems is a strength, and significant changes in features associated with β-cell identity are present across each system, suggestive of a conserved physiologic response of the β-cell to increases in miR-21.

    “Although inter-species differences in effects may exist, we consider the inclusion of multiple model systems a strength, and the fact that significant changes in features associated with β-cell identity are present across each of these systems is suggestive of a conserved physiologic response of the β-cell to increases in miR-21.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The phenotypes observed in zebrafish, mouse, and human islets are homologous manifestations of the same conserved biological process (loss of β-cell identity) rather than species-specific or model-specific artifacts.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tgfb2 overexpression in rat islets in vitro increases insulin secretion.

    “Tgfb2 overexpression in rat islets in vitro increases insulin secretion [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Totsuka, 1989, Stimulation of insulin secretion by transforming growth factor-beta, Biochemical and Biophysical Research Communications source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationown data

    Differences in phenotype between studies likely reflect differences in terminology, differences in models used, and the likely existence of this phenomenon on a spectrum with heterogeneous effects between disease states, individuals, or even between beta cells within islets.

    “Differences in this phenotype between studies likely reflect differences in terminology, differences in models used, and importantly, the likely existence of this phenomenon on a spectrum—with heterogeneous effects between disease states, individuals, or even between beta cells within islets.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    GSIS in INS1 cells was not normalized for differences in cell death.

    “Our GSIS in INS1 cells was not normalized for differences in cell death, which we previously observed on a larger scale in experiments performed using miR-21 mimics.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The study has identified a novel upstream molecular modulator of β-cell identity, and a mechanistic pathway initiating β-cell dedifferentiation in the context of islet inflammatory stress.

    “Furthermore, our study has identified a novel upstream molecular modulator of β-cell identity, and a mechanistic pathway initiating β-cell dedifferentiation in the context of islet inflammatory stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The use of several model systems and human islets ensure that these results are robust and relevant to human diabetes.

    “The use of several model systems and human islets ensure that these results are robust and relevant to human diabetes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The phenotypes observed in zebrafish, mouse, and human islets are homologous manifestations of the same conserved biological process (loss of β-cell identity) rather than species-specific or model-specific artifacts.
24 of 24

  • The paper relies on this without support.

    The lack of response in donor 4 is due to human disease heterogeneity rather than a technical or biological failure of miR-21 induction.

    “where islets from one donor did not show an effect of miR-21 on β-cell identity, consistent with heterogeneity in human disease.”

  • The paper relies on this without support.

    The phenotypes observed in zebrafish, mouse, and human islets are homologous manifestations of the same conserved biological process (loss of β-cell identity) rather than species-specific or model-specific artifacts.

    “Notwithstanding these differences, the overall similarities between our findings across model systems support the idea of miR-21 as a conserved modulator of β-cell identity.”
2 of 2

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Authors
Ibrahim, S., Johnson, M., Stephens, C. H., Xu, J., Moore, R., Mariani, A., Contreras, C., Syed, F., Mirmira, R. G., Anderson, R. M., & Sims, E. K.
Affiliations
University of Chicago (US)
Corresponding author
  • Anderson, Ryan M.
  • Sims, Emily K.
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2021-11
Volume
53
Pages
101289
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2021.101289
PMC
PMC8361274
OpenAlex
W3179737609
Semantic Scholar
c130a88f4147953a6b2737f1ce63308b6432f88b
Cited by
18
References
49
Citations by year
2026: 3 · 2025: 1 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 1
FWCI
2.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (2UC4DK098085)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R03 DK117253, K08DK103983, R01DK121929, R01 DK105588, R01 DK124906, U01 DK127786, R01 DK060851, UL1TR002529)
  • School of Medicine, Indiana University (F30DK122681)
  • National Center for Advancing Translational Sciences
  • Juvenile Diabetes Research Foundation United States of America (U01 DK127786, R01 DK124906, 2-SRA-2017-498-M-B, R01 DK060851, UL1TR002529, R01 DK105588)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
miR-21, beta-cell dysfunction, beta-cell identity, transforming growth factor-beta2, Smad2, glucose-stimulated insulin secretion, insulitis, beta-cell dedifferentiation, insulin secretion, glucagon, islet dysfunction, zebrafish model, mouse model
MeSH terms
Animals, Humans, RNA, Messenger, Zebrafish, Zebrafish Proteins, MicroRNAs, Insulin-Secreting Cells, Mice, Rats, Smad2 Protein, Transforming Growth Factor beta2

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