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Metformin induces mitochondrial remodeling and differentiation of pancreatic progenitor cells into beta-cells by a potential mechanism including suppression of the T1R3, PLCβ2, cytoplasmic Ca+2, and AKT

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Abstract

The main goal of this study was to investigate the molecular changes in pancreatic progenitor cells subject to high glucose, aspartame, and metformin in vitro. This scope of work glucose, aspartame, and metformin were exposed to pancreatic islet derived progenitor cells (PID-PCs) for 10 days. GLUT1’s role in beta-cell differentiation was examined by using GLUT1 inhibitor WZB117. Insulin+ cell ratio was measured by flow cytometry; the expression of beta-cell differentiation related genes was shown by RT-PCR; mitochondrial mass, mitochondrial ROS level, cytoplasmic Ca2+, glucose uptake, and metabolite analysis were made fluorometrically and spectrophotometrically; and proteins involved in related molecular pathways were determined by western blotting. Findings showed that glucose or aspartame exposed cells had similar metabolic and gene expression profile to control PID-PCs. Furthermore, relatively few insulin+ cells in aspartame treated cells were determined. Aspartame signal is transmitted through PLCβ2, CAMKK2 and LKB1 in PID-PCs. The most obvious finding of this study is that metformin significantly increased beta-cell differentiation. The mechanism involves suppression of the sweet taste signal’s molecules T1R3, PLCβ2, cytoplasmic Ca+2, and AKT in addition to the direct effect of metformin on mitochondria and AMPK, and the energy metabolism of PID-PCs is remodelled in the direction of oxidative phosphorylation. These findings are very important in terms of determining that metformin stimulates the mitochondrial remodeling and the differentiation of PID-PCs to beta-cells and thus it may contribute to the compensation step, which is the first stage of diabetes development.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

T2D:

Type 2 diabetes

PID-PCs:

Pancreatic islet-derived progenitor cells

AMPK :

AMP-activated protein kinase

T1R2 :

Taste receptor type 1 member 2

T1R3:

Taste receptor type 1 member 3

PLCβ2:

Phospholipase Cβ2

IP3:

Inositol 1,4,5-triphosphate

cAMP:

Cyclic AMP

GLUT1:

Glucose transporter 1

DCFDA:

2′, 7′-Dichlorofluorine diacetate

FBS:

Fetal bovine serum

PDX-1:

Pancreatic and duodenal homeobox 1

NKX6.1:

NKX homeobox 6.1

PAX4:

Paired box 4

NEUROG3 :

Neurogenin 3

NKX2.2:

NKX homeobox 2.2

INS2:

Insulin 2

GLUT2:

Glucose transporter 2

2-DG:

2-Deoxyglucose

UCP2:

Uncoupling protein 2

MDH2:

Malate dehydrogenase 2

PIP2:

Phosphatidylinositol 4,5-bisphosphate

CAMKK2:

Calcium/calmodulin-dependent protein kinase kinase 2

LKB1:

Liver kinase B1

AKT:

Protein kinase B

NMDA:

N-methyl D-aspartate

ZDF:

Zucker diabetic fatty

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Funding

This study is supported by The Scientific and Technological Research Council of Turkey (116Z560) and Istanbul University Scientific Research Foundation (26194 and 52123).

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Authors and Affiliations

  1. Molecular Biology Program, Biology Section, Institute of Science, Istanbul University, Istanbul, Turkey

    Ertan Celik & Merve Ercin

  2. Molecular Biology Section, Biology Department, Faculty of Science, Istanbul University, Vezneciler, 34134, Istanbul, Turkey

    Merve Ercin, Sehnaz Bolkent & Selda Gezginci-Oktayoglu

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  1. Ertan Celik
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  2. Merve Ercin
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  4. Selda Gezginci-Oktayoglu
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Contributions

Ertan Celik: executed cell culture applications, RT-PCR, immunocytochemistry, glucose uptake, cAMP assay, Ca2+ measurement, metabolite measurement, mitochondrial mass and mitochondrial protein measurement, mitochondrial ROS and insulin secretion assays; contributed to flow cytometric labelings, cell lysate preparation, western blotting and edited manuscript. Merve Ercin: executed flow cytometric labelings and analysis, cell culturing; contributed to metabolite measurement, cell lysate preparation, western blotting and edited manuscript. Sehnaz Bolkent: contributed to provide project and edited the manuscript. Selda Gezginci-Oktayoglu: created project idea, written project and carried it as a responsible researcher; set up the experiments; assessed results and written manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Selda Gezginci-Oktayoglu.

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Highlights

• Glucose does not alter the metabolic profile of pancreatic progenitors.

• Aspartame and metformin stimulate the beta-cell differentiation.

• Aspartame signal is transmitted via PLCβ2, CAMKK2, and LKB1 in pancreatic progenitors.

• Metformin suppresses T1R3, PLCβ2, Cytoplasmic Ca+2, and AKT.

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Suppl. Fig. 1. Glucose uptake rates (μmol/mg protein/20 min) in control (FM), aspartame (A), metformin (M) and aspartame/metformin combination (A+M) absence (white columns) or presence (black columns) GLUT1 inhibitor WZB117. ap<0.05 vs FM and , mp<0.05 vs A+M. (PNG 29 kb)

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Celik, E., Ercin, M., Bolkent, S. et al. Metformin induces mitochondrial remodeling and differentiation of pancreatic progenitor cells into beta-cells by a potential mechanism including suppression of the T1R3, PLCβ2, cytoplasmic Ca+2, and AKT. J Physiol Biochem 78, 869–883 (2022). https://doi.org/10.1007/s13105-022-00910-8

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