Abstract
Aim The development of type 2 diabetes (T2DM) is associated with disturbances of immune status that may be reflected by alterations of the profile of circulating immune cells. In order to study whether there exists genetic predisposition to these alterations, we investigated the relative content of circulating monocyte and lymphocyte subpopulations at fasting condition and upon stimulation by short-term hyperinsulinemia in nondiabetic first-degree relatives (FDR) of T2DM patients and in control subjects. Materials and Methods 19 nondiabetic (FDR) and 19 control subjects without a family history of diabetes (all men) matched for age and BMI underwent 2-hour hyperinsulinemic-euglycemic clamp. Blood samples taken before and at the end of the clamp were used for the flow cytometry analysis of lymphocyte and monocyte populations and for the assessment of cytokine levels. Results At fasting conditions, FDR showed a higher CD4/CD8 ratio of peripheral lymphocytes, a higher percentage of Th17 lymphocytes, and a lower content of intermediate monocytes when compared to controls. The CD4/CD8 ratio correlated with fat mass, insulin, and HOMA-IR in the entire group of subjects. Hyperinsulinemia decreased a relative content of peripheral CD4+ and increased a relative content of CD8+ T lymphocytes, thus decreasing the CD4/CD8 ratio by 18-22% in both groups of subjects. In FDR but not in controls, the decrease of CD4+ T lymphocyte content was partially based on the decrease of TH2 and TH17 lymphocyte subpopulations. In control subjects but not in FDR, the number of intermediate monocytes has declined in response to hyperinsulinemia. Conclusion The alterations of the CD4/CD8 lymphocyte ratio, relative content of TH17 cells, and intermediate monocytes in FDR are features of genetic predisposition to T2DM and may play a role in pathogenesis of T2DM. Short-term hyperinsulinemia affected mostly the immune cell populations deregulated in FDR subjects, which suggests important interplay between immune system homeostasis and insulin levels.
Highlights
Type 2 diabetes (T2DM) and its complications are associated with a systemic low-grade inflammation manifested by higher systemic levels of proinflammatory cytokines, such as IL-6, IL-1β, or TNFα [1]
We aimed to investigate the changes in lymphocyte and monocyte populations in association with genetic predisposition to T2DM and the response of these cells to short-term hyperinsulinemia in healthy first-degree relatives (FDR) of T2DM when compared to control subjects
At the fasting state, the T lymphocyte populations in the blood were not different between the groups, except for TH17 lymphocytes, which were higher in FDR (Figure 1)
Summary
Type 2 diabetes (T2DM) and its complications are associated with a systemic low-grade inflammation manifested by higher systemic levels of proinflammatory cytokines, such as IL-6, IL-1β, or TNFα [1]. It was suggested previously that the primary trigger of immune cell activation and low grade inflammation could be both acute and prolonged periods of hyperglycemia in obese patients and other patients at risk of T2DM development [5, 6]. A hormone released in response to increased glucose levels, is one of the factors, which may alleviate the detrimental effects of hyperglycemias on immune cell phenotypes. In response to acute hyperinsulinemia, a decrease of TNFα, IL-8, and IL-18 circulating levels was observed in healthy lean subjects, while in first-degree relatives (FDR) of type 2 diabetic patients, this antiinflammatory response was blunted [10]. It seems likely that the dysregulation of the immune response to insulin/nutritional stimuli represents one part of the genetic predisposition to T2DM
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