A High Glycemic Burden Relates to Functional and Metabolic Alterations of Human Monocytes in Patients With Type 1 Diabetes

Abstract

Diabetes 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 control subjects (n = 20) were recruited. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses, and transcriptome profiles. Upon ex vivo stimulation with Toll-like receptor (TLR) 4 or TLR-2 agonists, monocytes of patients with T1D secreted lower levels of various cytokines and showed lower glycolytic rates compared with monocytes isolated from matched control subjects. Stratification based on HbA1c levels revealed that lower cytokine secretion was coupled to higher glycolytic rate of monocytes in patients with a 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.

Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes

“…Furthermore, a decreased production of several cytokines was found relative to the production of lactate, compared with healthy individuals. These results are in accordance with earlier work, where a decreased association between glycolysis and cytokine production was found in monocytes of T1DM patients with a high glycemic burden [43] . The frequent occurrence of hyperglycemic events in patients with T1DM could lead to increased glucose availability for immune cells.…”

“…Interestingly, however, cytokine responses to other PAMPs, including Pam3Cys and C. albicans showed an even more profound difference between the different groups of responders. This is intriguing, especially because patients with diabetes are often more susceptible to infection with Candida [68] and stimulation of monocytes from T1DM patients with Pam3Cys has revealed uncoupling of glycolysis and cytokine production before [43] . It may be indicative of inefficient immune responses, particularly associated to the intermediate- or low-responding groups.…”

“…Diabetes mellitus is a metabolic disease that is known to associate with aberrated functional innate immune responses and altered metabolic responses of the immune cells [43] . Therefore, we explored whether the observed associations between lactate and cytokine production in healthy subjects were different in patients with T1DM.…”

Identification of monocyte-related transcriptomic signature of peripheral blood mononuclear cells in type 1 diabetes

“…Most importantly, hub genes CD33, CD86, and TLR4 were located primarily in monocytes. All these suggest that monocyte-related innate immunity plays an important role in the pathogenesis of T1D [5] . We assert that two hub proteins – CD33 and PRF1 – are likely candidates for new markers in the diagnosis of T1D.…”

CD36 Signaling in Diabetic Cardiomyopathy

“…Under physiological circumstances, FA metabolism and glucose metabolism are maintained in CMs [98]. During the progression of DM, there is a sharp loss (T1DM) or gradual reduction (T2DM) in insulin secretion, causing an increase in circulating glucose levels and more dependence on fatty acid oxidation [99,100]. In addition, lipolysis of adipose tissues increases the circulating levels of FAs and enhances the capacity of CD36 to transport FAs into CMs [101].…”