Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass

Abstract

ObjectiveRoux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.MethodsWe studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.ResultsWe found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.ConclusionAn early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.

Postprandial hypoglycaemia after Roux‐en‐Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide

“…Among others, Abrahamsson et al have reported positive outcomes during treatment with GLP‐1 analogues, including improved glycaemic control and reduced number of patient‐reported hypoglycaemic episodes. In the present study, treatment with liraglutide did not reduce hypoglycaemia nor hyperglycaemia during the MMTTs; however, it led to significant reductions in glucose values below fasting levels, suggestive of a blood glucose‐stabilizing effect.…”

“…A liquid meal (Fresubin Energy Drink, 300 kcal; Fresenius Kabi, Bad Homburg, Germany), consisting of 50% carbohydrates, 35% fat and 15% protein, was consumed at time 0 over a period of 15 minutes. The test meal was chosen based on its comparability with meals used in similar studies . Blood samples were collected at times −20, −10, 0, 5, 10, 20, 30, 45, 60, 90, 120, 150 and 180 minutes.…”

“…The hypoglycaemic onset is preceded by hyperglycaemia, hyperinsulinaemia and large elevations in glucagon‐like peptide‐1 (GLP‐1) concentrations . Individuals with more severe postprandial hypoglycaemia exhibit higher postprandial insulin and GLP‐1 levels and, although the pathophysiological mechanisms are not completely understood, the exaggerated insulin and GLP‐1 responses are believed to be of great importance . Continuous glucose monitoring (CGM) has shown that hypoglycaemia is detectable in up to 75% of a population that has undergone RYGB, but is not symptomatic in all individuals .…”

“…Somatostatin analogues, such as octreotide and pasireotide, have been shown to reduce PBH by inhibiting the secretion of insulin and GLP‐1 . Several groups have reported that treatment with GLP‐1 analogues reduces hypoglycaemic symptoms and glycaemic variability assessed by CGM, perhaps by delaying intestinal transit time . In general, treatment effects are mostly based on case reports and patient‐reported symptoms.…”

Mechanisms for the metabolic success of bariatric surgery

“…In the pancreas, predominant expression of proconvertase 2 leads to preproglucagon processing to produce glucagon. Although some studies have reported an increase in postprandial glucagon after RYGB, a later study suggested that this work was confounded by the fact that RYGB causes large increases glicentin, another preproglucagon peptide that has increasing cross‐reactivity with standard glucagon enzyme‐linked immunosorbent assays with increasing plasma concentrations . Thus, more research is needed from independent groups utilising sensitive and specific assays to determine whether glucagon is increased with surgery or not.…”