Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment
Abstract
:1. Introduction
2. The Main Mechanisms Involved in β-Cell Function and Identity
2.1. Inflammation
2.2. Metabolic Stress
2.3. Age-Related Dynamics of β-Cell Dedifferentiation and Transdifferentiation
2.4. Sex-Dependent Variations in Pancreatic Islet Plasticity
2.5. The Impacts of Chemicals on β-Cell Plasticity
3. Molecular Pathways Involved in β-Cell Plasticity
3.1. ER Stress
3.2. Angiotensin Receptors
3.3. mTOR Pathway
3.4. Role of Ubiquitin–Proteasome System in the Pancreatic β-Cell Plasticity
4. Transcriptional Regulation in β-Cell Plasticity
5. Translational Control
6. Epigenetic-Related Targets
6.1. Histon Modifications
6.2. Histone Acetylation
6.3. Histone Methylation
6.4. DNA Methylation
6.5. Chromatin Remodeling
6.6. MicroRNAs in Pancreatic β-Cell Function and Identity
miRNA | Affected Genes | De/Tra/Pro/Neo | Type of Impact | References |
---|---|---|---|---|
miRNA-148a | Pten, Ampk | De | P | [205] |
microRNA-483 | Aldh1a3, Socs3 | De | N | [206,207,208] |
miR-29-a | Cdc42, Irs1, AKT | De | P | [209,210] |
Pro | N | |||
miR-23a | SDF-1α | Tra | N | [211] |
miR-24 | Ire1α, MafA | De | P | [212] |
miR-7 | Pdx1, Isl1 | Neo | P | [213,214] |
miR-25/miR-92b | Neurod1, Mcl1 | De | P | [215] |
miR-9 | Stxbp1 | De/Tra | P | [216] |
miR-96 | PAK1 | β-cell dysfunction | N | [217] |
miR-33a-5p | Abca1 | De | Positive and negative | [218] |
miR-302s | NeuroD1 and Kat2b | De | P | [203] |
miR-203 | Zbtb20 | De | P | [219] |
miR-802 | NeuroD1, Fzd5 | De | P | [220] |
miR-30d | Socs3, Glp1r, Igf1r, MafA, Pdx1, Nkx6.1 | Tra | P | [221] |
miR-212/132 | Fbw7 | Neo | P | [222] |
miR-690 | Sox9, Ngn3, Pdx1 | Neo | N | [223] |
miR-223 | FoxO1, Sox6 | Pro | P | [121] |
miR-155 | Pdx1 | De | P | [224] |
miR-153 | SNAREs, MafA, NeuroD1, Bcl2, Ero1lb, Igf1r, Irs2 | De | P | [225] |
miR-320a | MafF | De | P | [226] |
miR-17-92 cluster | Pten, Cdkn1a, p57, Bcl2L11 | Pro | P | [227] |
miR-21 | Tgfb2, Fgfr3, Smad2 | De | P | [228,229] |
miR-184-3p | Crtc1, Slc25A2 | De and loss | P | [230] |
miR-199b-5p | Mlk3 | Pro | P | [231] |
miR-212-5p | Sirt2 | Insulin secretion and function | N | [232] |
miR-375 | Motn, Mapkap 1, Pdx1, Pdpk1, Notch2, Hnf1β, Cadm1, Pax6, Crem | De | N | [233,234,235,236,237,238,239] |
Pro | P | |||
Neo | P | |||
miR-200 | Zeb1 | De | P | [240] |
miR-146a | Numb | De | N | [241] |
miR-195 | Mfn2 | De | P | [242] |
6.7. Long Non-Coding RNAs (LncRNAs)
7. Reprogramming and Neogenesis of β-Cells
8. Mitigation of β-Cell Dedifferentiation and Transdifferentiation
8.1. Dietary Supplements
8.2. Dietary Interventions and β-Cell Function, Dedifferentiation, and Transdifferentiation
8.3. Physical Activity and β-Cell Plasticity
8.4. Antidiabetic Medications
8.4.1. Glucagon-like Peptide-1 Receptor Agonist (GLP-1 RA)
8.4.2. Sodium–Glucose Co-Transporter 2 (SGLT2) Inhibitors
8.4.3. Dipeptidyl Peptidase-4 Inhibitor (DPP-4 Inhibitor)
8.5. Hormones
8.6. Natural Products
8.7. The Role of the Gut Microbiome in β-Cell Plasticity
8.8. Other Interventions
9. Advancements in Stem Cell-Based Therapies for Diabetes Mellitus
10. β-Cell Proliferation and Regeneration
10.1. The Suppression of Dual-Specificity Tyrosine-Regulated Kinase 1A (DYRK1A)
10.2. Glucagon Receptor Antagonism in β-Cell Regeneration
10.3. The Polyamine Biosynthesis Pathway
10.4. Other Pathways Involved in β-Cell Proliferation
11. Conclusions
12. Limitations
- Lack of review on experimental models: In this study, we did not review the experimental models and the methods used to model β-cell dedifferentiation and transdifferentiation. A comprehensive examination of the various approaches to model β-cell dedifferentiation and transdifferentiation in both in vitro and in vivo settings would be highly beneficial.
