Diabetes & Metabolism Journal

Original Articles

Complications
Cardiorespiratory Fitness and Risk of Microvascular Complications in Patients with Type 2 Diabetes Mellitus: Anning Xu, Haofeng Zhou, Chaofan Wang, Qian He, Ping Wu, Wenjing Wu, Hongjiang Wu, Alice P.S. Kong, Huanyi Cao, Haixia Guan, Yunjiu Cheng; Received November 5, 2025 Accepted February 10, 2026 Published online May 18, 2026; DOI: https://doi.org/10.4093/dmj.2025.1109 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
To investigate the association between cardiorespiratory fitness (CRF) and the risk of incident microvascular complications in patients with type 2 diabetes mellitus (T2DM), and to assess the effect of genetic risk and potential mediation by circulating biomarkers.
Methods
This prospective analysis included 3,102 adults with T2DM from the UK Biobank. CRF was estimated as maximal oxygen uptake using a submaximal cycle test and categorized as low, moderate, or high. Cox proportional hazards models were used to estimate hazard ratios (HRs) for incident diabetic nephropathy, retinopathy, and neuropathy. Interactions with a polygenic risk score and mediating roles of biomarkers were evaluated.
Results
Over a median 12.47-year follow-up, 331 nephropathy, 268 retinopathy, and 88 neuropathy cases were recorded. Compared to low CRF, moderate and high CRF were associated with 22% (HR, 0.78; 95% confidence interval [CI], 0.61 to 0.99) and 45% (HR, 0.55; 95% CI, 0.36 to 0.85) lower risks of nephropathy, respectively. Each 1-metabolic equivalent of task increment in CRF was linked to 11% lower nephropathy risk. No significant associations were found for retinopathy or neuropathy. Genetic predisposition did not modify the association between CRF and diabetic nephropathy. Triglycerides and white blood cell count accounted for 7.46% and 12.88% of the association, respectively.
Conclusion
Higher CRF is independently associated with lower risk of diabetic nephropathy in T2DM, and genetic risk does not alter this relationship. The association was partially mediated by triglycerides and white blood cell count. Assessing CRF may improve risk stratification and prevention of diabetic kidney disease.

Genetics
Exon Sequencing of HNF1β in Chinese Patients with Early-Onset Diabetes: Siqian Gong, Hong Lian, Yating Li, Xiaoling Cai, Wei Liu, Yingying Luo, Meng Li, Si-min Zhang, Rui Zhang, Lingli Zhou, Yu Zhu, Qian Ren, Xiuying Zhang, Jing Chen, Jing Wu, Xianghai Zhou, Xirui Wang, Xueyao Han, Linong Ji; Diabetes Metab J. 2025;49(2):321-330. Published online November 13, 2024; DOI: https://doi.org/10.4093/dmj.2024.0159

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Abstract PDF Supplementary Material PubReader ePub

Background
Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients.
Methods
Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines.
Results
Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher.
Conclusion
MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Citations

Citations to this article as recorded by

Transient neonatal diabetes mellitus as an early diagnostic clue to HNF1B-related disease – two case reports and a literature review
Marcin Kołbuc, Paweł Bednarek, Rafał Motyka, Tomasz Jarmoliński, Marzena Michalak-Kloc, Bodo B. Beck, Małgorzata Urbańska-Kosińska, Marcin Zaniew
Molecular and Cellular Pediatrics.2026;[Epub] CrossRef
Diabetes associated with HNF1B: beyond Occam’s razor—A case report
Carolina Sager-La Ganga, Clara Solà, Karen Castillo, Carme Figueredo, Ignacio Conget
Acta Diabetologica.2025; 62(8): 1347. CrossRef

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