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Omics Reveal Far Reaching Effects of Verapamil Treatment in Subjects with Type 1 Diabetes

ABSTRACT: Proteomic data from recent onset T1D patients treated with verapamil where significant extension of the honeymoon phase was observed. Samples were depleted with MARS Hu-14 column, digested with trypsin, labeled with 11-plex TMT, then analyzed by LC-MS/MS. Data was searched with MS-GF+ using PNNL's DMS Processing pipeline. TMT data was extracted using PlexedPiper.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Wei-Jun Qian

PROVIDER: MSV000087598 | MassIVE | Wed Jun 09 14:14:00 BST 2021

SECONDARY ACCESSION(S): PXD026601

REPOSITORIES: MassIVE

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Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes.

Xu Guanlan G Grimes Tiffany D TD Grayson Truman B TB Chen Junqin J Thielen Lance A LA Tse Hubert M HM Li Peng P Kanke Matt M Lin Tai-Tu TT Schepmoes Athena A AA Swensen Adam C AC Petyuk Vladislav A VA Ovalle Fernando F Sethupathy Praveen P Qian Wei-Jun WJ Shalev Anath A

Nature communications 20220303 1

Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T ...[more]

PMID: 35241690

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Intestinal metaproteomics reveals host-microbiota interactions in subjects at risk for type 1 diabetes

Project description:Dysbiosis of the gut microbiota has been linked to disease pathogenesis in type 1 diabetes (T1D), yet the functional consequences to the host of this dysbiosis is unknown. Here, we have performed a metaproteomic analysis of 103 stool samples from subjects that either had recent-onset T1D, were high-risk autoantibody positive or low-risk autoantibody negative relatives of individuals with beta cell autoimmunity or healthy individuals to identify signatures in host and microbial proteins associated with disease risk. Multivariate modelling analysis demonstrated that both human host proteins and microbial derived proteins could be used to differentiate new-onset and seropositive individuals from low-risk and healthy controls. Significant alterations were identified between subjects with T1D or islet autoimmunity versus autoantibody negative and control subjects in the prevalence of individual host proteins associated with exocrine pancreas function, inflammation and mucosal function. Data integrationIntegrative analysis combining the metaproteomic data with bacterial abundance showed that taxa that were depleted in new-onset T1D patients were positively associated with host proteins involved in maintaining function of the mucous barrier, microvilli adhesion and exocrine pancreas. These data support the notion that T1D patients have increased intestinal inflammation and decreased barrier function. They also confirmed that pancreatic exocrine dysfunction occurs in new-onset T1D patients and show for the first time that this dysfunction is present in high-risk individuals prior to disease onset. Our data has identified a unique T1D-associated signature in stool that may be useful as a means to monitor disease progression or response to therapies aimed at restoring a healthy microbiota.

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Temporal Expression Profiling of Plasma Proteins in Type 1 Diabetes Progression

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The proteomic landscape of patient-derived CD4+ T cells in recent-onset type 1 diabetes

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Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes

Project description:Currently, no oral medications are available for individuals suffering from type 1 diabetes (T1D). Our randomized placebo-controlled phase 2 trial recently revealed that oral verapamil has short- term beneficial effects in subjects with new-onset type 1 diabetes (T1D) 1. However, what exact biological changes verapamil elicits in humans with T1D, how long they may last, and how to best monitor any associated therapeutic success has remained elusive. We therefore now conducted extended analyses of the effects of continuous verapamil use over a 2-year period, performed unbiased proteomics analysis of serum samples and assessed changes in proinflammatory T-cell markers in subjects receiving verapamil or just standard insulin therapy. In addition, we determined the verapamil-induced changes in human islets using RNA sequencing. Our present results reveal that verapamil regulates the thioredoxin system and promotes an anti-oxidative and anti-apoptotic gene expression profile in human islets, reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cells and interleukin-21 and normalizes serum levels of chromogranin A (CHGA), a recently identified T1D autoantigen 2,3. In fact, proteomics identified CHGA as the top serum protein altered by verapamil and as a potential therapeutic marker. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D.

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The proteomic landscape of patient-derived CD4+ T cells in recent-onset type 1 diabetes

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