Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

doi:10.1038/s41467-020-15935-0

. 2020 May 21;11(1):2538.

doi: 10.1038/s41467-020-15935-0.

Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

Qinglei Yin^#¹, Qicheng Ni^#¹, Yichen Wang^#¹, Hongli Zhang², Wenyi Li¹, Aifang Nie¹, Shu Wang¹, Yanyun Gu¹, Qidi Wang^{3

4}, Guang Ning⁵

Affiliations

¹ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
² Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 200137, Shanghai, China.
³ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. wqd11094@rjh.com.cn.
⁴ Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. wqd11094@rjh.com.cn.
⁵ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. guangning@medmail.com.cn.

^# Contributed equally.

PMID: 32439909
PMCID: PMC7242325
DOI: 10.1038/s41467-020-15935-0

Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

Qinglei Yin et al. Nat Commun. 2020.

. 2020 May 21;11(1):2538.

doi: 10.1038/s41467-020-15935-0.

Authors

Qinglei Yin^#¹, Qicheng Ni^#¹, Yichen Wang^#¹, Hongli Zhang², Wenyi Li¹, Aifang Nie¹, Shu Wang¹, Yanyun Gu¹, Qidi Wang^{3

4}, Guang Ning⁵

Affiliations

¹ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
² Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 200137, Shanghai, China.
³ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. wqd11094@rjh.com.cn.
⁴ Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. wqd11094@rjh.com.cn.
⁵ Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. guangning@medmail.com.cn.

^# Contributed equally.

PMID: 32439909
PMCID: PMC7242325
DOI: 10.1038/s41467-020-15935-0

Abstract

Compromised β-cell identity is emerging as an important contributor to β-cell failure in diabetes; however, the precise mechanism independent of hyperglycemia is under investigation. We have previously reported that mTORC1/Raptor regulates functional maturation in β-cells. In the present study, we find that diabetic β-cell specific Raptor-deficient mice (βRapKO^GFP) show reduced β-cell mass, loss of β-cell identity and acquisition of α-cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs β-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to β-cell failure. Moreover, loss of Raptor activates α-cell transcription factor MafB (via modulating C/EBPβ isoform ratio) and several α-cell enriched genes i.e. Etv1 and Tspan12, thus initiates β- to α-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing β-cell identity and repressing α-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Increased α/β cell ratio in βRapKO^GFP mice.**
a Heatmap of genes critical to endocrine cell in wild type (WT) and βRapKO islets (n = 4–5). b The number of Ins⁺ cells per islet (n = 3, p = 0.0008) and c the number of Gcg⁺ cells per islet were calculated (n = 3, p = 0.023). At least, 46 islets were used for quantifications. d The proportion of pancreatic α-cell mass among pancreatic α- and β-cell mass was shown (n = 4, p = 0.0017). e The proliferation of Gcg⁺ cell was determined by quantification of the percentage of Ki67⁺ cells in Gcg⁺ cells (n = 3). At least, 50 islets were used for quantifications. f Pancreatic sections from 8-week-old WT, βRapKO^GFP mice were immunostained for insulin (white), glucagon (green), and GFP (red). Nuclei were stained with DAPI (blue) (n = 3). The yellow arrows indicated insulin, glucagon, and GFP co-stained cells. Scale bars, 20 μm. g The percentage of GFP⁺Gcg⁺ cells among GFP⁺ cells in 8-week-old WT and βRapKO^GFP mice (n = 3, p = 1.83046E-05). At least, 1837 GFP⁺ cells over three mice each group were used for quantifications. h Representative pancreatic sections showed expression of α-cells marker—Arx (red), insulin (white), and glucagon (green) in WT and βRapKO^GFP mice at 8 weeks of age (n = 3). Scale bars, 20 μm. i Immunostaining showed expression of α-cells marker—MafB (red), insulin (white), and glucagon (green) in control and βRapKO^GFP mice at 8 weeks of age (n = 3). Yellow boxes showed the specific areas of the islet, which were enlarged and represented by arrows on the right to demonstrate protein expression within specific cells. Scale bars, 20 μm. j Transmission electron microscopy (TEM) of pancreatic islets reveals a combination of mature insulin, immature insulin, and glucagon-like granules in the same cell in βRapKO^GFP mice (n = 3 independent samples). Granule identity is indicated by colored arrows: glucagon (red), mature insulin (blue), and immature insulin (yellow). Data represent means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 by two-sided Student’s t-test.

