Evidence map›Paper›PMID 40272879›Full record

ArticleDiabetes2025

Genetic Variations in GCKR and PNPLA3 Regulate Metabolic Balance Across the Liver.

Yunyun Ma, Shiqi Zuo, Therlinder Lo, David Phan, Tyler Finley, Adrienne Mackay, Enrique Trigo, Jaana A Hartiala, Hooman Allayee, Anny H Xiang and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Diabetes, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing 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

3 citing papers in PubMed.

  1. Article
  2. Observational
  3. Article
4 · The record

Corrections and comments

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

12 authors.

Yunyun MaDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Shiqi ZuoDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Therlinder LoDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
David PhanDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Tyler FinleyDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Adrienne MackayDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Enrique TrigoDiabetes and Obesity Research Institute of USC, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Jaana A HartialaDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Hooman AllayeeDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Anny H XiangResearch and Evaluation Branch, Kaiser Permanente of Southern California, Pasadena, CA.
Thomas A BuchananDiabetes and Obesity Research Institute of USC, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Richard M WatanabeDepartment of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.ORCID 0000-0003-1015-0531

Funding

Southern California Clinical and Translational Science InstituteUL1TR001855 · NCATS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Thomas A Buchanan, Michele D. Kipke · 2016 to 2026
$81.3M
ZOPOLRESTAT IN NORMOTENSIVE, TYPE 1 DIA WITH INCIPIENT NEPHROPATHYM01RR000043 · NCRR · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZAIA, JOHN A · 1985 to 2010
$76.4M
Genetics of Beta Cell Failure in Mexican AmericansR01DK061628 · NIDDK · UNIVERSITY OF SOUTHERN CALIFORNIA · PI BUCHANAN, THOMAS A, XIANG, ANNY H · 2003 to 2012
$10.0M
EXTRAMURAL RESEARCH FACILITIES CONTRUCTION PROJECTC06CA062528 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI KEDES, LAURENCE H · 1993 to 1994
–
RESEARCH FACILITIES IMPROVEMENT PROGRAM AND REMODELINGC06RR014514 · NCRR · UNIVERSITY OF SOUTHERN CALIFORNIA · PI KEDES, LAURENCE H · 1999 to 1999
–
Merck 32983NCATS NIH HHS UL1 TR001855NCI NIH HHS C06 CA062528NCRR NIH HHS C06 RR014514NCRR NIH HHS CA62528-01NCRR NIH HHS M01 RR000043NCRR NIH HHS RR10600-01NCRR NIH HHS RR14514-01NIDDK NIH HHS R01 DK061628NIH HHSNIH HHS DK-061628University of Southern California General Clinical Research Center M01-RR-00043University of Southern California General Clinical Research Center UL1-TR-001855
6 · The paper itself

Abstract

We tested genetic variants in GCK, GCKR, and PNPLA3 in a large sample of self-identified Mexican Americans from the BetaGene Study for association with type 2 diabetes-related phenotypes under the hypothesis that they may regulate metabolic balance across the liver and contribute to hepatic steatosis and insulin resistance. We further tested whether interactions with dietary fructose and total sugar contributes to the observed associations. GCK rs1799831 was not associated with any type 2 diabetes-related phenotypes either alone or with any interaction tested. We replicated previous associations reported for GCKR rs780094 and PNPLA3 rs738409. We also show the interaction between GCKR rs780094 and dietary fructose is associated with both glucose effectiveness and glucose effectiveness at zero insulin, measures reflective of hepatic glucose uptake. We further show the interaction between GCKR rs780094 and PNPLA3 rs738409 is associated with type 2 diabetes-related traits, including insulin sensitivity. We conclude variations in GCKR and PNPLA3 and their interactions with each other and dietary fructose are partial determinants of hepatic fat, likely due to alterations in relative contributions of different metabolic pathways in the liver. These findings point to both GCKR and PNPLA3 as important therapeutic targets to mitigate hepatic metabolic dysfunction. ARTICLE HIGHLIGHTS: We examined genetic variation in GCKR and PNPLA3 for association with type 2 diabetes-related traits in Mexican Americans without diabetes. We addressed three questions: Are these loci associated with type 2 diabetes-related traits? Is there interaction between these loci? Is there interaction with dietary sugars? These loci individually, and in an interaction, are associated with type 2 diabetes-related traits; these loci also interact with dietary fructose to alter hepatic glucose uptake. Our findings support the hypothesis that these loci, coupled with dietary fructose and total sugars, alter hepatic metabolic balance and may contribute to hepatic fat and insulin resistance.

Indexed as

Adaptor Proteins, Signal TransducingDiabetes Mellitus, Type 2LipaseLiverMembrane ProteinsAcyltransferasesAdultFatty LiverFemaleGenetic VariationHumansInsulin ResistanceMaleMexican AmericansMiddle AgedPhospholipases A2, Calcium-IndependentAcyltransferasesAdaptor Proteins, Signal TransducingGCKR protein, humanLipaseMembrane ProteinsPhospholipases A2, Calcium-IndependentPNPLA3 protein, human

Identifiers

PMID40272879
PMCPMC12185970

What OpenQuestion holds

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LicenceTDM
Read underepoch 390

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 OpenQuestion graph.