A high glycemic burden relates to functional and metabolic alterations of human monocytes in patients with type 1 diabetes

Diabetes mellitus is associated with increased cardiovascular risk and higher occurrence of infections. These complications suggest altered responses of the innate immune system. Recent studies have shown that energy metabolism of monocytes is crucial in determining their functionality. Here we investigate whether monocyte metabolism and function are changed in patients with diabetes and aim to identify diabetes-associated factors driving these alterations. Patients with type 1 diabetes (T1D) (n=41) and healthy age-, sex- and BMI-matched controls (n=20) were recruited. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses and transcriptome profile. Upon ex vivo stimulation with TLR-4 or TLR-2 agonists, monocytes of patients with T1D secreted lower levels of various cytokines and showed lower glycolytic rates in comparison to monocytes isolated from matched controls. Stratification based on HbA_1c levels revealed that lower cytokine secretion was coupled to higher glycolytic rate of monocytes in patients with higher glycemic burden. Circulating monocytes displayed an enhanced inflammatory gene expression profile associated with high glycemic burden. These results suggest that a high glycemic burden in patients with T1D is related to expression of inflammatory genes of monocytes and is associated with an impaired relationship between metabolism and inflammatory function upon activation.