- Limited scope on cell plasticity: This review primarily focused on β-cell plasticity and did not cover the plasticities of other cell types. It would be valuable to briefly explore the plasticities of other cells such as hepatocytes, hepatic stellate cells, epidermal stem cells, melanocytes, astrocytes, intestinal stem cells, cardiac fibroblasts, club cells, podocytes, and others. Investigating the plasticities of these diverse cell types could offer insights into the broader applications and implications of cellular plasticity.
- Context of cell plasticity in other diseases: While this review centered on β-cell plasticity, it would have been beneficial to study cell plasticity in the context of other diseases such as liver diseases, neurodegenerative diseases, and cancer. Understanding how cellular plasticity manifests and contributes to the pathology of these diseases could inform the development of new therapeutic strategies and enhance our knowledge of disease progression and treatment.
13. Unanswered Questions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Transcription Factor | Full Name | Targets Genes | Impact on the Genes | De/Tra/Neo/Pro | Impact on β-Cell Plasticity/Regeneration | References |
---|---|---|---|---|---|---|
Pax4 | Paired Box 4 | GCG | R | De | N | [101,102,103,104] |
Arx | R | |||||
Ins | I | Tra | N | |||
Bcl-xL | I | |||||
Gherlin | R | Neo | P | |||
SST | R | |||||
IAPP | R | Pro | P | |||
C-myc | I | |||||
Nkx2.2 | NK2 homeobox 2 | Ins | I | De | N | [105,106,107,108,109,110] |
Pax6 | I | |||||
Nkx6-1 | I | Tra | N | |||
MafA | I | |||||
NeuroD1 | I | Neo | P | |||
Arx | R | |||||
SST | R | Pro | NM | |||
Gherlin | R | |||||
Mnx1 (also known as HLXB9 or HB9) | Motor neuron and pancreas homeobox 1 | Nkx6.1 | I | De | N | [111,112,113,114,115] |
Tra | N | |||||
Ins | I | Neo | NM | |||
Pro | P | |||||
FoxO1 | Forkhead box O1 | Ins1 | R/I | De | N and P | [116,117,118,119,120,121,122,123] |
Pdx1 | R | Tra | N and P | |||
NeuroD | I | |||||
Superoxide dismutase 1 (Sod1) | I | Neo | N | |||
Catalase (Cat) | I | |||||
MafA | I | Pro | P | |||
Glutathione peroxidase 1 | I | |||||
Pdx1 | Pancreatic and Duodenal Homeobox 1 | Ins | I | De | N | [124,125,126,127,128] |
Glut2 | I | |||||
Gck | I | Tra | N | |||
IAPP | I | |||||
SST | I | Neo | P | |||
Pdx1 | I | |||||
Ngn3 | I | Pro | P | |||
NFκB | R | |||||
MafA | I | |||||
MafA | Musculoaponeurotic Fibrosarcoma Oncogene Family, Protein A | Ins | I | De | N | [129,130,131,132,133,134,135] |
Glut2 | I | |||||
Gck | I | Tra | N | |||
Cacng4 | I | |||||
Nanog | R | Neo | P | |||
