Reduced Expression of the Co-regulator TLE1 in Type 2 Diabetes Is Associated with Increased Islet α-Cell Number

Area of Science:

• Endocrinology
• Molecular Biology
• Diabetes Research

Background:

• Type 2 diabetes (T2D) is characterized by β-cell dysfunction, including loss of cellular identity and altered hormone expression.
• Core β-cell transcription factors regulate β-cell identity, and their dysregulation is implicated in T2D.
• TLE1, a transcriptional coregulator near a T2D locus, has known repressive actions on glucagon.

Purpose of the Study:

• To investigate TLE1 expression in human T2D islets.
• To determine if TLE1 disruption is associated with increased glucagon-expressing cells in T2D.
• To explore the role of TLE1 in maintaining β-cell identity.

Main Methods:

• Automated image analysis of immunofluorescence staining in human pancreatic islets from donors with and without T2D.
• Quantification of islet α/β cell ratio and bihormonal (insulin+/glucagon+) cells.
• Assessment of TLE1 expression levels in islets and correlation with cellular composition.
• TLE1 knockdown in EndoC-βH1 cells to evaluate effects on glucagon gene expression.

Main Results:

• T2D islets showed a higher α/β cell ratio and increased frequency of bihormonal cells compared to controls.
• TLE1 expression was significantly reduced in T2D islets.
• Reduced TLE1 expression inversely correlated with the α/β cell ratio.
• TLE1 knockdown in cell models increased glucagon mRNA and mis-expression in insulin-positive cells.

Conclusions:

• TLE1 expression is dysregulated in human T2D.
• Reduced TLE1 is associated with altered islet cell composition, including increased glucagon expression.
• TLE1 may function as a key regulator of human β-cell identity, with its loss potentially driving β- to α-cell conversion in T2D.