Understanding post-bariatric hypoglycaemia
Bariatric surgery can put type 2 diabetes into remission, but it’s not without complications, including hypoglycaemia after meals. A new study in Diabetologia sheds some light on the underlying pathophysiology, looking at counter-regulatory responses in the postprandial phase in participants with post-bariatric hypoglycaemia. Dr Susan Aldridge reports.
Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the two most commonly performed bariatric surgeries and have a proven track record for treating obesity and putting type 2 diabetes into remission. However, post-bariatric hypoglycaemia (PBH) is an increasingly recognised metabolic complication, particularly after RYGB.
The reported incidence of PBH varies widely because of variability in the diagnostic criteria used, but it may affect up to 30% of those having RYGB. For many, PBH will have a negative impact on quality of life, offsetting the health benefits of the surgery.
Typically, an episode of PBH will occur after a meal of high glycaemic index foods. Hyperinsulinaemia is known to play a role in PBH, but the underlying pathophysiology is probably more complex, with an impaired glucose counter-regulatory response possibly playing a role. This response is involved in recovery from hypoglycaemia, where glucagon and other hormones are released in response to falling plasma glucose levels.
In this study, Lia Bally of Bern University Hospital in Switzerland and colleagues assessed counter-regulatory hormones and glucose fluxes during induced postprandial hypoglycaemia in participants with PBH. Their responses were compared with those of three control groups: individuals who had undergone RYGB and SG without experiencing PBH and individuals who had not had bariatric surgery.
A proper evaluation of the behaviour of counter-regulatory hormones, such as glucagon, during hypoglycaemia is done with a clamp experiment, which allows the participants to be exposed to a given level of hypoglycaemia during which samples can be taken.
In this study, there were eight participants in each of the four groups. First, a glucose infusion was started and, 100 minutes later, participants ingested a ‘meal’ of 15 g of glucose. A continuous insulin aspart infusion was started 90 minutes after this and the infusion rates controlled to reach a state of hypoglycaemia of 2.5 mmo/l, starting 150 minutes after the ‘meal’ and maintained for 20 minutes, after which time the glucose infusion was increased to restore euglycaemia. This clamp experiment therefore simulated ingesting a meal and experiencing hypoglycaemia afterwards.
The researchers measured blood glucose every 15 minutes, then every five minutes from 75 minutes after the ‘meal’. They also sampled for endogenous insulin, C-peptide, insulin aspart, glucagon, adrenaline, cortisol, growth hormone and pancreatic polypeptide (PPP), and GLP-1 and isotopic glucose enrichments were collected at pre-defined time points.
Hypoglycaemic symptoms – autonomic (sweating, palpitations, tremor, hunger), neuroglycopenic (confusion, dizziness, odd behaviour, speech difficulties, incoordination) and general malaise (headache, nausea) were also recorded. Thus, the researchers built a detailed picture of the biochemical, physiological and clinical features of postprandial hypoglycaemia to uncover differences between those with and without PBH following bariatric surgery compared with those who had not had surgery.
Reduced glucagon responses
There were reduced glucagon responses to hypoglycaemia in all of the surgical groups compared with the non-surgical controls. However, contrary to the hypothesis being tested, there was no difference in this glucagon response between those with and without PBH in the surgical groups. No other counter-regulatory hormone responses differed among the three groups, save for PPP, which was significantly lower in the PBH group compared with the non-surgical controls.
These findings are consistent with previous longitudinal studies that suggested that surgery-induced weight loss lowers the glucagon response to induced hypoglycaemia. Decreased glucagon responses to insulin-induced hypoglycaemia have also been demonstrated after short-term fasting in healthy men. These findings suggest that an energy deficit, whether surgical or non-surgical, alters glucagon responses to hypoglycaemia. And, although it didn’t reach statistical significance, a similarly lower response to hypoglycaemia was observed for the second most important counter-regulatory hormone, namely adrenaline, for the surgical groups compared with the controls.
Also, PPP, a marker (in addition to glucagon and catecholamines) of autonomic hypoglycaemia counter-regulation, appeared to be lower in the surgical group, but with significant differences only between the PBH and non-surgical controls.
The authors’ findings are in line with other evidence and seem to suggest a global attenuation of neurohormonal responses to insulin-induced hypoglycaemia in post-bariatric surgery patients experiencing substantial weight loss. A recent study assessing brain glucose utilisation, blood flow and neuronal activity pre- and post-RYGB found that these responses were accompanied by adaptive changes in the brain. The re-routing of gastrointestinal anatomy by RYGB and SG produces consistently lower postprandial nadir glucose levels. This might lead to decreased sensitivity to the level of hypoglycaemia and promote the use of alternatives to glucose, thereby overriding the need for prompt secretion of counter-regulatory hormones during hypoglycaemia.
The counter-regulatory responses to hypoglycaemia did not differ significantly between the PBH and RYGB control group. The common factor is RYGB, so the diminished glucagon response might be a consequence of altered post-bariatric surgery physiology, rather than a cause of PBH. However, the small glucose ‘meal’ load of 15 g might not have been enough to reveal differences between PBH and non-PBH participants. There is also a high variability of clinical manifestations of BPH, from mild to severe. All of this suggests a multifactorial model of glucose dysregulation in PBH.
This study was novel in using a postprandial hypoglycaemic clamp experiment to contrast counter-regulatory responses in people with PBH after RYGB, comparing them with controls who had undergone surgery and had no PBH and those who had not had surgery.
Although the sample size was small, the groups were similar in terms of age, sex, body composition, HbA1c, fasting hormonal concentrations and insulin sensitivity. However, these were experimental rather than real-world findings, so further research in a clinical setting is needed.
In conclusion, the glucagon response to standardised insulin-induced postprandial hypoglycaemia is attenuated after both RYGB and SG compared with non-surgical controls. These findings support adaptive reactions to bariatric surgery that can predispose to PBH, but glucagon and other counter-regulatory responses did not significantly differ between symptomatic PBH patients and other surgical control individuals. Therefore, attenuated counter-regulation is not a cause of PBH, but may be a contributor to its multifactorial and complex pathophysiology. This new study provides a basis for further research into the impact of bariatric surgery and weight loss on the regulation of glucagon secretion.
To read this paper, go to: Tripyla A, Herzig D, Reverter-Branchat G, Pavan J, Schiavon M, Eugster P, Grouzmann E, Nakas CT, Sauvinet V, Meiller L, Zehetner J, Giachino D, Nett P, Gawinecka J, Del Favero S, Thomas A, Thevia M, Dalla Man C, Bally L. Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals. Diabetologia 17 January 2023. https://doi.org/10.1007/s00125-022-05861-9
To learn more about metabolic surgery, enrol on the EASD e-Learning course ‘Metabolic surgery’: https://easd-elearning.org/courses/metabolic-surgery/
To learn more about hypoglycaemia, enrol on the EASD e-Learning course ‘Hypoglycaemia’:https://easd-elearning.org/courses/hypoglycaemia/
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.