Pdx1 | I | |||||
NeuroD1 | I | Pro | P | |||
Nkx6.1 | I | |||||
Glis3 | I | |||||
Ngn3 | Neurogenin 3 | NeuroD1 | I | De | N | [99,136,137,138,139] |
Pax4 | I | |||||
Pax6 | I | Tra | N | |||
Isl1 | I | |||||
Cdkn1a | I | Neo | P | |||
Nkx2-2 | I | |||||
Insm1 | I | Pro | N | |||
Kcnj11 | I | |||||
Gck | I | |||||
Slc30a8 | I | |||||
Slc18a2 | I | |||||
SOX9 | Sex-determining region Y (SRY)-box 9 | Ngn3 | I | De | N | [140,141,142,143] |
Nkx6.1 | I | Tra | N | |||
Pax6 | I | Neo | P | |||
Ins | I | Pro | P | |||
HNF1A | Hepatocyte Nuclear Factor 1 A | HNF4A | I | De | N | [144,145,146,147,148,149] |
AS1 | I | |||||
Tmem27 | I | |||||
Kcnj11 | I | |||||
Glut2 | I | Tra | N | |||
Ins | I | Ne | P | |||
NeuroDI | I | Pro | P | |||
Gck | I | |||||
MafB | I | |||||
Gipr | I | |||||
Glpr1 | I | |||||
G6pc2 | I | |||||
Slc5a1 | I | |||||
Pdx1 | I | |||||
Bcl2li(Bcl-xL) | I | |||||
ARX | Aristaless-Related Homeobox | Gcg | I | De | p | [150,151,152,153] |
Pax4 | R | |||||
SST | R | Tra | p | |||
Neo | N | |||||
Pro | ||||||
GATA6 | GATA Binding Protein 6 | iNOS | R | De | N | [154,155,156,157,158] |
Ins | I | |||||
Glut2 | I | Tra | N | |||
Abcc8 | I | |||||
Snap-25 | I | Neo | P | |||
Pdx1 | I | |||||
Nkx6.1 | I | Pro | P | |||
MafA | I | |||||
GLIS3 | GLI Similar 3 | Ins | I | De | N | [159,160,161,162,163] |
Ngn3 | I | Tra | N | |||
MafA | I | Neo | P | |||
Glut2 | I | Pro | P | |||
PAX6 | Paired Box 6 | Ins | I | De | N/P | [164,165,166,167] |
GCG | R | |||||
Glut2 | I | |||||
Gipr | I | |||||
Nkx2.2 | I | |||||
PC1/3 | I | |||||
Glp1r | I | |||||
SST | R | Tra | N/P | |||
Gherlin | R | |||||
Isi | R | Neo | P | |||
Foxa2 | R/I | |||||
Ngn3 | R/I | Pro | P | |||
Pdx1 | R/I | |||||
NeuroD1 | R/I | |||||
MafA | R/I | |||||
Nkx6.1 | R/I | |||||
MafB | Musculoaponeurotic Fibrosarcoma Oncogene Homolog B | GAST | R | De | N | [168,169,170,171] |
SST | R | |||||
P2ry1 | I | Tra | N | |||
Adra2A | I | |||||
Tph1 | I | Neo | P | |||
Ins | I | |||||
ChrnA3, ChrnA4, ChrnB4 | I | Pro | P | |||
Robo1, Robo2, Nrp1, Nrp2 | I | |||||
Hes1 | Hairy and Enhancer of Split-1 | Ngn3 | R | De | P | [172,173,174,175] |
NeuroD | R | Tra | P | |||
Ptf1a | R | Neo | N | |||
p27Kip1 and p57Kip2 | R | Pro | P | |||
HNF4 A | Hepatocyte Nuclear Factor 4 A | Aldolase B | I | De | N | [176,177] |
Glut2 | I | |||||
Gck | I | Tra | N | |||
L-pyruvate kinase | I | |||||
Kir6.2 | I | Neo | P | |||
Ins | I | |||||
Pdx1 | I | Pro | P | |||
Pax4 | I | |||||
Ngn3 | I | |||||
Ki67 | I | |||||
NeuroD1 | Neurogenic Differentiation 1 | Ins | I | De | N | [178,179,180] |
