Evidence map›Paper›PMID 42019957›Full record

ArticleThe Journal of clinical endocrinology and metabolism2026

Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.

Makie Honda, Ryo Honda, Teiko Komori Nomura, Yuichi Nishikado, Yoshihiro Takahashi, Kazuyoshi Hosomichi, Shin Tsunekawa, Daisuke Yabe, Yukio Horikawa

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PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical endocrinology and metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

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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

1 citing paper in PubMed.

  1. Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.The Journal of clinical endocrinology and metabolism · 2026
    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

9 authors.

Makie HondaDepartment of Diabetes and Endocrinology, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan.
Ryo HondaUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1194, Japan.ORCID 0000-0003-3698-5975
Teiko Komori NomuraUnited Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1194, Japan.
Yuichi NishikadoChildren's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya 453-8511, Japan.
Yoshihiro TakahashiDepartment of Diabetes and Endocrinology, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan.ORCID 0000-0002-4841-9914
Kazuyoshi HosomichiLaboratory of Computational Genomics, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
Shin TsunekawaDepartment of Diabetes and Endocrinology, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan.
Daisuke YabeDepartment of Diabetes and Endocrinology, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan.
Yukio HorikawaDepartment of Diabetes and Endocrinology, Gifu University, Graduate School of Medicine, Gifu 501-1194, Japan.ORCID 0000-0001-7268-6871

Funding

JSPS KAKENHI 23K27835JSPS KAKENHI 23K28017
6 · The paper itself

Abstract

contextOligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood.

objectiveTo investigate the pathogenicity and mechanistic contribution of multiple MODY gene variants identified in a MODY-like family and determine their role in early-onset diabetes.

methodsComprehensive genetic analysis of known MODY genes was performed in a MODY-like family. Functional effects of HNF1A and HNF1B variants were assessed using luciferase reporter assays in HEK293T cells. Functional characterization of ABCC8 variants included Kir6.2-dependent thallium (Tl+) flux assays, sulfonylurea responsiveness, and channel stability.

resultsFour variants in 3 MODY genes were identified in the proband: novel HNF1A p.Ser551Lysfs*2, HNF1B p.Glu102Ala, and ABCC8 p.Arg298Cys and p.Arg521Gln. Functional analysis showed that HNF1A p.Ser551Lysfs*2 retained approximately 5% of wild-type transactivation activity, consistent with loss-of-function, whereas HNF1B p.Glu102Ala and ABCC8 p.Arg521Gln exhibited wild-type-like function. In contrast, ABCC8 p.Arg298Cys reduced channel activity to 77% of wild-type levels while preserving sulfonylurea responsiveness. Segregation analysis identified HNF1A p.Ser551Lysfs*2 and ABCC8 p.Arg298Cys in affected parents. The proband, who inherited both pathogenic variants, developed diabetes earlier than either parent and was exposed to maternal hyperglycemia in utero, which may also have contributed to this early onset.

conclusionFunctional characterization distinguishes pathogenic from variants of unknown significance and supports digenic inheritance of HNF1A and ABCC8. Their additive effects, together with intrauterine hyperglycemia, likely accelerated disease onset. This study provides mechanistic evidence for oligogenic contributions to MODY and expands the genetic architecture of early-onset diabetes.

Indexed as

Diabetes Mellitus, Type 2Hepatocyte Nuclear Factor 1-alphaSulfonylurea ReceptorsAdultAge of OnsetFemaleHEK293 CellsHepatocyte Nuclear Factor 1-betaHumansMalePedigreeABCC8 protein, humanHepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 1-betaHNF1A protein, humanSulfonylurea ReceptorsABCC8digenic inheritanceHNF1AKATP channelMODYβ-cell dysfunction

Identifiers

PMID42019957
PMCPMC13577729

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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.