Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals

Abstract

Aims/hypothesis Post-bariatric hypoglycaemia is an increasingly recognised complication of bariatric surgery, manifesting particularly after Roux-en-Y gastric bypass. While hyperinsulinaemia is an established pathophysiological feature, the role of counter-regulation remains unclear. We aimed to assess counter-regulatory hormones and glucose fluxes during insulin-induced postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia after Roux-en-Y gastric bypass vs surgical and non-surgical control individuals. Methods In this case–control study, 32 adults belonging to four groups with comparable age, sex and BMI (patients with post-bariatric hypoglycaemia, Roux-en-Y gastric bypass, sleeve gastrectomy and non-surgical control individuals) underwent a postprandial hypoglycaemic clamp in our clinical research unit to reach the glycaemic target of 2.5 mmol/l 150–170 min after ingesting 15 g of glucose. Glucose fluxes were assessed during the postprandial and hypoglycaemic period using a dual-tracer approach. The primary outcome was the incremental AUC of glucagon during hypoglycaemia. Catecholamines, cortisol, growth hormone, pancreatic polypeptide and endogenous glucose production were also analysed during hypoglycaemia. Results The rate of glucose appearance after oral administration, as well as the rates of total glucose appearance and glucose disappearance, were higher in both Roux-en-Y gastric bypass groups vs the non-surgical control group in the early postprandial period (all p<0.05). During hypoglycaemia, glucagon exposure was significantly lower in all surgical groups vs the non-surgical control group (all p<0.01). Pancreatic polypeptide levels were significantly lower in patients with post-bariatric hypoglycaemia vs the non-surgical control group (median [IQR]: 24.7 [10.9, 38.7] pmol/l vs 238.7 [186.3, 288.9] pmol/l) (p=0.005). Other hormonal responses to hypoglycaemia and endogenous glucose production did not significantly differ between the groups. Conclusions/interpretation The glucagon response to insulin-induced postprandial hypoglycaemia is lower in post-bariatric surgery individuals compared with non-surgical control individuals, irrespective of the surgical modality. No significant differences were found between patients with post-bariatric hypoglycaemia and surgical control individuals, suggesting that impaired counter-regulation is not a root cause of post-bariatric hypoglycaemia. Trial registration ClinicalTrials.gov NCT04334161 Graphical abstract

Mixed Meal Tolerance Test Versus Continuous Glucose Monitoring for an Effective Diagnosis of Persistent Post-Bariatric Hypoglycemia

“…An imbalance in the counter-regulatory response mediated by glucagon has also been suggested; specifically, lower early peak levels have been observed after MMTT in patients with hypoglycemia, which were unable to counter-regulate the over-elevated levels of insulin [ 12 , 13 ]. Even though this mitigated glucagon response has been consistently reported in several studies, some authors have not observed a significant difference in levels of patients with no PBH after RYGB [ 15 ], suggesting that this analytical finding may be inherent to altered post-bariatric surgery physiology, in the setting of sustained weight loss and lower nadir glucose levels, and not a true cause of PBH. Interestingly, in the aforementioned study, the authors found that levels of pancreatic polypeptide (PP) were significantly decreased in patients with PBH, in comparison to the control group.…”

Clinical evaluation of a decision support system for glucose infusion in hypoglycaemic clamp experiments

“…Further characteristics of the population (e.g. body composition) are available in Tripyla et al 13 Of the 32 total participants, two (both in the GB non-PBH group)…”

“…This introduces a confounding effect in evaluating Gluclas, as the contribution of Gluclas to the success of the clamps cannot be fully disentangled from the contribution of the clinical team. On the other hand, this choice enabled testing Gluclas in a clinical trial designed for other purposes, 13 without exposing the patients to the risks associated with a trial exclusively dedicated to the evaluation of Glucas.…”

“…During these experiments, investigators were assisted by Gluclas for the GIR modulation. For a detailed presentation of the study and its main findings, we refer the reader to Tripyla et al 13 In the current work, we instead focus on the effectiveness of the GC achieved by the study team with the assistance of Gluclas. In the following, those aspects of the study that were relevant for evaluating the performance of Gluclas are reviewed.…”

“…To date, Gluclas has been validated in silico on 100 virtual subjects on different GC protocols 12 . In this work, we evaluate the performance of Gluclas‐supported hypoglycaemic clamp experiments that were performed within the framework of a clinical trial involving 32 participants belonging to four different groups, matched for age, body mass index (BMI) and sex, but with differences in glucose‐insulin dynamics 13 . Performance evaluation focused on control accuracy and patient safety, as well as acceptance and trust by the medical staff.…”