Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets

Area of Science:

• Endocrinology
• Cell Biology
• Molecular Medicine

Background:

• Aberrant proinsulin processing and secretion are hallmarks of both type I and type II diabetes.
• Inflammatory cytokines are known to induce pancreatic islet stress and dysfunction, but their precise mechanisms in diabetes remain unclear.

Purpose of the Study:

• To investigate the impact of diabetes-associated cytokines on proinsulin folding, trafficking, secretion, and overall beta-cell function.
• To elucidate the molecular mechanisms by which inflammatory cytokines dysregulate proinsulin processing and secretion in pancreatic beta cells.

Main Methods:

• Human islets were treated with interleukin-1β and interferon-γ.
• Analysis included measurements of cytokine and nitrite release, proinsulin and insulin secretion, RNA sequencing, and affinity purification-mass spectrometry to profile the proinsulin interactome.
• Proinsulin interactions with chaperones, oxidoreductases, and other proteins were assessed.

Main Results:

• Cytokine treatment led to increased secretion of interleukin-6, nitrites, insulin, and aberrant proinsulin release.
• RNA sequencing indicated upregulation of endoplasmic reticulum stress genes, with mass spectrometry revealing altered proinsulin binding to endoplasmic reticulum chaperones and oxidoreductases.
• Novel interactions between proinsulin and diabetes-associated candidate proteins, as well as microtubule motor proteins, were identified, with microtubule destabilization exacerbating proinsulin secretion.

Conclusions:

• Diabetes-associated cytokines significantly dysregulate beta-cell function by altering proinsulin processing and secretion.
• Short-term exposure to an inflammatory environment reshapes proinsulin interactions with key chaperones and secretory pathway regulators, offering new insights into diabetes pathogenesis.