Hypoglycemia acutely activates the immune system and is associated with an increased risk for atherosclerotic disease. Since atherosclerosis is driven by inflammation, we set out to determine the duration of the pro-inflammatory response to a hypoglycemic event in people with and without diabetes.Adults with type 1 diabetes (n = 47) or insulin-treated type 2 diabetes (n = 15) , and age-matched controls without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic (5.2 ± 0.4 mmol/L) -hypoglycemic (2.8 ± 0.1 mmol/L) glucose clamp. Before, during and up to a week thereafter, blood was drawn to determine circulating immune cell composition and function combined with measurements of and circulating hs-CRP concentrations. At baseline, participants with diabetes had higher counts of produced cytokines and hs-CRP compared to individuals without diabetes (all p < 0.01) . In response to hypoglycemia, absolute numbers of lymphocytes (1.57 ± 0.53 vs. 2.69 ± 0.95·103/µL) and monocytes (0.40 ± 0.14 vs. 0.62 ± 0.22·103/µL) increased acutely and remained elevated for one week in all subgroups (all p < 0.001) . During hypoglycemia, the proportion of pro-inflammatory CD16+-monocytes increased from 26.9 ± 13.3% to 38.1 ± 14.9% and the proportion of phagocytotic CD14+-monocytes decreased from 65.2 ± 14.4% to 54.5 ± 15.9% in all subgroups (all p < 0.01) . Stimulated monocytes released more TNF-α and IL-1β, and less IL-during hypoglycemia. Similarly, hs-CRP concentrations increased from 2.± 3.20 µg/mL to 2.71 ± 3.57 µg/mL 1 day after the clamp (p < 0.001) and remained elevated for one week (p < 0.001) thereafter to similar extent in all subgroups.

In conclusion, a single hypoglycemic event induces a prolonged immune response in humans independent of the presence of diabetes.


C.E.Verhulst: None. J.Van heck: None. T.W.Fabricius: None. R.Stienstra: None. C.Tack: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. B.E.De galan: Research Support; Novo Nordisk. Hypo-resolve consortium: n/a.


The Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 777460. The JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, International Diabetes Federation (IDF) , The Leona M. and Harry B. Helmsley Charitable Trust.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.