**Fig. 2. Impaired proinsulin synthesis and ATP levels for GSIS.**
a Schematic of insulin pump implantation. b Random blood glucose levels were monitored every other day in WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP mice from 4 weeks to 8 weeks old (n = 6 for WT, n = 7 for diabetic KO, n = 13 for euglycemic KO). c Representative pancreatic sections immunostained for insulin (green) and glucagon (red). The ratio of Gcg⁺ cells to Ins⁺ cells was calculated (n = 3). At least 50 islets or 2000 insulin-positive cells were used for quantifications. Scale bars, 20 μm. d Images of islets labeled with insulin (green) and UCN3 (red). MFI of UCN3 in these three groups (n = 3). At least 10 islets from three sections were used for MFI. Yellow boxes showed the expression of UCN3. Scale bars, 20 μm. e In vitro glucose-stimulated C-peptide secretion in islets at 2.8 and 16.7 mM glucose levels for 1 h (reported as percent of C-peptide content) (n = 7 for WT, n = 6 for diabetic KO, n = 6 for euglycemic KO). White, black, and gray circles represented the WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP groups, respectively. Stimulation index of C-peptide secretion in diabetic βRapKO^GFP and euglycemic βRapKO^GFP mice as compared with controls (n = 7 for WT, n = 6 for diabetic KO, n = 6 for euglycemic KO). f ATP content at 2.8 mM glucose and 16.7 mM glucose (n = 3). g Pancreatic C-peptide content (n = 3 independent samples) and h pancreatic proinsulin content normalized by protein concentration were shown (n = 3 independent samples). i The ratio of pancreatic proinsulin to C-peptide content was determined (n = 3 independent samples). j The ratio of islet proinsulin to C-peptide content per 10 size-matched islets at 2.8 mM and high 16.7 mM glucose levels was determined (n = 6 for WT, n = 5 for diabetic KO, n = 5 for euglycemic KO). k INS-1 cells were transfected with SiRaptor or SiNC for 72 h. Immunoblotting and quantification of insulin and proinsulin in INS-1 cells transfected with SiNC or SiRaptor (n = 4 independent cell experiments). Data represent means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 by two-sided Student’s t-test and one-way ANOVA adjusted by LSD multiple comparison, p values included in source data.

**Fig. 3. Impaired metabolic coupling of insulin secretion.**
a The number of differentially expressed genes within the three groups (n = 3–4). b Gene expression profiles regulated by *Raptor* were subjected to hierarchical clustering (n = 3–4). c GO analysis of differentially expressed genes as identified by RNA-seq of 8-week-old WT (n = 3) and euglycemic βRapKO^GFP β-cells (n = 4) was associated with β-cell function. d Visualization of differential expression of genes involved in insulin secretion. **e–g** Relative expression of selected transcripts associated with β-cell secretion function (n = 5 independent sample for WT, n = 5 independent sample for diabetic βRapKO^GFP, n = 4 independent sample for euglycemic βRapKO^GFP, p values included in source data) (e), mitochondrial metabolism (n = 5 independent sample for WT, n = 5 independent sample for diabetic βRapKO^GFP, n = 4 independent sample for euglycemic βRapKO^GFP, p values included in source data) (f), and disallowed genes (n = 5 independent sample for WT, n = 5 independent sample for diabetic βRapKO^GFP, n = 4 independent sample for euglycemic βRapKO^GFP, p values included in source data) (g) in WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP β-cells by qRT-PCR. h Representative immunofluorescent staining for Glut2 (red) and insulin (green) among 8-week-old WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP mice (n = 3). Insets showed different expression levels of Glut2. Quantification of Glut2 areas in Ins⁺ areas in WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP mice (n = 3, WT vs diabetic βRapKO^GFP: p = 0.002; diabetic βRapKO^GFP vs euglycemic βRapKO^GFP: p = 0.613; WT vs euglycemic βRapKO^GFP: p = 0.001), at least 10 islets from three sections were used for quantifications of Glut2. Scale bars, 20 μm. Data represent means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 by one-way ANOVA.

