transcriptional analysis of bulk monocytes isolated from patients post-bariatric surgery undergoing a standardized liquid mixed-meal test intended to provoque postprandial hypoglycemia, upon treatment with either placebo, anakinra or empagliflozin

Postprandial hypoglycemia is a disabling complication of bariatric surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1ß leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo controlled, randomized, double-blind, cross-over study with the SGLT2-inhibitor empagliflozin (Jardiance [10mg]) and the IL-1 receptor antagonist anakinra (Kineret [100mg]). Both drugs reduced postprandial insulin release and prevented hypoglycemia. Moreover, analysis of monocytes taken from this patient population ex-vivo revealed a hyper-reactive inflammatory state in these cells. Our study proposes a role for glucose-induced IL-1ß in postprandial hypoglycemia after bariatric surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition. Overall design: We conducted a placebo controlled, double-blind, randomized, cross-over proof-of concept study in patients with postprandial hypoglycemia after bariatric surgery. Patients were randomly assigned to receive either anakinra, empagliflozin or placebos on three study days followed by a standardized liquid mixed-meal test. Episodes of hypoglycemia were defined as (1) the appearance of typical symptoms, (2) low plasma glucose and (3) relief of symptoms following glucose administration (Whipple's triad). Following our hypothesis of an overactivation of the innate immune-system in patients experiencing post-bariatric hypoglycemia, we assessed transcriptional changes in our patient population's innate immune cells, using an unbiased RNA sequencing approach. Therefore, we isolated monocytes from peripheral blood samples taken immediately before and 60 min (i.e. before rescue glucose application when needed) after ingestion of the mixed meal test on all three treatment days. Due to scheduling conflicts, only a subset of patients enrolled in the trial could be processed (11 patients in total). Furthermore, two samples failed library preparation, leaving us with 64 samples for sequencing. Out of these 64 samples, 16 were obtained on study visits where hypoglycemia occured, while 48 were not. For more details regarding the protocol, see publication.