Targeted pharmacological therapy restores β-cell function for diabetes remission.

Nature Metabolism
Stephan SachsHeiko Lickert

Abstract

Dedifferentiation of insulin-secreting β cells in the islets of Langerhans has been proposed to be a major mechanism of β-cell dysfunction. Whether dedifferentiated β cells can be targeted by pharmacological intervention for diabetes remission, and ways in which this could be accomplished, are unknown as yet. Here we report the use of streptozotocin-induced diabetes to study β-cell dedifferentiation in mice. Single-cell RNA sequencing (scRNA-seq) of islets identified markers and pathways associated with β-cell dedifferentiation and dysfunction. Single and combinatorial pharmacology further show that insulin treatment triggers insulin receptor pathway activation in β cells and restores maturation and function for diabetes remission. Additional β-cell selective delivery of oestrogen by Glucagon-like peptide-1 (GLP-1-oestrogen conjugate) decreases daily insulin requirements by 60%, triggers oestrogen-specific activation of the endoplasmic-reticulum-associated protein degradation system, and further increases β-cell survival and regeneration. GLP-1-oestrogen also protects human β cells against cytokine-induced dysfunction. This study not only describes mechanisms of β-cell dedifferentiation and regeneration, but also reveals pharma...Continue Reading

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Citations

Mar 11, 2020·Nature Reviews. Endocrinology·Claire Greenhill
Jul 23, 2020·Nature Metabolism·Dario F De Jesus, Rohit N Kulkarni
Oct 30, 2020·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·Jinli PeiDayong Wang
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Dec 24, 2020·Trends in Pharmacological Sciences·Sara BilekovaHeiko Lickert
Feb 15, 2021·Molecular Metabolism·Ciro SalinnoHeiko Lickert
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Nov 4, 2021·Diabetes/metabolism Research and Reviews·Justyna FlotyńskaAleksandra Uruska

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Datasets Mentioned

BETA
GSE87375

Methods Mentioned

BETA
hormone replacement therapy
scRNA-seq
protein folding
reverse phase chromatography
ELISA
FCS
protein assay
chip
Assay
RNA-seq

Software Mentioned

PAGA
trend
FreeStyle
Excel
CellRanger
Genomics
EnrichR
Scrublet
Bioconductor
Envigo

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