**Fig. 4. Induction of α-cell-enriched genes in euglycemic βRapKO^GFP.**
a α-Cell-enriched genes and β-cell-enriched genes were subjected to perform principle component analysis based on the dataset from Qiu et al.. b Venn diagram representation of the subsets of *Raptor*-regulated genes that were enriched in α-cells. c Heatmap showed the differential expression of 57 overlapped genes in 8-week-old WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP β-cells (n = 3-4). d Relative expression of genes involved in cell identity by qRT-PCR (n = 5 independent sample for WT, n = 5 independent sample for diabetic βRapKO^GFP, n = 4 independent sample for euglycemic βRapKO^GFP, p values included in source data). e Representative immunofluorescent staining for GFP (red) and glucagon (green) among 8-week-old WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP mice (n = 4 for WT, n = 4 for diabetic βRapKO^GFP, n = 3 for euglycemic βRapKO^GFP). The yellow arrows indicated glucagon and GFP co-stained cells. Percentage of Gcg⁺GFP⁺ cells among GFP⁺ cells in WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP mice was determined (n = 4 independent sample for WT, n = 4 independent sample for diabetic βRapKO^GFP, n = 3 independent sample for euglycemic βRapKO^GFP, WT vs diabetic βRapKO^GFP: p = 0.007; diabetic βRapKO^GFP vs euglycemic βRapKO^GFP: p = 0.012; WT vs euglycemic βRapKO^GFP: p = 0.009). At least 50 islets were used for quantifications. Scale bars, 20 μm. f Representative immunofluorescent staining for ALDH1A3 (red) and insulin (green) among 8-week-old WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP mice (n = 3). Insets showed different expression levels of ALDH1A3. Percentage of ALDH1A3⁺Ins⁺ cells among Ins⁺ cells in WT, diabetic βRapKO^GFP, and euglycemic βRapKO^GFP mice was calculated (n = 3, WT vs diabetic βRapKO^GFP: p < 0.001; diabetic βRapKO^GFP vs euglycemic βRapKO^GFP: p = 0.628; WT vs euglycemic βRapKO^GFP: p < 0.001). For ALDH1A3 quantification, at least 36 islets were used. Scale bars, 20 μm. Data represent means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 by one-way ANOVA.

**Fig. 5. mTORC1 regulates α-cell transcriptional factor MafB.**
a Relative expression of *glucagon*, *Arx,* and *MafB* in 2-week-old WT and βRapKO^GFP β-cells by qRT-PCR (n = 4). b Quantification of Gcg⁺GFP⁺, Arx⁺GFP⁺, and MafB⁺GFP⁺ cells in GFP⁺ cells in 2-week-old WT and βRapKO^GFP mice (n = 3, Gcg: p = 0.58; Arx: p = 0.86; MafB: p = 9.00122E-07). At least 1783 GFP⁺ cells were used for quantifications. c Representative immunofluorescent staining for MafB (green) and GFP (red) in 2-week-old WT and βRapKO^GFP mice (n = 3). Yellow box showed the specific area of the islet, which was enlarged and represented by arrows to demonstrate MafB⁺GFP⁺ cell. Scale bars, 20 μm. d Relative expression of selected transcripts associated with α-cell-enriched genes in INS-1 cells which were transfected with SiNC or SiRaptor in the presence or absence of SiMafB by qRT-PCR (n = 4 independent cell experiments, p values included in source data). e, f Western blotting showed the expression of C/EBPβ(LAP) in 8-week-old WT and βRapKO^GFP mice (n = 3, p = 0.049). g, h INS-1 cells were treated with Rapamycin (25 nM), C/EBPβ(LAP) protein expression was assayed by immunoblot (n = 3 independent cell experiments). i Luciferase reporter gene assays revealed that Rapamycin treatment for 12 h positively regulated the luciferase activity of MafB (n = 5 independent cell experiments, p = 0.0011). j Immunoblotting to evaluate the LAP and LIP protein levels after LAP and LIP overexpression (n = 2 independent cell experiments). k Luciferase reporter assay using a rat MafB promoter reporter. INS-1 cells were transfected with GFP or LAP overexpression vector (n = 3 independent cell experiments, p = 0.001). l qRT-PCR analysis of *MafB* expression in GFP and LAP overexpressed INS-1 cells (n = 4 independent cell experiments, p = 0.0023). m Luciferase reporter assay using a rat MafB promoter reporter. INS-1 cells were transfected with GFP or LIP overexpression vector in the absence and presence of Rapamycin (n = 3 independent cell experiments, GFP + Vehicle vs GFP + Rapamycin, p < 0.001; LIP + Vehicle vs LIP + Rapamycin, p = 0.001). n qRT-PCR analysis of *MafB* expression in GFP and LIP overexpressed INS-1 cells in the absence or presence of Rapamycin (n = 4 independent cell experiments, GFP + Vehicle vs GFP + Rapamycin, p = 0.002; LIP + Vehicle vs LIP + Rapamycin, p = 0.177). Data represent means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 by two-sided Student’s t-test and one-way ANOVA.

