Marijn S. Hendriksz1, Ilyas F. Mustafajev1, Bastiaan E. de Galan1,2,3, Rinke Stienstra1,4, Cees J. Tack1, Rick I. Meijer1
1.Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
2. Department of Internal Medicine, Maastricht University Medical Centre, MUMC+, Maastricht, The Netherlands.
3. CARIM Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
4. Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
Background: In people with type 1 diabetes (T1DM) and without diabetes, a single experimental hypoglycaemic event acutely alters immune cell subsets and increases ex vivo cytokine production by monocytes. To determine whether adrenaline drives this pro-inflammatory response, we investigated its effect at concentrations seen during hypoglycaemia in people with T1DM and matched controls without diabetes (CON).
Methods: Fifteen adults with T1DM and CON received intravenous adrenaline at 0.04 µg/kg/min for 1 hour. Blood was collected before start (baseline), 30, 60 and 180 minutes, 1, 3 and 7 day(s) after start of adrenaline infusion to determine immune cell subsets by flow cytometry and monocyte function via ex vivo stimulation with Pam3Cys (P3C) or lipopolysaccharide (LPS) from E.coli. Serial data were analyzed using mixed model analysis.
Results: Plasma adrenaline levels peaked to 2.37±0.28 and 2.23±0.25 nmol/L in adults with T1DM and CON respectively (p=NS). Adrenaline significantly increased the proportion of non-classical (CD16+) monocytes and cytotoxic (CD8+) T-cells and decreased the proportion of classical (CD14+) monocytes and helper (CD4+) T-cells after 30 and 60 minutes in both groups (p<0.001). After 180 minutes, opposite shifts were observed, with proportions of CD16+ monocytes and CD8+ T-cells decreasing, and CD14+ monocytes and CD4+ T-cells increasing compared to baseline in both groups (p<0.01). No significant changes regarding these immune cell subsets were observed during subsequent days. Upon LPS stimulation, IL-1β and TNF-α production by monocytes significantly increased after 30 and 60 minutes (p<0.05) and normalized after 1 day in both groups. Similar trends were seen when monocytes were stimulated with P3C.
Discussion/Conclusion: Adrenaline at levels observed during hypoglycaemia acutely shifts monocyte and T-cell subsets and ex vivo cytokine production by monocytes towards a proinflammatory profile, consistent with previous hypoglycaemic clamp studies. These findings support a prominent role of adrenaline in modifying immune cell subsets and monocyte function during hypoglycaemia.