Introduction: Recent studies have concluded that elevated circulating branched chain amino acids (BCAA) are associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and obesity. However, the development of this association over time and the quantification of the strength of this association for individual BCAAs prior to T2DM diagnosis remains unexplored. Methods: A systematic search was conducted using the Healthcare Databases Advance Search (HDAS) via the National Institute for Health and Care Excellence (NICE) website. The data sources included EMBASE, MEDLINE and PubMed for all papers from inception until November 2021. Nine studies were identified in this systematic review and meta-analysis. Stratification was based on follow-up times (0–6, 6–12 and 12 or more years) and controlling of body mass index (BMI) through the specific assessment of overweight cohorts was also undertaken. Results: The meta-analysis revealed a statistically significant positive association between BCAA concentrations and the development of T2DM, with valine OR = 2.08 (95% CI = 2.04–2.12, p < 0.00001), leucine OR = 2.25 (95% CI = 1.76–2.87, p < 0.00001) and isoleucine OR = 2.12, 95% CI = 2.00–2.25, p < 0.00001. In addition, we demonstrated a positive consistent temporal association between circulating BCAA levels and the risk of developing T2DM with differentials in the respective follow-up times of 0–6 years, 6–12 years and ≥12 years follow-up for valine (OR = 2.08, 1.86 and 2.14, p < 0.05 each), leucine (OR = 2.10, 2.25 and 2.16, p < 0.05 each) and isoleucine (OR = 2.12, 1.90 and 2.16, p < 0.05 each) demonstrated. Conclusion: Plasma BCAA concentrations are associated with T2DM incidence across all temporal subgroups. We suggest the potential utility of BCAAs as an early biomarker for T2DM irrespective of follow-up time.

/pdf/the-association-between-circulating-branched-chain-amino-2fxqze67.pdf

The Association between Circulating Branched Chain Amino Acids and the Temporal Risk of Developing Type 2 Diabetes Mellitus: A Systematic Review & Meta-Analysis

Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment

Branched-chain amino acids (BCAAs) are essential amino acids in human bodies. They have complex metabolic pathways and various metabolites. Both BCAAs and its metabolites are involved in various processes such as protein anabolism and catabolism, energy supply, signaling transduction and so on. Previous studies have observed the widely alternations of BCAAs and its related proteins in multiple tumor phenotypes, which suggests that BCAAs metabolic disorders may have emerged as a powerful factor for tumor metabolism reprogramming. BCAAs metabolism has a pivotal role in tumorigenesis and progression, including cell growth, proliferation, migration, invasion, and so on. In this review, we try to shed light on the crucial role of BCAAs metabolic disorders in different tumor types by focusing on the impacts of metabolic disorders of BCAAs and discussing the notable proteins involved in cancer metabolic reprogramming of BCAAs, such as BCAT1/2, BCKDH-BCKDK-PPM1K complex, transporters of BCAAs and its metabolites, transcription factors and so on, and present several possible diagnose approaches and therapies to BCAAs-related cancers. 

The role of branched chain amino acids metabolic disorders in tumorigenesis and progression.

Major depression disorder (MDD) is one of the most common psychiatric disorders and one of the leading causes of disability in worldwide. Both inflammation and GABAergic dysfunction have been implicated in the pathophysiology of MDD. Caspase-1, a classic inflammatory caspase, regulates AMPARs-mediated glutamatergic neurotransmission. However, the role of caspase-1 in chronic stress-induced GABAergic dysfunction remains largely unknown. In this study, we found that serum and hippocampal caspase-1-IL-1β levels increased significantly in chronic restraint stress (CRS) mice, and a significant negative correlation occurred between levels of caspase-1 and depression-like behaviors. Furthermore, CRS significantly decreased GAD67 mRNA levels and GABAergic neurotransmission accompanied by the reduction of GABA concentration, reduced the amplitude and frequency of mIPSCs inhibitory postsynaptic currents (mIPSCs) and the decreased surface expression of GABAARs γ2 subunit in the hippocampus. Genetic deficiency of caspase-1 not only blocked CRS-induced depression-like behaviors, but also alleviated CRS-induced impairments in GABAergic neurotransmission. Finally, reexpression of caspase-1 in the hippocampus of Caspase-1-/- mice increased susceptibility to stress-induced anxiety- and depression-like behaviors through inhibiting GAD67 expression and GABAARs-mediated synaptic transmission. Our study suggests that CRS dysregulates GABAergic neurotransmission via increasing the levels of caspase-1-mediated neuroinflammation in the hippocampus, ultimately leading to depression-like behaviors. This work illustrates that targeting caspase-1 may provide potential therapeutic benefits to stress-related GABAergic dysfunction in the pathogenesis of MDD. 

