Zinc-alpha2-glycoprotein, dysglycaemia and insulin resistance: a systematic review and meta-analysis

To systematically review the current literature investigating associations between zinc-alpha2-glycoprotein (ZAG) and dysglycaemia (including type 2 diabetes (T2DM), poly-cystic-ovary syndrome (PCOS), pre-diabetes or insulin resistance). This included relationships between ZAG and continuous measures of insulin and glucose. Additionally, we performed a meta-analysis to estimate the extent that ZAG differs between individuals with or without dysglycaemia; whilst examining the potential influence of adiposity. A systematic search was performed on four databases for studies on circulating ZAG concentrations in adult human populations, comparing healthy controls to individuals with dysglycaemia. Key characteristics, including the mean ZAG concentrations (mg∙L−1), and any correlational statistics between ZAG and continuous measures of glucose, glycated haemoglobin (HbA1c) or insulin were extracted. Meta-analyses were performed to compare metabolically healthy controls to cases, and on studies that compared controls and cases considered overweight or obese (body mass index (BMI) ≥25 kg.m2). 1575 papers were identified and 14 studies (16 cohorts) were considered eligible for inclusion. Circulating ZAG was lower in individuals with dysglycaemia compared to metabolically healthy controls (−4.14 [−8.17, −0.11] mg.L−1; I2 = 98.5%; p < 0.001). When using data from only studies with overweight or obese groups with or without dysglycaemia (three studies (four cohorts); pooled n = 332), the difference in circulating ZAG was no longer significant (−0.30 [−3.67, 3.07] mg. L−1; I2 = 28.0%; p = 0.225). These data suggest that ZAG may be implicated in dysglycaemia, although there was significant heterogeneity across different studies and the mediating effect of adiposity cannot be excluded. Therefore, more research is needed before robust conclusions can be drawn

Dysglycaemia and South Asian ethnicity: a proteomic discovery and confirmation analysis highlights differences in ZAG

Aims To (1) explore and verify differences in the plasma proteome of white European (WE) and South Asian (SA) adults with normal glycaemic control (NGC) or non-diabetic hyperglycaemia (NDH) and to (2) validate these findings using a separate WE and SA cohort at a high risk of NDH. Methods Mass spectrometry analysis was performed on fasted samples from 72 WE or SA men with NGC or NDH. These results were verified using specific biochemical assays and validated by repeating the analysis in an additional cohort of 30 WE and 30 SA adults. Proteomic results were analysed using independent samples t test and univariate analysis. The targeted assay results were analysed using generalised linear models with adjustment for appropriate covariates including age, BMI, fasting plasma glucose, high-density lipoprotein-cholesterol, triglycerides and sex. Results Only zinc-alpha-2-glycoprotein (ZAG) significantly differed between both ethnicities and glycaemic control groups. ZAG-specific biochemical assays verified the lower circulating ZAG in SAs (41.09 versus 37.07 (mg L−1); p = 0.014), but not the difference between NGC and NDH groups (p = 0.539). Validation of the ethnicity difference in a separate cohort confirmed that, after adjustment for covariates, ZAG was lower in SAs (p = 0.018). There was no association between ZAG and glycaemic control in the validation cohort. Conclusions Our analyses identified that ZAG is lower in SAs compared to WEs, but its difference between glycaemic control statuses was uncertain. Further research is needed to establish whether lower ZAG in SAs is associated with, or prognostic of, health outcomes, particularly regarding the risk of dysglycaemia

Investigations into dysglycaemia and ethnic health disparities using mass spectrometry based plasma proteomics and targeted assay analysis

Background:Mass Spectrometry (MS) - proteomics is emerging in diabetes research. Ethnicity is an important factor in the development of dysglycaemia, with South Asians (SA) in particular at increased risk. The use of MS-proteomics to compare ethnic differences in dysglycaemia is under-researched and may aid in understanding disease aetiology.Aims:1. To investigate differences in the fasting proteomes of white European (WE) and SA adults with either normal glycaemic control or non-diabetic hyperglycaemia.2. To verify and validate the identified proteins to confirm differences.3. To quantify the role of the verified protein(s) in dysglycaemia in existing literature4. To examine associations of the protein(s) with energy expenditure (EE) and consumption of a plant-based diet.5. To investigate differences in the post-prandial proteomes of WE and SA adults in response to an acute physical activity intervention.Key findings:1. MS-proteomic analysis identified zinc-alpha-2-glycoprotein (ZAG) as being lower in SA versus WE and lower in individuals with NDH versus NGC.2. Targeted verification/validation analyses ZAGs confirmed differences between WE and SA individuals but not glycaemic control.3. The current literature demonstrates that circulating ZAG was lower in dysglycaemic individuals but this was attenuated after body mass index adjustment.4. ZAG was inversely associated with exercise-related EE and adopting a plant-based diet resulted in lower ZAG.5. Post-prandial proteome analysis identified 60 proteins that may explain mechanisms for disease-risk differences between ethnicities, in response to physical activity and ethnicity/physical activity interaction.Conclusions:Fasting proteomic differences were explored in WEs and SAs and differing level of dysglycaemia, highlighting ZAG as a protein of interest. Associations between ZAG and lifestyle factors relating to glycaemic control were then explored. The post-prandial proteome of WE and SA adults was also investigated to determine protein mechanisms for ethnic health disparities and responses to physical activity.</div