Insulin Producing Cells Specific dilp2 Knockdown Induced T1D Model Reveals Circadian and Oxidative Stress Associated DEPs

May 23, 2026FASEB journal : official publication of the Federation of American Societies for Experimental Biology

A Diabetes Model Caused by Reducing Insulin-Producing Cells Shows Changes in Daily Rhythms and Stress-Related Proteins

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Abstract

Drosophila with targeted knockdown of dilp2 exhibits T1D-like symptoms without affecting body size or weight.

The model mimics key features of Type 1 diabetes, including metabolic disturbances and altered circadian rhythms.
Molecular analysis indicates elevated phosphorylated Akt and reduced expression of dfoxo and mTOR.
Lifespan extension is observed, suggesting compensatory mechanisms involving dilp3 and dilp5.
Five differentially expressed proteins were identified, with specific roles linked to oxidative stress and stress responses.
Circadian rhythm analysis shows hyperactivity and arrhythmic behavior in the Drosophila model.

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Type 1 diabetes (T1D) is a chronic metabolic disease characterized by impaired glucose homeostasis and persistent hyperglycemia. Drosophila has emerged as a valuable model to study conserved insulin signaling mechanisms; proteomic insights into T1D-like conditions remain limited. Existing T1D models based on complete ablation of insulin-producing cells (IPCs) often exhibit severe developmental defects limiting their utility for dissecting disease-associated molecular and circadian mechanisms. Here, we report the establishment of an alternative Drosophila T1D model by targeting IPC-specific knockdown of dilp2, a homolog of human insulin, without IPC ablation. This novel model recapitulates key T1D-like features without affecting body size or weight, unlike other conventional models. Molecular analysis revealed elevation in phosphorylated Akt, reduced dfoxo and mTOR expression, and lifespan extension, suggesting a compensatory upregulation of dilp3 and dilp5. Our HRAMS-based proteomics study, for the first time, identifies five differentially expressed proteins (DEPs): Disc overgrown kinase (dco), Glutathione S-transferase 1 (GstS1), Turandot A (TotA), Turandot C (TotC), and Proteasome subunit beta type 6 (Prosβ6), validated by qRT-PCR. Downregulation of dco and GstS1 is associated with circadian arrhythmicity and elevated oxidative stress, respectively, whereas upregulation of TotA, TotC, and Prosβ6 reflects activation of stress responses and disruption of proteostasis under T1D-like conditions. Notably, circadian rhythm analysis exhibited hyperactivity and arrhythmic locomotor behavior in T1D flies. Collectively, these findings demonstrate dilp2 knockdown alone can induce T1D-like symptoms including multiple metabolic, circadian, and proteomic insights. The newly identified DEPs may serve as potential candidates for biomarker/therapeutic targets in T1D pathophysiology.

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Insulin Producing Cells Specific dilp2 Knockdown Induced T1D Model Reveals Circadian and Oxidative Stress Associated DEPs

Abstract

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