Incretin Peptides Like Tirzepatide Partially Restore Glucagon Response Damaged by Inflammation in Type 1 Diabetes Model

What the researchers found

Long-term (6-day) exposure of human islet microtissues to proinflammatory cytokines (IL-1β, IFN-γ, TNF-α) created a type 1 diabetes-like phenotype with dose-dependent suppression of glucagon secretion at low glucose (2.8 mmol/L), reduced insulin and somatostatin secretion, decreased ATP content, increased cell death, and diminished key transcription factors (ARX, NKX6.1).

Critically, while incretin treatment during cytokine exposure did not prevent damage, acute treatment with [D-Ala2]-GIP (with or without liraglutide) or tirzepatide after cytokine exposure partially restored low-glucose glucagon secretion. Alpha cells also retained partial responsiveness to L-arginine stimulation despite cytokine damage.

Why it matters

Hypoglycemia is the most immediate life-threatening complication in type 1 diabetes, and impaired glucagon counterregulation makes it worse. If incretin peptides can restore some glucagon response, they could provide a new strategy to reduce hypoglycemia risk — addressing an unmet need that affects nearly every person with type 1 diabetes.

How the study worked

Human pancreatic islet microtissues were exposed to proinflammatory cytokines for 1 or 6 days. Alpha cell function was measured using sequential glucose-dependent secretion assays. Additional assessments included ATP content, caspase-3/7 activity (cell death), chemokine secretion, and islet transcription factor and hormone content. Incretin receptor agonists were tested both during and after cytokine exposure.

What this study cannot tell us

This is an in vitro study using isolated human islet microtissues, which don't fully replicate the complex in vivo environment of the pancreas. The cytokine model approximates but doesn't perfectly replicate type 1 diabetes pathology. Glucagon restoration was partial, not complete. No in vivo validation was performed, and the clinical relevance of the degree of restoration is uncertain.

How to read the evidence

This is a well-designed in vitro study using human islet tissue with thorough mechanistic characterization. However, it remains preclinical with no in vivo or clinical validation, placing it at an early translational stage.

When this study was published

Published in 2025, this study reflects the latest research into repurposing incretin drugs for type 1 diabetes, an area of growing clinical interest.

The bigger picture

Incretin-based therapies have transformed type 2 diabetes management, and there is growing interest in their potential for type 1 diabetes. This study provides mechanistic support for a novel application — not for insulin secretion, but for restoring the glucagon counterregulatory response that protects against hypoglycemia. It adds biological rationale to ongoing clinical investigations of incretin drugs in type 1 diabetes.

Questions still open

• Would tirzepatide or GIP agonists improve glucagon counterregulation in people with type 1 diabetes during clinical hypoglycemia?
• Could long-term incretin treatment prevent or slow alpha cell dysfunction in early type 1 diabetes?
• What is the mechanism by which incretin receptor agonism restores glucagon secretion in cytokine-damaged alpha cells?

Common questions

Read the original research

Proinflammatory cytokine-induced alpha cell impairment in human islet microtissues is partially restored by dual incretin receptor agonism.

Diabetologia, 68(7), 1492-1508

Citation

Henriksen, Kristine; Rufer, Chantal; Title, Alexandra C; Jawurek, Sayro; Hartmann, Bolette; Holst, Jens J; Knop, Filip K; Yesildag, Burcak; Størling, Joachim. (2025). Proinflammatory cytokine-induced alpha cell impairment in human islet microtissues is partially restored by dual incretin receptor agonism.. Diabetologia, 68(7), 1492-1508. https://doi.org/10.1007/s00125-025-06425-3