Effect of Weight‐Neutral Treatment With Semaglutide or Tirzepatide on β‐Cell Identity in db / db Mice

Dec 7, 2025Acta physiologica (Oxford, England)

Weight-neutral treatment with Semaglutide or Tirzepatide and its effects on insulin-producing cell identity in diabetic mice

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Abstract

After 4 weeks of treatment, both semaglutide and tirzepatide lowered glucose levels in db/db mice but did not reverse early β-cell dedifferentiation.

Tirzepatide stabilized body weight, while semaglutide did not prevent weight gain in db/db mice.
Both treatments increased insulin levels and improved glucose clearance capacity.
Neither treatment reversed β-cell dedifferentiation, indicated by markers such as ALDH1A3 and FOXO1.
The number of β-cells with low PDX1 levels remained higher in treated groups compared to controls.
Gene expression analyses showed muted transcriptional responses with no clear candidate target genes identified.

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AIM: Insulin resistance and pancreatic β-cell failure are key characteristics of type 2 diabetes (T2D). Impaired β-cell function is associated with loss of β-cell identity, resulting in β-cell dedifferentiation or trans-differentiation to other endocrine cells. We have shown that β-cell dedifferentiation can be reversed, restoring insulin secretion. The aim of this study was to investigate whether semaglutide or tirzepatide treatment can reverse early stages of β-cell dedifferentiation in db/db mice independent of their effect on body weight.

METHODS: After 4 weeks of treatment, 12-week-old db/db mice were assessed by oral glucose tolerance test and immunofluorescence to evaluate glucose clearance capacity and effects on pancreatic β-cell. Body weight, fasting blood glucose, and plasma insulin levels were monitored weekly. Bulk RNA sequencing from islets was performed to identify potential targets.

RESULTS: At the doses employed, tirzepatide stabilized, whereas semaglutide was unable to reverse the weight gain of db/db mice. After a 4-week course, both groups showed comparable glucose lowering and increased insulin levels. However, both treatments failed to reverse pancreatic β-cell dedifferentiation, as assessed by either the percentage of cells expressing the dedifferentiation marker ALDH1A3or FOXO1 translocation. Furthermore, the number of β-cells expressing low levels of PDX1 was higher in both treatment groups than in controls. Gene expression analyses showed a muted transcriptional response in overlapping patterns in islets treated with either compound but no obvious candidate target genes. +

CONCLUSION: The findings highlight that the early glucose-lowering effects of semaglutide and tirzepatide in db/db mice occur independently of changes to β-cell identity.

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Effect of Weight‐Neutral Treatment With Semaglutide or Tirzepatide on β‐Cell Identity in db / db Mice

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