Measurement of serum 1,5-AG provides insights for diabetes management and the anti-viral immune response

Abstract

Background: Achieving an in-range glycated haemoglobin (HbA1c) is essential for managing diabetes mellitus (DM). However, this parameter provides an estimate of long-term blood glucose control rather than daily glycaemic variations. Glycaemic variability can be more predictive than HbA1c in terms of identifying those at risk for diabetes complications, including risk of severe respiratory virus infections and is usually measured via a continuous glucose monitor (CGM). For individuals for whom a CGM is not available, serum 1,5 anhydroglucitol (1,5-AG) level has shown potential as an alternative method for monitoring glycaemic variability. Despite this, at present 1,5-AG is not routinely used in the clinical assessment of DM. Here, we aim to determine whether assessing 1,5-AG, in addition to HbA1c, is of any potential clinical utility to the management of DM for patients.

Methods: Using machine learning and data derived from 78 patients with type I DM (for whom CGM data is available) we show that the combination of 1,5-AG and HbA1c improves the prediction of a patient's glycemia risk index (GRI) compared to HbA1c alone.

Results: The GRI is an essential tool in the management of DM as it reflects both clinical priorities and patient centred outcomes. The inclusion of 1,5-AG in this prediction was particularly important for individuals who had very high or very low GRI. Furthermore, in the context of glycaemic variability and susceptibility to severe respiratory virus infections, we show that reduced 1,5-AG in the plasma is associated with reduced ex vivo CD4 + T cell cytokine responses to influenza virus in individuals with a matched HbA1c.

Conclusions: Taken together, these data argue for an increased monitoring of 1,5-AG in the clinic for individuals without a CGM to provide additional insights for diabetes management.

Keywords: 1-5-AG; Glycaemic variability; HbA1c; Immune response.

Fig. 1

HbA1c and 1, 5-AG are highly correlated in patients with type 1 diabetes. Data was obtained from 49 type 1 diabetes patients recruited from France and 29 recruited from Australia. Statistical significance was determined with Person’s correlation coefficient where p < 0.0001(****)

Fig. 2

Regression tree for GRI incorporating age, sex, site, HbA1c and 1,5-AG. Numbers at the end of each node indicate the predicted GRI

Fig. 3

Feature importance in model 1 (HbA1c, 1,5-AG, age, sex, site and BMI)

Fig. 4

1,5-AG provides the greatest predictive value for individuals with a GRI is Zone A and E. Zones were defined according to [26]. True GRI values are shown in black. Predicted values from Model 1 (1,5-AG, HbA1c, BMI, Age, Site and Sex) are shown in red circles. Predicted values from Model 2 (1,5-AG, BMI, Age, Site and Sex) are shown with a blue cross. Predicted values from Model 3 (HbAc1, BMI, Age, Site and Sex) are shown with a purple asterisk. Individual Index refers to the donor ID number. MSE = Average Mean Square Error

Fig. 5

Low 1,5-AG is associated with reduced CD4 + T cell cytokine production in response to ex vivo stimulation with influenza virus. (A) Polyfunctional analysis of CD4 + T cells. (B) Total percentage of MIP1β, IFNγ or TNFα positive CD4 + T cells. Statistical significance was assessed using a paired t-test (normally distributed data) or a Wilcoxon test (not normally distributed data). *p < 0.05 1,5-AG ≤ 1.1 is shown in light blue squares whilst 1,5-AG > 1.1 is shown in dark blue circles

Fig. 6

Low 1,5-AG is not associated with reduced CD4 + T cell cytokine production in response to ex vivo stimulation with PMA/I. (A) Polyfunctional analysis of CD4 + T cells. (B) Total percentage of MIP1β, IFNγ or TNFα positive CD4 + T cells. Statistical significance was assessed using a paired t-test (normally distributed data) or a Wilcoxon test (not normally distributed data). *p < 0.05

Fig. 7

Low 1,5-AG is not associated with reduced CD4 + T cell cytokine production in response to ex vivo stimulation with CD3/CD28 magnetic beads. (A) Polyfunctional analysis of CD4 + T cells. (B) Total percentage of MIP1β, IFNγ or TNFα positive CD4 + T cells. Statistical significance was assessed using a paired t-test (normally distributed data) or a Wilcoxon test (not normally distributed data). *p < 0.05