**Fig. 6. Induction of α-cell-enriched genes in 2-week-old βRapKO^GFP.**
a GO analysis of differentially expressed genes as identified by microarray of 2-week-old WT (n = 3) and βRapKO^GFP β-cells (n = 4) was associated with β-cell function and metabolism. b Venn diagram representation of the subsets of *Raptor*-regulated genes in 2-week-old purified β-cells that were enriched in α-cells and heatmap showed the differential expression of nine overlapped genes in 2-week-old WT and βRapKO^GFP β-cells (n = 3–4). c Analysis strategy to identify *Raptor*-dependent genes in β-cells is shown. d Heatmap of seven *Raptor*-dependent genes obtained from 8-week-old RNA-seq and 2-week-old microarray. e Volcano plot shows differential genes between 2-week-old WT and βRapKO^GFP β-cells. Microarray identification of *Etv1* and *Tspan12* as significantly upregulated α-cell-enriched genes in 2-week-old βRapKO^GFP β-cells. f INS-1 cells were transfected with SiRaptor or SiNC for 48 h. qRT-PCR confirmed *Raptor*-dependent genes in INS-1 cells (n = 4 independent cell experiments, for *Raptor*, p = 0.029; for *Slc2a2*, p = 0.048; for *Msln*, p = 0.031; for *Ppp1r1a*, p = 0.28; for *Etv1*, p = 0.004; for *Tspan12*, p = 0.008; for *Aass*, p = 0.02). g, h INS-1 cells were transfected with GFP, Etv1, or Tspan12 overexpression vector. g Luciferase reporter assay using a rat glucagon promoter reporter (n = 3 independent cell experiments, p = 0.039). h qRT-PCR analysis of *glucagon* expression in vector transfected INS-1 cells (n = 4 independent cell experiments, p = 0.02). Data represent means ± SEM. *p < 0.05, **p < 0.01 by two-sided Student’s t-test.

**Fig. 7. The role of *Raptor* in β-cell identity maintenance and α-cell gene repression.**
*Raptor* is required for maintaining β-cell identity as well as repressing α-cell signature. At euglycemia, loss of *Raptor* results in β-cell dedifferentiation (marked as UCN3^low, Glut2^low, and Aldh1a3^high) with compromised β-cell identity, metabolic uncoupling, and regression to multi-hormonal state with α-cell features. We propose *Raptor*/C/EBPβ/*MafB*-dependent and *MafB*-independent ways in silencing α-cell-enriched genes and glucagon expression in healthy β-cells. *Raptor*-deficient β-cells with compromised identity become dysfunctional and eventually cause diabetes; in turn, hyperglycemia further aggravates dedifferentiation and reprogramming process.

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References

1. Weir GC, Bonner-Weir S. Five of stages of evolving β-cell dysfunction during progression to diabetes. Diabetes. 2004;53:S16–S21. - PubMed
1. Accili D, et al. When β-cells fail: lessons from dedifferentiation. Diabetes Obes. Metab. 2016;18:117–122. - PMC - PubMed
1. Remedi MS, Emfinger C. Pancreatic β-cell identity in diabetes. Diabetes Obes. Metab. 2016;18:110–116. - PMC - PubMed
1. Brereton MF, Rohm M, Ashcroft FM. β-Cell dysfunction in diabetes: a crisis of identity? Diabetes Obes. Metab. 2016;18:102–109. - PMC - PubMed
1. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150:1223–1234. - PMC - PubMed

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[1] Weir GC, Bonner-Weir S. Five of stages of evolving β-cell dysfunction during progression to diabetes. Diabetes. 2004;53:S16–S21. - PubMed

[2] Weir GC, Bonner-Weir S. Five of stages of evolving β-cell dysfunction during progression to diabetes. Diabetes. 2004;53:S16–S21. - PubMed

[3] Accili D, et al. When β-cells fail: lessons from dedifferentiation. Diabetes Obes. Metab. 2016;18:117–122. - PMC - PubMed

[4] Accili D, et al. When β-cells fail: lessons from dedifferentiation. Diabetes Obes. Metab. 2016;18:117–122. - PMC - PubMed

[5] Remedi MS, Emfinger C. Pancreatic β-cell identity in diabetes. Diabetes Obes. Metab. 2016;18:110–116. - PMC - PubMed

[6] Remedi MS, Emfinger C. Pancreatic β-cell identity in diabetes. Diabetes Obes. Metab. 2016;18:110–116. - PMC - PubMed

[7] Brereton MF, Rohm M, Ashcroft FM. β-Cell dysfunction in diabetes: a crisis of identity? Diabetes Obes. Metab. 2016;18:102–109. - PMC - PubMed

[8] Brereton MF, Rohm M, Ashcroft FM. β-Cell dysfunction in diabetes: a crisis of identity? Diabetes Obes. Metab. 2016;18:102–109. - PMC - PubMed

[9] Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150:1223–1234. - PMC - PubMed

[10] Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150:1223–1234. - PMC - PubMed

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Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

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Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

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