A proteomic approach to obesity and type 2 diabetes

López-Villar, Elena; Martos‐Moreno, Gabriel Ángel; Chowen, Julie A.; Okada, Shigeru; Kopchick, John J.; Argente, Jesús

doi:10.1111/jcmm.12600

Cited by 34 publications

(21 citation statements)

References 112 publications

(137 reference statements)

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“…Pathway analyses help to organize a list of proteins into a cohesive list of pathway maps to interpret proteomics results. These analyses have proved to be a very powerful interpretation tool in biological research, facilitating novel insights in disparate fields including development 50 , apoptosis 51 , cancer 52,53 , and other diseases 54,55 . Several biological pathways have been linked to AD using similar methods 30,[56][57][58] .…”

Section: Use Case 4: Identification and Quantification Of Signaling Pmentioning

confidence: 99%

Global quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer’s disease

Ping

Kundinger

Duong

et al. 2020

Preprint

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Alzheimer's disease (AD) is characterized by an early, asymptomatic phase (AsymAD) in which individuals exhibit amyloid-beta (Aβ) plaque accumulation in the absence of clinically detectable cognitive decline. Here we report an unbiased multiplex quantitative proteomic and phosphoproteomic analysis using tandem mass tag (TMT) isobaric labeling of human post-mortem cortex (n=27) across pathology-free controls, AsymAD and symptomatic AD individuals. With off-line high-pH fractionation and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on an Orbitrap Lumos mass spectrometer, we identified 11,378 protein groups across three TMT 11-plex batches. Immobilized metal affinity chromatography (IMAC) was used to enrich for phosphopeptides from the same TMT-labeled cases and 51,736 phosphopeptides were identified. Of these, 48,992 were quantified by TMT reporter ions representing 33,652 unique phosphosites. Two reference standards in each TMT 11-plex were included to assess intra-and inter-batch variance at the protein and peptide level. This comprehensive human brain proteome and phosphoproteome dataset will serve as a valuable resource for the identification of biochemical, cellular and signaling pathways altered during AD progression. Background & SummaryAlzheimer's disease (AD) is the most common age-related neurodegenerative disease, currently affecting more than 47 million people worldwide 1,2 . AD is characterized by an early, asymptomatic phase (AsymAD) in which individuals exhibit amyloid-beta (Aβ) plaque accumulation in the absence of significant tau neurofibrillary tangles (NFT) and cognitive decline 3,4 . Currently the downstream biochemical and cellular processes that eventually lead to changes in cognition and even dementia are not well understood. Thus, a holistic or systems-level approach that aims to understand these altered processes may yield insight into new drug targets and biomarkers for AD.Proteins are the proximate mediators of disease, integrating the effects of genetic, epigenetic, and environmental factors. It is well established that distinct mechanisms regulate expression and turnover of RNA and proteins, resulting in weak correlations in their respective levels 5 . This is mainly attributed to the complexity of the human proteome in which 90% of genes yield alternatively-spliced RNA transcripts 6,7 , and each translated protein isoform is potentially altered by up to 300 or more posttranslational modifications (PTMs) 8,9 . Protein phosphorylation is one of the key PTMs that govern signaling pathways and pathophysiological mechanisms in AD 10,11 , inspiring a large body of research that has identified several kinases including GSK-3β, CDK5, PKC, MAPK, and ROCK2 that have been implicated in the phosphorylation of tau and other key substrates in AD brain [12][13][14][15][16] . Conversely, reduced expression and activity of protein phosphatases like PP2A are also thought to contribute to enhanced phosphorylation of tau and other substrates 17 . Thus, quantifying total protein ...

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Section: Use Case 4: Identification and Quantification Of Signaling Pmentioning

confidence: 99%

Global quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer’s disease

Ping

Kundinger

Duong

et al. 2020

Preprint

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“…A promising approach, metabolomics, has shown its value in the identification of circulating small molecules, such as branched-chain amino acids, acylcarnitines and aromatic amino acids, that can serve early detection and diagnosis of T2D [17][18][19][20][21]. Advances have also occurred in proteomics; the Human Proteome Organization is opening a new door to better understand T2D pathology through the application of proteomics to improve identification of persons at risk and improvement of current therapies [22]. At the same time, modulation of gene expression by epigenetic modifications and the action of microRNAs have been recognized as critical processes affecting T2D risk [23].…”

Section: Multi-omics: Beyond Genetic Variationmentioning

confidence: 99%

The Continuing Evolution of Precision Health in Type 2 Diabetes: Achievements and Challenges

Lin

Wessel

2019

Curr Diab Rep

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Purpose of Review The purpose of this review was to summarize recent advances in the genomics of type 2 diabetes (T2D) and to highlight current initiatives to advance precision health. Recent Findings Generation of multi-omic data to measure each of the 'biologic layers', developments in describing genomic function and annotation in T2D relevant tissue, along with the increasing recognition that T2D is a heterogeneous disease, and large-scale collaborations have all contributed to advancing our understanding of the molecular basis of T2D. Summary Substantial advances have been made in understanding the molecular basis of T2D pathogenesis, such that precision health diabetes is increasingly becoming a reality. For precision diabetes to become routine in clinical and public health, additional large-scale multiomic initiatives are needed along with better assessment of our environment to delineate an individual's diabetes subtype for improved detection and management.

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“…63,64 Genetic and proteomic studies continue to inform on the multivariable causes and pathogenesis of type 2 diabetes and identify specific treatment targets for a few patients, but for most patients these approaches have yet to inform the design of new drugs. [65][66][67]…”

Section: Epigenetics Genetics and Proteomicsmentioning

confidence: 99%

Future glucose-lowering drugs for type 2 diabetes

Bailey

Tahrani

Barnett

2016

The Lancet Diabetes & Endocrinology

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The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision.

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A proteomic approach to obesity and type 2 diabetes

Cited by 34 publications

References 112 publications

Global quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer’s disease

Global quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer’s disease

The Continuing Evolution of Precision Health in Type 2 Diabetes: Achievements and Challenges

Future glucose-lowering drugs for type 2 diabetes

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