The Welander TIA1 mutation dedifferentiates insulin-producing cells: Reversal by a GLP-1 receptor agonist – PubMed

https://www.sciencedirect.com/science/article/pii/S0021925826002061

Artikeln blev utvald som Editor’s Pick av JBC.

Huvuddragen kommer att presenteras på det Nordiska Diabetesmötet SSSD i maj,  SSSD Annual Meeting,21-23 May in Gävle Sweden

Vad som på motsvarande sätt händer hos patienter med Lisa Welanders sjukdom (”Hedesundasjukan”), som bär på just denna mutation, kommer också att presenteras på SSSD samt på EASD-mötet i Milano i höst.

Inskickat till www red DiabetologNytt

Av Åke Sjöholm, Gävle

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Nyhetsinfo

ABSTRACT

The Welander TIA1 mutation dedifferentiates insulin-producing cells: Reversal by a GLP-1 receptor agonist

Tongjian Zhao  1 , Jing Cen  1 , Xuan Wang  1 , Mingyu Yang  1 , Joey Lau  1 , Anders Tengholm  1 , Åke Sjöholm  2 , Nils Welsh  3

The RNA-binding proteins TIAR and TIA1 have been reported to affect beta-cell insulin production and viability. The missense E384K TIA1 autosomal dominant mutation is known to cause Welander distal myopathy. This study aimed to study the effects of the TIA1 E384K mutation in human insulin-producing EndoC-βH1 cells. The prime editing technique was used to generate EndoC-βH1 cell clones with the homozygous E384K TIA1 mutation. The E384K TIA1 mutation did not affect high glucose + palmitate-induced stress granule formation and cell death. Instead, the mutated cells respired and proliferated faster than wild-type cells. This was paralleled by a higher MYC mRNA and protein level, a profoundly reduced GLP-1 receptor mRNA expression, increased expression of ”disallowed” beta cell genes, a proinsulin-to-insulin processing defect, a decreased insulin content and release, a decreased PAX4/ARX mRNA ratio, and an increased glucagon production. The TIA1 mutation reduced MYC mRNA binding to TIA1. Downregulation of MYC mRNA levels normalized insulin/glucagon and PAX4/ARX mRNA ratios.

Long-term treatment of TIA1-mutated cells with the GLP-1R agonist liraglutide restored insulin production and reversed beta cell dedifferentiation. It is concluded that the TIA1 E384K mutation, via increased MYC levels and cell proliferation rates, causes beta cell dedifferentiation. Thus, dysfunction of RNA-binding proteins may, at least in certain cases, contribute to the impaired insulin production observed in diabetes.

A better understanding of RNA-binding protein-mediated control of beta cell differentiation, and the protective impact of GLP-1 receptor agonism, could facilitate the development of new treatment strategies in diabetes.

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From AI

The Welander TIA1 mutation (E384K) causes pancreatic β-cell dedifferentiation by increasing MYC levels, leading to reduced insulin production, higher glucagon expression, and dysfunction, according to studies published in 2026. This dysfunction, resulting from impaired RNA-binding protein function, is reversible with a GLP-1 receptor agonist like liraglutide, which restores insulin production.  DiVA portal

Mechanism of Damage: The TIA1 E384K mutation increases cell proliferation and respiratory activity while decreasing TIA1 binding to MYC mRNA, elevating MYC expression, which induces dedifferentiation.
Cellular Impact: Mutated cells demonstrate reduced insulin content and release, increased expression of ”disallowed” β
𝛽-cell genes, increased proinsulin-to-insulin processing errors, and higher glucagon production.
Reversal Mechanism: Long-term treatment with the GLP-1 receptor agonist liraglutide[] successfully reversed the β
𝛽-cell dedifferentiation and restored normal insulin production.
Significance: The findings suggest that RNA-binding protein dysfunction contributes to diabetes-related β
𝛽-cell failure, and GLP-1 agonists can serve as a protective therapeutic strategy.  DiVA portal +1

The study, ”The Welander TIA1 mutation dedifferentiates insulin-producing cells — reversal by a GLP-1 receptor agonist,” was published in the Journal of Biological Chemistry.

https://www.sciencedirect.com/science/article/pii/S0021925826002061

www red DiabetologNytt