Objective: Hypoglycemia complicates intensive glycemia regimens in type 2 diabetes (T2D). Hyperglycemia induces macrophage priming and dysregulates T-cell activation/function. Immune cell response to acute hypoglycemia has not been investigated in T2D. Thus, immune mediators associated with macrophage/T-cell activation in response to insulin-induced hypoglycemia were studied.

Methods: Hypoglycaemia (<2.2mmol/l; <40mg/dl) was achieved in T2D (n=23) and controls (n=23) by intravenous insulin infusion. Somalogic analysis of plasma proteins related to macrophage/T-cell activation was performed at baseline, hypoglycemia and post-hypoglycemia to 24 hours.

Results: IL-4 and IL-13 (promotors of alternative macrophage activation (M2 macrophages)) decreased 2hours post-hypoglycemia in T2D (p<0.05). Co-stimulatory molecules of T-cell activation expressed in antigen presenting cells (APCs), CD80 and CD86, were decreased at 2h post-hypoglycemia (CD86 in T2D, p<0.05; CD80 in controls and T2D, p<0.05). Hypoglycemia did not affect ligands of co-stimulatory molecules, CTLA4 (ligand of CD80, expressed in APCs) and CD40LG (ligand of CD40, expressed in dendritic cells). The negative regulator of T-cell activation, IL-10, was decreased at 2h (p<0.001) and increased at 4h post-hypoglycemia (p<0.01). Elevation of CD80 (p<0.05) and CD86 (p<0.05), with increased T-cell proliferator IL-6 (p<0.05) was seen in T2D at 4h post-hypoglycemia. Positive correlations of IL10 with IL6, IL4, were observed at 2h post-hypoglycemia in T2D, suggesting a role for IL10 in altering immune cell activation mediators following hypoglycemia in T2D. No correlations with glucagon suggest changes are independent of glucose counter-regulation.

Conclusion: Induced hypoglycemia is associated with decreases in macrophage and T-cell activation mediators (cytokines) in T2D. Thus, this study reveals a novel link between hypoglycemia and inefficient immune system activation.


A.S.Moin: None. T.Sathyapalan: Other Relationship; Novo Nordisk, Abbott Diabetes, Research Support; Abbott Diabetes, Novo Nordisk, Eli Lilly and Company. S.Atkin: None. A.E.Butler: None.

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