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Modeling different types of diabetes using human pluripotent stem cells

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Abstract

Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia as a result of progressive loss of pancreatic β cells, which could lead to several debilitating complications. Different paths, triggered by several genetic and environmental factors, lead to the loss of pancreatic β cells and/or function. Understanding these many paths to β cell damage or dysfunction could help in identifying therapeutic approaches specific for each path. Most of our knowledge about diabetes pathophysiology has been obtained from studies on animal models, which do not fully recapitulate human diabetes phenotypes. Currently, human pluripotent stem cell (hPSC) technology is a powerful tool for generating in vitro human models, which could provide key information about the disease pathogenesis and provide cells for personalized therapies. The recent progress in generating functional hPSC-derived β cells in combination with the rapid development in genomic and genome-editing technologies offer multiple options to understand the cellular and molecular mechanisms underlying the development of different types of diabetes. Recently, several in vitro hPSC-based strategies have been used for studying monogenic and polygenic forms of diabetes. This review summarizes the current knowledge about different hPSC-based diabetes models and how these models improved our current understanding of the pathophysiology of distinct forms of diabetes. Also, it highlights the progress in generating functional β cells in vitro, and discusses the current challenges and future perspectives related to the use of the in vitro hPSC-based strategies.

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Abbreviations

C-PEP:

C-PEPTIDE

Ctr-iPSCs:

Control iPSCs

DE:

Definitive endoderm

DM:

Diabetes mellitus

ER:

Endoplasmic reticulum

GSIS:

Glucose-stimulated insulin secretion

GWAS:

Genome-wide association studies

hESCs:

Human embryonic stem cells

INS:

Insulin

INSR:

Insulin receptor

iPSCs:

Induced pluripotent stem cells

IR:

Insulin resistance

KO:

Knockout

MD:

Monogenic diabetes

NDM:

Neonatal diabetes mellitus

ND:

Non-diabetic

PBMCs:

Peripheral blood mononuclear cells

PNDM:

Permanent neonatal diabetes

RNA-seq:

High-throughput RNA sequencing;

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

TF:

Transcription factor

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Acknowledgements

This work was supported by grants from Qatar National Research Fund (QNRF) (a member of Qatar Foundation) (Grant No. NPRP9-283-3-056; NPRP10-1221-160041).

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  1. Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar

    Essam M. Abdelalim

  2. College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Education City, Doha, Qatar

    Essam M. Abdelalim

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Abdelalim, E.M. Modeling different types of diabetes using human pluripotent stem cells. Cell. Mol. Life Sci. 78, 2459–2483 (2021). https://doi.org/10.1007/s00018-020-03710-9

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