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Proteomic Based on Mass Spectrometry Reveals MEGF8 as a Potential Biomarker for Diabetes

ABSTRACT: Diabetes mellitus constitutes a major global health challenge. Current diagnostic markers, such as fasting glucose and glycated hemoglobin A1c (HbA1c), show limitations in accuracy and sensitivity in epidemiological settings. This study aimed to identify novel serum biomarkers for diabetes using a multi-stage approach encompassing discovery, verification, and clinical correlation. In the discovery phase, data-independent acquisition mass spectrometry (DIA-MS) analysis of serum from 107 individuals (53 controls, 54 diabetic subjects) identified 345 differentially expressed proteins (DEPs) after filtering. Receiver operating characteristic (ROC) analysis of these DEPs highlighted five proteins—MEGF8, PLXNB2, SHBG, CLEC3B, and GSN—with high diagnostic potential (AUC > 0.85). Subsequent parallel reaction monitoring (PRM) verification in an independent cohort (46 diabetic vs. 46 control samples) confirmed consistent expression trends for four of these candidates (MEGF8, PLXNB2, SHBG, and GSN), with AUCs of 0.782, 0.763, 0.845, and 0.671, respectively. Further validation by ELISA in a clinical cohort (43 diabetic vs. 31 control subjects) demonstrated significant upregulation of MEGF8 in diabetic serum (1081.00 ± 250.49 pg/mL vs. 950.30 ± 189.64 pg/mL; P = 0.0187). Correlation analysis within this cohort revealed that serum MEGF8 levels were specifically and positively associated with key glycemic and insulin resistance indices, including fasting blood glucose (r = 0.268, P = 0.021), HbA1c (r = 0.295, P = 0.011), and HOMA-IR (r = 0.350, P = 0.002), but not with adiposity measures or lipid profiles. Collectively, through multi-stage validation, MEGF8 emerges as a promising and specific serum biomarker closely linked to hyperglycemia and insulin resistance in diabetes.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wenxu Hong

PROVIDER: PXD074916 | iProX | Wed Feb 25 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Type 1 diabetes mellitus (T1DM) results from immune mediated destruction of pancreatic beta cells. However, clinical and immunologic phenotypes of T1DM are variable. Several auto-antibodies including GADA, IA-2A, and ZnT8A, were identified in T1DM, but the prevalence of these auto-antibodies varied for a broad spectrum of T1DM. Here, we systemically profiled auto-antibodies from serum samples of 16 T1DM, 16 type 2 diabetes (T2DM) patients, and 27 healthy controls with normal glucose tolerance (NGT) using protein microarrays containing 9,480 proteins. Among 9,480 different proteins on the array, we identified novel auto-antibody candidates (EEF1A1-AAb and UBE2L3-AAb) by M-test coupled with PLS-DA. These auto-antibodies were highly present in T1DM than controls and detected in 40% of T1DM without GADA. Furthermore, these auto-antibodies might help to differentiate subtype of T1DM when combined with GADA. These novel auto-antibodies provide new diagnostic information of T1DM, as well as new insights into the pathogenesis of T1DM. Auto-antibodies from serum samples were profiled using a high-density, fluorescence-based protein microarray containing duplicate spots of 9,480 human proteins derived from the Ultimate ORF collection The cohort of patients and controls consisted of 16 T1DM, 16 T2DM patients, and 27 healthy controls with NGT. This cohort was used to screen candidate auto-antibodies using protein microarrays (ProtoArray platform version 5.0, Invitrogen Corp., Carlsbad, CA). Serum samples were drawn from T1DM patients who have 1) fasting C-peptide level <0.3 nmol/L or serum C-peptide <0.6 nmol/L after glucagon loading, 2) initiation of insulin treatment within six months after diagnosis, and 3) duration of diabetes M-bM-^IM-$12 months. Mean age of T1DM in the first cohort was 42 M-BM-1 16 years. The control serum samples were obtained from T2DM patients who were treated only with oral anti-diabetic drug at least 5 years and from NGTs who had no history of diabetes, no first-degree relatives with diabetes, a fasting plasma glucose concentration of <6.1 mmol/l, and a HbA1c value of <5.8%.

Project description:Background/aims: Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type‐2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO) opening the possibility that FGF21 is a cross‐talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion. Methods/study design: In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole‐body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro. Results: Serum FGF21 concentrations were more than two‐fold higher in MUHO as compared to 37 MHO subjects (457 ±378 vs. 211 ±123 pg/mL; p<0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p<0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, ‐15% and ‐40%, respectively; p<0.01 both), reduced adiponectin expression (‐20%; p<0.05), markedly reduced adiponectin release (‐60%; p<0.01), and substantially increased leptin (+60%; p<0.01) and interleukin‐6 (+50%; p<0.001) release. Interpretation/conclusions: The hepatokine FGF21 exerts weak lipogenic and anti‐adipogenic actions and marked adiponectin‐suppressive and leptin and interleukin‐6 release‐promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes. We analysed in vitro differentiated preadipocytes from 20 human donors treated with FGF21 or control cultures.

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Proteomic Based on Mass Spectrometry Reveals MEGF8 as a Potential Biomarker for Diabetes

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