Evidence mapPaperPMID 40908405Full record

ArticleDiabetologia2025

Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs-PKCε-insulin receptor kinase

Jie Zheng, Rafael C Gaspar, Ikki Sakuma, Brandon T Hubbard, Dongyan Zhang, Ali Nasiri, Mario Kahn, Mark Perelis, Varman T Samuel, Kitt F Petersen and 1 more

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Article in Diabetologia, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Jie ZhengDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Rafael C GasparDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Ikki SakumaDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Brandon T HubbardDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Dongyan ZhangDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Ali NasiriDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Mario KahnDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Mark PerelisIonis Pharmaceuticals, Carlsbad, CA, USA.
Varman T SamuelDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Kitt F PetersenDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Gerald I ShulmanDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. gerald.shulman@yale.edu.ORCID http://orcid.org/0000-0003-1529-5668

Funding

Yale Diabetes Research CenterP30DK045735 · YALE UNIVERSITY · 1993 to 2025
$10.2M
Medical Scientist Training ProgramT32GM136651 · YALE UNIVERSITY · 2025 to 2025
$2.3M
Training Program in Investigative HepatologyT32DK007356 · YALE UNIVERSITY · 1986 to 2025
$1.7M
Development of Controlled Release Mitochondrial Protonophore (CRMP) as a Novel Treatment for Type-2 Diabetes and Non-Alcoholic Steatohepatitis in Dysmetabolic Non-Human PrimatesR01DK119968 · NIDDK · YALE UNIVERSITY · PI GERALD I SHULMAN · 2023 to 2023
$532k
Elucidating the pathophysiology and molecular mechanisms of renal insulin resistanceF30DK131846 · YALE UNIVERSITY · 2025 to 2025
$55k
NIDDK NIH HHS F30 DK131846NIDDK NIH HHS F31 DK126362NIDDK NIH HHS P30 DK045735NIDDK NIH HHS P30 DK34989NIDDK NIH HHS R01 DK113984NIDDK NIH HHS R01 DK119968NIDDK NIH HHS T32 DK007356NIGMS NIH HHS T32 GM136651
6 · The paper itself

Abstract

aims/hypothesisCIDEB (cell death-inducing DFF45-like effector B) deficiency is associated with a reduced incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) in humans; however, the underlying mechanism responsible for this protective effect remains unclear.

methodsC57BL/6J male mice were fed a high-fat diet (HFD) to recapitulate key aspects of MASLD and hepatic insulin resistance. Cideb knockdown (KD) was achieved using a 2'-O-methoxyethyl (MOE) antisense oligonucleotide (ASO). In vivo rates of hepatic mitochondrial gluconeogenesis and tricarboxylic acid (TCA) cycle flux were assessed by Q-Flux. The Comprehensive Lab Animal Monitoring System (CLAMS) was used to evaluate rates of whole-body energy expenditure. Hepatic and peripheric insulin sensitivity were evaluated using hyperinsulinaemic-euglycaemic clamp studies combined with radio-labelled isotopes.

resultsWe showed that Cideb ASO treatment increased rates of whole-body energy expenditure by ~25% and decreased hepatic triacylglycerol by ~65% in a HFD mouse model of MASLD compared with the wild-type mice. Cideb KD reduced hepatic fat content, which could mostly be attributed to increased rates of hepatic mitochondrial oxidation, in combination with reduced hepatic lipogenesis. Additionally, Cideb KD ameliorated HFD-induced insulin resistance, which could be attributed to decreased plasma membrane sn-1,2-diacylglycerols (DAGs)-protein kinase C (PKC)ε-insulin receptor kinase (IRK) CONCLUSIONS/

interpretationThese findings demonstrate that Cideb KD enhances mitochondrial fat oxidation and reduces hepatic lipogenesis, which in turn mitigates HFD-induced hepatic steatosis and insulin resistance via the plasma membrane sn-1,2-DAGs-PKCε-IRK

Indexed as

Fatty LiverInsulin ResistanceMitochondriaAnimalsCell MembraneDiet, High-FatDiglyceridesEnergy MetabolismLiverMaleMiceMice, Inbred C57BLOxidation-ReductionProtein Kinase C-epsilonDiglyceridesProtein Kinase C-epsilonCideb deficiencyEnergy expenditureHepatic lipid accumulationInsulin sensitivityMASLDMitochondrial oxidationMOE ASO

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.