Abstract

Diabetes is a group of diseases characterized by chronic hyperglycemia triggered by the inability of the body to produce and/or use sufficient insulin. It occurs when pancreatic insulin-producing β-cells fail to meet the insulin demand due to destruction or dysfunction. An important cause of β-cell loss is apoptosis triggered by terminal endoplasmic reticulum (ER) stress characterizing severely overworked β-cells. This depletion generates increasing stress on the remaining β-cells, impairing their function. Despite major advances, self-management of diabetes remains an unremitting challenge. Therefore, there is an imperious need for the development of a reliable curative therapy implying a robust glucose control limiting the necessity of constant interventions. For both type 1 and type 2 diabetes, an important therapeutic goal is to develop novel β-cell regeneration strategies. To respond to this considerable need, BETAUPREG project proposes to design, refine and consolidate a clinically relevant therapeutic approach aimed at restoring β-cell function in the diabetic pancreas by modulating the unfolded protein response (UPR). This is particularly promising therapeutic target as the ER of β-cells, “professional secretory cells”, manages a tremendous amount of proteins, eliciting a strong pressure on the ER intrinsic folding capacity. Of note, UPR is a conserved mechanism, which helps the secretory performance of a cell by improving its capacity to cope with increased ER load. Our proposed novel strategy is aimed at promoting the β-cells’ secretory function by ameliorating their capacity to cope with increased ER load. We aim to induce a mild or adaptive UPR that would prepare and prime the β-cell for a more efficient protein processing, granting stress resistance and inherently restoring homeostatic glucose levels control. We are certain that our results we will prove instrumental in better designing, refining and consolidating therapeutic interventions that target UPR modulation in diabetes and will be inspirational for other chronic disorders with an ER stress component. 

Objective

The scientific objective of BETAUPREG project was to design, refine and consolidate a clinically relevant therapeutic approach to regenerate β cell function of the diabetic pancreas by modulating a fundamental cellular process, the unfolded protein response (UPR). This was achieved through the following aims: a. Identifying and characterizing the early secretory pathway disturbances that occur during diabetes progression of different models in conjunction with varied insults; b. Defining UPR subclasses that occur in β cells during diabetes progression for different diabetes models; c. Modulating UPR in different diabetes models in order to restore insulin homeostasis.

Estimated results

- Mapping the early secretory pathway morphological events that arise prior occurrence and during diabetes progression in conjunction with different insults;

- Comprehensive and dynamic molecular characterization of UPR specific for each diabetes model/etiology;

- Evaluation of treatment (UPR modulation) efficacy done by determination of glycemia control correlated with insulin secretion, β-cell counts, integrity of early secretory pathway morphology and functionality measured in the intervention groups. 

Project registration code: RO-NO-2019-0544 

Budget: €1,163,385.20

Project implementation period: October 2020 - March 2024

Project financed by Norway Grants 2014-2021 and operated by UEFISCDI.