Gck | I | |||||
Abcc8/Sur1, Kcnj11 | I | |||||
Cacna1a | I | Tra | N | |||
Mafa | I | |||||
Nkx6-1 | I | |||||
Pdx1 | I | Neo | P | |||
Nkx2-2 | I | |||||
Insm1 | I | |||||
Isl1 | I | Pro | P | |||
Pax6 | I | |||||
Rfx6 | I | |||||
Cdh4 | R | |||||
Ocln | R | |||||
Mecom | R | |||||
ldha | R | |||||
Nkx6.1 | NK6 homeobox 1 | Glut2 | I | De | N | [130,181,182,183,184] |
G6pc2 | I | |||||
Arx | R | Tra | N | |||
Pdx1 | I | |||||
MafA | I | Neo | P | |||
Ero1lb | I | Pro | P | |||
Slc30a8 | I | |||||
Nr4a1 and Nr4a3 | I | |||||
ISL1 | ISL LIM homeobox 1 | MafA | I | De | N | [185,186,187,188] |
Pdx1 | I | |||||
Glut2 | I | |||||
Ins | I | |||||
NeuroD1 | I | Tra | N | |||
Pax6 | I | |||||
MafB, | I | |||||
Nkx6.2 | I | |||||
Insm1 | I | Neo | P | |||
Sox9 | I | |||||
Arx | I | |||||
Foxa2 | I | |||||
Nkx6.1 | I | Pro | P | |||
GCG | I | |||||
SST | I | |||||
G6pc2 | I |
LncRNAs | Direct and Indirect Targets | De/Tra/Pro/Neo | Type of Effect | References |
---|---|---|---|---|
Gm16308 | Pro | P | [243] | |
DANCR | miR-33a-5p | Pro | P | [218,244] |
H19 | miRNA let-7- miRNA-29a | Pro | P | [245,246,247] |
TUNAR | EZH2 | Pro | P | [248] |
Meg3 | EZH2, Pdx1, MafA | De | N | [249,250] |
βFaar | miR-138-5p | De | N | [251] |
PLUTO | Pdx1 | De | N | [124] |
HILNC25 | Glis3 | De | N | [252] |
Gm10451 | miR-338-3p | De | N | [253] |
810019D21Rik (RIOT) | Nkx6.1 | De | N | [254] |
p3134 | Pdx1 | De | N | [124,255] |
linc-p21 | miR-766-3p | Pro | N | [256] |
HOTAIR | Pdx1 | De | N | [124] |
LncCplx2 | EZH2 | Pro | N | [257] |
MALAT1 | Pdx1 | De | P | [258] |
MIR503HG | CtBP1 | Neo | N | [175] |
GAS5 | miR-29a-3p, miR-96-3p, miR-208a-3p | De | N | [259,260] |
Pro | P | |||
LINC01018 | miR-499a-5p | De | P | [261] |
Pro | N |
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Ghasemi Gojani, E.; Rai, S.; Norouzkhani, F.; Shujat, S.; Wang, B.; Li, D.; Kovalchuk, O.; Kovalchuk, I. Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment. Curr. Issues Mol. Biol. 2024, 46, 7621-7667. https://doi.org/10.3390/cimb46070453
Ghasemi Gojani E, Rai S, Norouzkhani F, Shujat S, Wang B, Li D, Kovalchuk O, Kovalchuk I. Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment. Current Issues in Molecular Biology. 2024; 46(7):7621-7667. https://doi.org/10.3390/cimb46070453
Chicago/Turabian StyleGhasemi Gojani, Esmaeel, Sweta Rai, Farzaneh Norouzkhani, Salma Shujat, Bo Wang, Dongping Li, Olga Kovalchuk, and Igor Kovalchuk. 2024. "Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment" Current Issues in Molecular Biology 46, no. 7: 7621-7667. https://doi.org/10.3390/cimb46070453