bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/542027

Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D

Sims, E. K.·Nyalwidhe, J.·Syed, F.·Bahnson, H. T.·Haataja, L.·Speake, C.·Morris, M.·Mirmira, R. G.·Nadler, J.·Mastracci, T. L.·Arvan, P.·Greenbaum, C. J.·Evans-Molina, C.
View original source ↗Export metadata ↓

Abstract

Work by our group and others has suggested that elevations in circulating proinsulin relative to C-peptide is associated with development of Type 1 diabetes (T1D). We recently described the persistence of detectable serum proinsulin in a large majority (95.9%) of individuals with longstanding T1D, including individuals with undetectable serum C-peptide. Here we describe analyses performed on human pancreatic sections from the nPOD collection (n=30) and isolated human islets (n=10) to further explore mechanistic etiologies of persistent proinsulin secretion in T1D. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with an inflammatory cytokine cocktail reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced {beta} cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.

Source connections

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Sims, E. K., Nyalwidhe, J., Syed, F., Bahnson, H. T., Haataja, L., Speake, C., Morris, M., Mirmira, R. G., Nadler, J., Mastracci, T. L., Arvan, P., Greenbaum, C. J., Evans-Molina, C.. 2019-02-08. Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D. https://doi.org/10.1101/542027

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗
bioRxiv2019

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreichs ataxia (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to cool temperature in association with limited PKA-mediated lipolysis and downregulation of the expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures detected in KIKO mice.\n\nCollectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to overcome metabolic complications in FRDA.

pathology↗
bioRxiv2019

Parallel Capsule Net for Ischemic Stroke Segmentation

Stroke is one of the leading causes of disability. Segmentation of ischemic stroke could help in planning an optimal treatment. Currently, radiologists use manual segmentation, which can often be time-consuming, laborious and error-prone. Automatic segmentation of ischemic stroke in MRI brain images is a challenging problem due to its small size, multiple occurrences and the need to use multiple image modalities. In this paper, we propose a new architecture for image segmentation, called Parallel Capsule Net, which uses max pooling in every parallel pathways along with dense connections between the parallel layers. We hypothesise that the spatial information lost due to max pooling in these layers can be retrieved by the use of such dense connections. In order to combine the information encoded by the parallel layers, outputs of the layers are concatenated before upsampling. We also propose the use of a modified loss function which consists of a regional term (Generalized Dice loss + Focal Loss) and a boundary term (Boundary loss) to address the problem of class imbalance which is prevalent in medical images. We achieved a competitive Dice score of 0.754, on ISLES SISS data set, compared to a score of 0.67 reported in earlier studies. We also obtained a Dice score of 0.902 with another popular data set, ATLAS. The proposed parallel capsule net can be extended to other similar medical image segmentation problems.

pathology↗