Prospective Proteomic Associations with Incident Type 2 Diabetes and Responses to Metabolic Stress in Women with and Without Polyendocrine Metabolic Ovarian Syndrome
4 affiliations
- 1School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
- 2Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, Hull HU6 7RU, UK
- 3Data Science Centre, School of Population Health, Royal College of Surgeons in Ireland, RCSI, D02 YN77 Dublin, Ireland
- 4School of Postgraduate Studies and Research, Royal College of Surgeons in Ireland-Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain
Abstract
Women with polyendocrine metabolic ovarian syndrome (PMOS) have heterogeneous metabolic risk. We investigated whether targeted circulating proteins were associated with incident type 2 diabetes (T2D) and whether the retained proteins responded to experimentally induced lipid stress. In Cohort 1, 231 women with (n = 135) or without (n = 96) PMOS had T2D outcome data, of whom 25 developed T2D during a median follow-up of 12.7 years (range 10.2–15.1); 221 women (20 incident cases) had complete covariate data for adjusted analyses. Of 44 available proteins, 27 were prespecified from prior literature; following Benjamini–Hochberg adjustment, eight biomarkers (Adiponectin (ADIPOQ), Endocan (ESM1), Mast/stem cell growth factor receptor-Kit (KIT), Chordin Like 1 (CHRDL1), Cell Adhesion Molecule L1 Like (CHL1), Cathepsin V (CTSV), L1 Cell Adhesion Molecule (L1CAM) and Delta Like Canonical Notch Ligand 4 (DLL4)) had a statistically significant association with T2D in univariate models. However, following adjustment for group, body mass index (BMI) and age, only ADIPOQ remained statistically significant. In Firth penalised logistic regression adjusted for PMOS status, age and BMI, each 1 SD higher ADIPOQ was associated with lower odds of incident T2D (OR 0.12; 95% CI 0.04–0.31); the association persisted when events were restricted to a common 10-year follow-up horizon, after adjustment for baseline fasting glucose, and after excluding women with baseline fasting glucose ≥7.0 mmol/L. Adding ADIPOQ to PMOS status, age and BMI increased the bootstrap optimism-corrected AUC from 0.74 to 0.87. In an independent experimental cohort (PMOS, n = 11; controls, n = 9, with SOMAscan data), ADIPOQ, neural cell adhesion molecule L1-like protein (CHL1), mast/stem cell growth factor receptor-Kit (KIT), chordin-like protein 1 (CHRDL1) and neural cell adhesion molecule L1 (L1CAM) were measured at 0, 180 and 300 min of 5 h saline and Intralipid infusions and analysed using linear mixed-effects models. Relative to saline, Intralipid lowered L1CAM, CHL1 and KIT at 180 min (differences in change from baseline −0.33, −0.30 and −0.25 log2 units; FDR-adjusted p ≤ 0.029), with no evidence that responses differed between women with PMOS and controls, and no lipid-specific change in ADIPOQ was detected; only the L1CAM response persisted after excluding turbid or haemolysed samples. Lower adiponectin was the only protein independently associated with incident T2D, whereas L1CAM, and less robustly CHL1 and KIT, responded to acute lipid exposure. The small number of events, differential outcome ascertainment between groups, absence of external validation and the exploratory experimental cohort preclude claims of clinical prediction. These findings support further evaluation of prognostic and stress-responsive protein phenotypes in larger, independently validated cohorts.
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BibTeX
@article{darwish2026prospective,
title = {{Prospective Proteomic Associations with Incident Type 2 Diabetes and Responses to Metabolic Stress in Women with and Without Polyendocrine Metabolic Ovarian Syndrome}},
author = {Radwan Darwish and Thozhukat Sathyapalan and Laura Dempsey and Mohammed Altigani Abdalla and Alexandra E. Butler and Stephen L. Atkin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219894},
url = {https://www.mdpi.com/1422-0067/27/21/9894},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Prospective Proteomic Associations with Incident Type 2 Diabetes and Responses to Metabolic Stress in Women with and Without Polyendocrine Metabolic Ovarian Syndrome
AU - Radwan Darwish
AU - Thozhukat Sathyapalan
AU - Laura Dempsey
AU - Mohammed Altigani Abdalla
AU - Alexandra E. Butler
AU - Stephen L. Atkin
PY - 2026
DA - 2026/11/04
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219894
UR - https://www.mdpi.com/1422-0067/27/21/9894
AB - Women with polyendocrine metabolic ovarian syndrome (PMOS) have heterogeneous metabolic risk. We investigated whether targeted circulating proteins were associated with incident type 2 diabetes (T2D) and whether the retained proteins responded to experimentally induced lipid stress. In Cohort 1, 231 women with (n = 135) or without (n = 96) PMOS had T2D outcome data, of whom 25 developed T2D during a median follow-up of 12.7 years (range 10.2–15.1); 221 women (20 incident cases) had complete covariate data for adjusted analyses. Of 44 available proteins, 27 were prespecified from prior literature; following Benjamini–Hochberg adjustment, eight biomarkers (Adiponectin (ADIPOQ), Endocan (ESM1), Mast/stem cell growth factor receptor-Kit (KIT), Chordin Like 1 (CHRDL1), Cell Adhesion Molecule L1 Like (CHL1), Cathepsin V (CTSV), L1 Cell Adhesion Molecule (L1CAM) and Delta Like Canonical Notch Ligand 4 (DLL4)) had a statistically significant association with T2D in univariate models. However, following adjustment for group, body mass index (BMI) and age, only ADIPOQ remained statistically significant. In Firth penalised logistic regression adjusted for PMOS status, age and BMI, each 1 SD higher ADIPOQ was associated with lower odds of incident T2D (OR 0.12; 95% CI 0.04–0.31); the association persisted when events were restricted to a common 10-year follow-up horizon, after adjustment for baseline fasting glucose, and after excluding women with baseline fasting glucose ≥7.0 mmol/L. Adding ADIPOQ to PMOS status, age and BMI increased the bootstrap optimism-corrected AUC from 0.74 to 0.87. In an independent experimental cohort (PMOS, n = 11; controls, n = 9, with SOMAscan data), ADIPOQ, neural cell adhesion molecule L1-like protein (CHL1), mast/stem cell growth factor receptor-Kit (KIT), chordin-like protein 1 (CHRDL1) and neural cell adhesion molecule L1 (L1CAM) were measured at 0, 180 and 300 min of 5 h saline and Intralipid infusions and analysed using linear mixed-effects models. Relative to saline, Intralipid lowered L1CAM, CHL1 and KIT at 180 min (differences in change from baseline −0.33, −0.30 and −0.25 log2 units; FDR-adjusted p ≤ 0.029), with no evidence that responses differed between women with PMOS and controls, and no lipid-specific change in ADIPOQ was detected; only the L1CAM response persisted after excluding turbid or haemolysed samples. Lower adiponectin was the only protein independently associated with incident T2D, whereas L1CAM, and less robustly CHL1 and KIT, responded to acute lipid exposure. The small number of events, differential outcome ascertainment between groups, absence of external validation and the exploratory experimental cohort preclude claims of clinical prediction. These findings support further evaluation of prognostic and stress-responsive protein phenotypes in larger, independently validated cohorts.
SN - 1422-0067
ER -