Endoplasmic Reticulum Overcrowding as a Mechanism of β-Cell Dysfunction in Diabetes

• Published in: Biophysical journal Vol. 98; no. 8; pp. 1641 - 1648
• Main Author: Despa, F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-04-2010; The Biophysical Society
• Subjects: Amyloid - metabolism; Crowding; Diabetes; Diabetes Mellitus - physiopathology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Genetic algorithms; Insulin; Insulin-Secreting Cells - metabolism; Islet Amyloid Polypeptide; Kinetics; Models, Biological; Proinsulin - chemistry; Proinsulin - metabolism; Protein; Protein Biosynthesis; Protein Folding; Proteins; Time Factors; Transit; Transport
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2009.12.4295

This study suggests a molecular mechanism that explains the accumulation of denaturated proinsulin in the endoplasmic reticulum (ER) of β-cells. Such states were frequently observed in β-cells experiencing increased demand for insulin production and were shown to lead to secretory dysfunction and diabetes. Here, a self-consistent kinetic model is used to investigate changes in protein translation due to ER overloading. The model is based on a molecular theory that relates the molecular composition and level of molecular crowding in the ER to the kinetic rates of protein folding/misfolding and transit to the Golgi apparatus (GA). This study suggests that molecular crowding forces can increase protein misfolding and impair the transport to the GA, thus overwhelming the quality control mechanism in the ER. A continual accumulation of toxic residues in the ER enhances even further the molecular crowding, accelerating protein denaturation. This article shows that molecular crowding affects differently the transit of various proteins through the ER. Apparently, the molecular crowding level that can inhibit the transport of native proinsulin to the GA influences to a lesser extent the transit of proamylin, a much smaller peptide cosynthesized with proinsulin in the ER. Smaller-volume misfolded proinsulin species may also win the passage competition through the ER and move on the secretory track. However, misfolded proinsulin fails the conversion to active insulin. This study can help us to decipher circumstances leading to the alteration of the secretory function in susceptible β-cells and the onset of diabetes.