52 research outputs found
Ī²-Cell failure in type 2 diabetes: a case of asking too much of too few?
The islet in type 2 diabetes (T2DM) is characterized by a deficit in Ī²-cells, increased Ī²-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low Ī²-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased Ī²-cell workload results in T2DM in some but not all individuals. We propose that the extent of the Ī²-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate Ī²-cell mass in the face of subsequent insulin resistance may expose Ī²-cells to a burden of insulin and IAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising Ī²-cell function and inducing Ī²-cell apoptosis
Ī²-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.
ObjectiveThe islet in type 2 diabetes is characterized by Ī²-cell apoptosis, Ī²-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in Ī²-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system.Research design and methodsWe used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.ResultsWe report accumulation of polyubiquinated proteins and UCH-L1 deficiency in Ī²-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in Ī²-cells induced endoplasmic reticulum stress leading to apoptosis.ConclusionsOur results indicate that defective protein degradation in Ī²-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises Ī²-cell viability
Ī²-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.
UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in Ī²-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy.
Voies de signalisation au sein de la cellule b pancrƩatique (aspects normaux et physiopathologiques)
MONTPELLIER-BU MĆ©decine UPM (341722108) / SudocMONTPELLIER-BU MĆ©decine (341722104) / SudocSudocFranceF
Insulin-degrading enzyme inhibition, a novel therapy for type 2 diabetes?
The insulin-degrading enzyme (IDE) has been identified as a type 2 diabetes and Alzheimer's disease susceptibility gene, though its physiological function remains unclear. Maianti etĀ al. (2014) now propose that an IDE inhibitor may be a promising therapeutic strategy for type 2 diabetes
- ā¦