Marijn S. Hendriksz1, Ilyas F. Mustafajev1, Rinke Stienstra1,2, Cees J. Tack1, Bastiaan E. de Galan1,3,4, Rick I. Meijer1
1.Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. 2. Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands. 3. Department of Internal Medicine, Maastricht University Medical Centre, MUMC+, Maastricht, The Netherlands. 4. CARIM Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Marijn.Hendriksz@radboudumc.nl
Background: Insulin-induced hypoglycaemia elicits both an acute and a sustained inflammatory response. To examine whether the counterregulatory hormone adrenaline mediates these responses, we compared inflammatory responses to experimental hypoglycaemia under combined adrenergic blockade with those during saline, in people with and without type 1 diabetes.
Methods: Using a single-blinded cross-over design, 12 adults with type 1 diabetes (T1DM) and 11 adults without diabetes (CON) underwent a hyperinsulinaemic normoglycaemic-hypoglycaemic (2.8 mmol/l) clamp, during co-infusion with both the α-adrenergic receptor blocker phentolamine and the β-adrenergic receptor blocker propranolol, or a matching volume of saline. White blood cell counts, cytokine secretion following ex vivo LPS stimulation of monocytes, and 92 circulating inflammatory proteins (Olink Proteomics AB inflammation panel) were measured during normoglycaemia, after 60 minutes of hypoglycaemia, and on days one, three, and seven after the intervention.
Results: Hypoglycaemia acutely increased lymphocyte (+0.26±0.07×109/l, p<0.001) and monocyte counts (+0.06±0.03×109/l, p<0.05) in T1DM, an effect that was blunted by combined adrenergic blockade (lymphocytes: +0.18±0.06×109/l, p<0.05; monocytes: +0.04±0.02×109/l, p=ns). Acute hypoglycaemia-induced increases in ex vivo monocyte secretion of IL-1β (+1025.7±296.6 pg/ml, p<0.001) and TNF (+654.1±146.2 pg/ml, p<0.001) were suppressed by combined adrenergic blockade (IL-1β: 40.3±179.2 pg/ml, p=ns; TNF: +35.6±116.4 pg/ml, p=ns). Similar responses were observed in CON. Finally, the increase in number of inflammatory proteins (p all <0.05) in response to hypoglycaemia was markedly lower with combined adrenergic blockade in both groups at all timepoints, predominantly at day one, 9 vs. 41 (T1DM) and 14 vs. 41 (CON). Combined adrenergic blockade suppressed an acute hypoglycaemia-responsive protein cluster enriched for MAPK signaling (gene ratio 6/15; p=0.01, q=0.12) and a sustained-response cluster enriched for Interleukin-10 signaling (gene ratio 11/29; p=0.007, q=0.14).
Discussion/Conclusion: Combined adrenergic blockade suppresses acute and in part prolonged inflammatory responses following hypoglycaemia on a cellular, functional and protein level. These findings establish that adrenaline drives the acute, and to a lesser extent the prolonged inflammatory responses to hypoglycaemia.