Real-life hypoglycemia partially blunts the inflammatory response to experimental hypoglycemia in people with type 1 diabetes

Background: People with type 1 diabetes experience hypoglycemia on a regular basis. A single experimental hypoglycemic episode has been shown to induce a pro-inflammatory response, which includes an increase in circulating immune cell numbers, ex vivo monocyte responses, and circulating inflammatory proteins. The aim of this study was to determine whether recent repeated exposure to real-life hypoglycemia attenuates this response. Methods This was a post-hoc analysis of a hyperinsulinemic normoglycemic-hypoglycemic clamp study involving 40 participants with type 1 diabetes. Glucose levels a week before the clamp were monitored using a Freestyle Libre 1 glucose sensor. Blood was drawn during normoglycemia and hypoglycemia, and 24h after resolution of hypoglycemia for measurements of inflammatory responses and counterregulatory hormone levels. We determined the relationship between frequency, duration of spontaneous hypoglycemia, and time below range (TBR) and the inflammatory response to experimental hypoglycemia. Results Experimental hypoglycemia increased the number of circulating cells, ex vivo cytokine productions of LPS-stimulated monocytes, and circulating inflammatory proteins ( P  < 0.05 for all). A high variability of hypoglycemia frequency (0.79 [0.43,1.14] episode per day), duration (78 [47,110] mins), and TBR (5.5 [2.8,8.5]%) was observed between participants. TBR and hypoglycemia frequency were inversely associated with the increase in circulating granulocyte and lymphocyte cell counts during hypoglycemia. Numbers of circulating immune cells were also associated with the adrenaline response to experimental hypoglycemia ( P  < 0.05 for all). A protein network consisting of DNER, IF-R, uPA, Flt3L, FGF-5, TWEAK was negatively associated with hypoglycemia frequency ( P  < 0.05), but not with the adrenaline response. Conclusion Repeated exposure to spontaneous hypoglycemia is associated with blunted effects of subsequent hypoglycemia on circulating immune cells and a number of inflammatory proteins. To what extent this blunted response is mediated by the attenuated adrenaline response requires further study. Trial registration : ClinicalTrials.gov NCT03976271