Hypoglycaemia induces recruitment of non-classical monocytes and cytotoxic lymphocyte subsets in type 1 diabetes

Abstract

Abbreviation PBMC Peripheral blood mononuclear cellTo the Editor: We recently reported enhanced ex vivo cytokine production of immune cells during hypoglycaemia in humans [1]. Chronic inflammation contributes to cardiovascular disease and atherosclerosis and may link hypoglycaemia to increased cardiovascular risk and mortality observed in individuals with diabetes [2].Hypoglycaemia induces leucocytosis, possibly mediated by marked increases in plasma adrenaline (epinephrine) and cortisol levels. Adrenaline recruits immune cells from the marginal pool (vascular endothelium), likely by interfering with CD11a-and CX3CR1-dependent adhesion of leucocytes to the vessel wall [3]. Indeed, gene expression levels of CD11a and CX3CR1 were increased in peripheral blood mononuclear cells (PBMCs) isolated during hypoglycaemia [1].It remains unknown which specific immune cell subsets are recruited in response to hypoglycaemia. To identify these subsets, we analysed blood samples collected during clamped euglycaemia or hypoglycaemia from seven people with type 1 diabetes (three men, age 27.1 ± 9.7 years, HbA 1c 55.9 ± 8.9 mmol/mol [7.2 ± 0.8%] and diabetes duration 11.4 ± 5.4 years; mean ± SD) by flow cytometry. This was a substudy of a larger study (ClinicalTrials.gov registration no.

Limited impact of impaired awareness of hypoglycaemia and severe hypoglycaemia on the inflammatory profile of people with type 1 diabetes

“…We and others have shown that acute hypoglycaemia leads to increased numbers of leukocytes, particularly due to increased monocyte, lymphocyte and neutrophil counts, 16,17 and induction of pro‐inflammatory functional changes in immune cells in people with and without type 1 diabetes 18 . Importantly, we showed that hypoglycaemia‐induced monocytosis is mainly driven by increases in non‐classic monocytes, which produce more pro‐inflammatory cytokines and contribute more to the development of cardiovascular disease than other monocyte subsets 17 …”

“…12 Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis with monocyte-derived macrophages contributing to plaque instability 13,14 and recent suggestions of cardiovascular benefit after anti-inflammatory treatment. 15 We and others have shown that acute hypoglycaemia leads to increased numbers of leukocytes, particularly due to increased monocyte, lymphocyte and neutrophil counts, 16,17 and induction of pro-inflammatory functional changes in immune cells in people with and without type 1 diabetes. 18 Importantly, we showed that hypoglycaemia-induced monocytosis is mainly driven by increases in non-classic monocytes, which produce more pro-inflammatory cytokines and contribute more to the development of cardiovascular disease than other monocyte subsets.…”

“…18 Importantly, we showed that hypoglycaemia-induced monocytosis is mainly driven by increases in non-classic monocytes, which produce more pro-inflammatory cytokines and contribute more to the development of cardiovascular disease than other monocyte subsets. 17 Since hypoglycaemia occurs particularly frequently in people with type 1 diabetes and IAH or with a recent history of SH, we hypothesized that these people would be characterized by a pro-inflammatory profile. To test this hypothesis, we extensively measured circulating inflammatory markers and anti-and pro-inflammatory cytokine production after ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) in a large group of carefully characterized people with type 1 diabetes, and compared the results between those with and without IAH or a history of SH.…”

Mass Cytometry Studies of Patients With Autoimmune Endocrine Diseases Reveal Distinct Disease-Specific Alterations in Immune Cell Subsets

“…Although peripheral blood is not optimal to study immune responses in affected organs, biopsies from the pancreas and adrenal glands are rarely taken for medical and ethical reasons due to the severe complications entailing this procedure. To avoid immunological changes provoked by metabolic disturbances (51,73), only individuals with good hormonal and metabolic control at the time of sampling were included in the study. All patients were medicated according to clinical standards and were treatment-responsive.…”

Glucose Variability: How Does It Work?

“…It was found that hypoglycemia promotes the mobilization of specific leukocyte subsets into the bloodstream and induces proinflammatory changes in the leukocytes in healthy individuals and patients with T1D [46]. Specifically, the mobilization of cluster of differentiation 8-positive (CD8+) T cells, cytotoxic natural killers and natural killer T cells, as well as non-classical monocytes, was observed [47]. In patients with T1D, an episode of two-hour hypoglycemia was followed by an increase in the levels of soluble ICAM-1 (sICAM-1) and IL-6 [48].…”