/pdf/caspase-1-affects-chronic-restraint-stress-induced-206v80eb.pdf

Caspase-1 affects chronic restraint stress-induced depression-like behaviors by modifying GABAergic dysfunction in the hippocampus

BCAA dysmetabolism in the host and gut microbiome, a key player in the development of obesity and T2DM

Dysregulation of glucagon is associated with the pathophysiology of type 2 diabetes. We previously reported that postprandial hyperglucagonemia is more obvious than fasting hyperglucagonemia in type 2 diabetes patients. However, which nutrient stimulates glucagon secretion in the diabetic state and the underlying mechanism after nutrient intake are unclear. To answer these questions, we measured plasma glucagon levels in diabetic mice after oral administration of various nutrients. The effects of nutrients on glucagon secretion were assessed using islets isolated from diabetic mice and palmitate-treated islets. In addition, we analyzed the expression levels of branched chain amino acid (BCAA) catabolism-related enzymes and their metabolites in diabetic islets. We found that protein, but not carbohydrate or lipid, increased plasma glucagon levels in diabetic mice. Among amino acids, BCAAs, but not the other essential or nonessential amino acids, increased plasma glucagon levels. BCAAs also directly increased the intracellular calcium concentration in α cells. When BCAAs transport was suppressed by an inhibitor of system L-amino acid transporters, glucagon secretion was reduced even in the presence of BCAAs. We also found that the expression levels of BCAA catabolism-related enzymes and their metabolite contents were altered in diabetic islets and palmitate-treated islets compared to control islets, indicating disordered BCAA catabolism in diabetic islets. Furthermore, BCKDK inhibitor BT2 suppressed BCAA-induced hypersecretion of glucagon in diabetic islets and palmitate-treated islets. Taken together, postprandial hypersecretion of glucagon in the diabetic state is attributable to disordered BCAA catabolism in pancreatic islet cells.

Disordered branched chain amino acid catabolism in pancreatic islets is associated with postprandial hypersecretion of glucagon in diabetic mice.

Reduced expression of glutamate decarboxylase 67 (GAD67), encoded by the Gad1 gene, is a consistent finding in postmortem brains of patients with several psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. The dysfunction of GAD67 in the brain is implicated in the pathophysiology of these psychiatric disorders; however, the neurobiological consequences of GAD67 dysfunction in mature brains are not fully understood because the homozygous Gad1 knockout is lethal in newborn mice. We hypothesized that the tetracycline-controlled gene expression/suppression system could be applied to develop global GAD67 knockdown mice that would survive into adulthood. In addition, GAD67 knockdown mice would provide new insights into the neurobiological impact of GAD67 dysfunction. Here, we developed Gad1tTA/STOP−tetO biallelic knock-in mice using Gad1STOP−tetO and Gad1tTA knock-in mice, and compared them with Gad1+/+ mice. The expression level of GAD67 protein in brains of Gad1tTA/STOP−tetO mice treated with doxycycline (Dox) was decreased by approximately 90%. The GABA content was also decreased in the brains of Dox-treated Gad1tTA/STOP−tetO mice. In the open-field test, Dox-treated Gad1tTA/STOP−tetO mice exhibited hyper-locomotor activity and decreased duration spent in the center region. In addition, acoustic startle responses were impaired in Dox-treated Gad1tTA/STOP−tetO mice. These results suggest that global reduction in GAD67 elicits emotional abnormalities in mice. These GAD67 knockdown mice will be useful for elucidating the neurobiological mechanisms of emotional abnormalities, such as anxiety symptoms associated with psychiatric disorders.

/pdf/global-knockdown-of-glutamate-decarboxylase-67-elicits-3qx45q35ao.pdf

Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Touko Hirano

Author Tools

Chat about Author

Papers

Disordered branched chain amino acid catabolism in pancreatic islets is associated with postprandial hypersecretion of glucagon in diabetic mice.

Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice.