Sunita M. C. De Sousa1,2,3  · Jennifer M. N. Phan4,5 · Amanda Wells4  · Kathy H. C. Wu6,7,8,9 · Hamish S. Scott1,4,10

Received: 12 December 2024 / Accepted: 3 January 2025 / Published online: 16 January 2025 © The Author(s) 2025, corrected publication 2025

Abstract

Aims To assess the utility of reanalysing GCK variants of uncertain significance (VUS) as an intervention to improve the detection of monogenic diabetes.

Methods We examined GCK VUS in a local cohort of individuals with suspected monogenic diabetes and re-curated each variant against the recent ClinGen GCK-specific variant classification guidelines.

Results Variant reanalysis achieved a new ‘likely pathogenic’ classification (i.e., positive results) in 4/8 identified VUS.The single most common newly applied criterion indicating variant pathogenicity was a confirmed phenotype of GCK-hyperglycaemia. RNA sequencing and segregation studies were performed in two cases but not additive to reclassification.

Conclusions This is the first VUS reclassification study in monogenic diabetes using gene-specific guidelines. Within the limits of this small study, we observed a high rate (50%) of VUS upgrades to a positive result, thereby confirming the util-ity of VUS reanalysis– particularly with biochemical phenotyping– in increasing the detection of monogenic diabetes. We recommend HbA1c, fasting blood glucose and either pancreatic autoantibody negativity or a small oral glucose tolerance test increment as a feasible minimum dataset to inform variant classification at the individual patient level, noting the ongoing work of the ClinGen Monogenic Diabetes Expert Panel in systematically reviewing GCK variants at the international level.

Keywords Glucokinase · Monogenic diabetes · DNA sequencing · Genetics

Abbreviations

PVS Pathogenic very strong

PS Pathogenic strong

PM Pathogenic moderate

PP Pathogenic supporting

FHx Family history

AR Autosomal recessive

del/ins Deletion/insertion

IFG Impaired fasting glucose

OGTT Oral glucose tolerance test

Communicated by Massimo Federici, M.D.

Sunita M. C. De Sousa

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1 Adelaide Medical School, University of Adelaide, Adelaide, Australia

2 Endocrine & Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia

3 Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia

4 Department of Genetics & Molecular Pathology, SA Pathology, Adelaide, Australia

5 Flinders Medical School, Flinders University, Adelaide, Australia

6 Clinical Genomics, St Vincent’s Hospital, Darlinghurst, Australia

7 School of Medicine, University of New South Wales, Sydney, Australia

8 Discipline of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, Australia

9 School of Medicine, University of Notre Dame, Sydney, Australia

10 Centre for Cancer Biology, an alliance between SA Pathology, University of South Australia, Adelaide, Australia

Tim Mori1,2  · Katsiaryna Prystupa2,3  · Klaus Straßburger1,2  · Marc Bonn2,4 · Oana Patricia Zaharia2,3,5  · Olaf Spörkel2,4 · Oliver Kuß1,2,6  · Michael Roden2,3,5  · Robert Wagner2,3,5

Received: 10 December 2024 / Accepted: 13 December 2024 / Published online: 17 January 2025 © The Author(s) 2025

Chiara M. Soldavini1  · Gabriele Piuri1  · Paola A. Corsetto2  · Irma Colombo2  · Veronica Resi3  · Stefania Zava2  · Gabriele Rossi1  · Enrico Ferrazzi1,4 · Angela M. Rizzo2

Received: 27 December 2024 / Accepted: 2 March 2025 / Published online: 1 April 2025 © The Author(s) 2025

Abstract

Normal pregnancy is characterized by changes in lipid metabolism with significant implications for the health of both mother and offspring. When these changes develop into maternal dyslipidemia, a significant association with adverse pregnancy outcomes has been observed, including the development of gestational diabetes (GD), modulation of the inflam-matory response, and excessive fetal growth. In the present study, we performed a lipidomic assessment of patients at GD diagnosis (24–28 weeks of gestation) and 12 weeks after diagnosis. We found higher levels of esterified oleic acid in plasma at the time of GD diagnosis in women who subsequently required pharmacological therapy to control blood glu-cose levels compared to those who did not require additional treatment, suggesting that the measurement of plasma oleic acid might be an additional tool for the early identification of patients with a more severe form of gestational diabetes. Moreover, plasma oleic acid levels showed a positive correlation with fetal growth in the context of adequate glycemic control, supporting a metabolic dysregulation of other pathways whose identification could help clinicians to discriminate different cases within the spectrum of severity of the disease. Finally, the correlation between plasma oleic acid and circu-lating BAFF levels at the time of diagnosis and 12 weeks later adds a possible mechanism to support the pro-inflammatory and pro-diabetic state in the metabolic set of GD. Overall, these findings strongly support the role of plasma oleic acid as a possible early marker for GD severity stratification during pregnancy.

Keywords Gestational diabetes · Lipidomics · Oleic acid · Fatty acid · Pregnancy inflammation · Biomarker

Claus Vinter Bødker Hviid1,2 · Nicklas Højgaard-Hessellund Rasmussen2,3 · Johan Røikjer2,3,4

Received: 5 December 2024 / Accepted: 22 March 2025 / Published online: 7 April 2025© The Author(s) 2025

Abstract

Background Objective and easily applicable biomarkers for diabetic polyneuropathy (DPN) are warranted. Circulating nerve-specific proteins have emerged as valuable biomarkers for central nervous system disease but few of these have been tested in peripheral neuropathy. Glial Fibrillary Acidic Protein (GFAP) is highly expressed in non-myelinating Schwann cells while UCH-L1 is a neuron expressed stress protein not previous analyzed in DPN. In this pilot study, we explore serum  GFAP and UCH-L1 levels in patients with/without DPN and controls.

Methods Persons with DPN (n=28), without DPN (n=31), and controls (n=30) were evaluated in a cross-sectional design. Sural nerve conduction (velocity and amplitude) was evaluated by NC-stat DPNCheck™ and quantitative sensory testing of cold detection and pain was performed. GFAP and UCH-L1 levels were compared across study groups and the unadjusted correlation with nerve assessments evaluated.

Results Serum GFAP were lower in persons with DPN (20.9±10.9 pg/ml) than in persons without DPN (26.2±14.1 pg/ ml) (p=0.04) or controls (31.7±26.0 pg/ml) (p=0.02). GFAP levels were not different in persons without DPN and controls (p=0.61). UCH-L1 levels were not different between study groups (p=0.48). GFAP levels correlated with cold pain thresh-old (Rho= − 0.320, p=0.02) but failed to reach significance for cold detection (Rho= − 0.236, p=0.09). No correlation was observed between GFAP and nerve amplitude (p=0.58) or conductivity (p=0.86).

Conclusion Serum GFAP levels are reduced in persons with DPN compared to persons without DPN and controls. Reduced serum GFAP levels may be associated with reduced markers of small nerve fiber damage obtained from quantitative sensory testing in people with diabetes.

Keywords Diabetic polyneuropathy · Diabetes · Biomarkers · Glial fibrillary acidic protein · Quantitative sensory testing