Altered bile acid kinetics contribute to postprandial hypoglycaemia after Roux-en-Y gastric bypass surgery

Abstract

Background/objectives Bile acids (BA) act as detergents in intestinal fat absorption and as modulators of metabolic processes via activation of receptors such as FXR and TGR5. Elevated plasma BA as well as increased intestinal BA signalling to promote GLP-1 release have been implicated in beneficial health effects of Roux-en-Y gastric bypass surgery (RYGB). Whether BA also contribute to the postprandial hypoglycaemia that is frequently observed post-RYGB is unknown. Methods Plasma BA, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), GLP-1, insulin and glucose levels were determined during 3.5 h mixed-meal tolerance tests (MMTT) in subjects after RYGB, either with (RYGB, n = 11) or without a functioning gallbladder due to cholecystectomy (RYGB-CC, n = 11). Basal values were compared to those of age, BMI and sex-matched obese controls without RYGB (n = 22). Results Fasting BA as well as FGF19 levels were elevated in RYGB and RYGB-CC subjects compared to non-bariatric controls, without significant differences between RYGB and RYGB-CC. Postprandial hypoglycaemia was observed in 8/11 RYGB-CC and only in 3/11 RYGB. Subjects who developed hypoglycaemia showed higher postprandial BA levels coinciding with augmented GLP-1 and insulin responses during the MMTT. The nadir of plasma glucose concentrations after meals showed a negative relationship with postprandial BA peaks. Plasma C4 was lower during MMTT in subjects experiencing hypoglycaemia, indicating lower hepatic BA synthesis. Computer simulations revealed that altered intestinal transit underlies the occurrence of exaggerated postprandial BA responses in hypoglycaemic subjects. Conclusion Altered BA kinetics upon ingestion of a meal, as frequently observed in RYGB-CC subjects, appear to contribute to postprandial hypoglycaemia by stimulating intestinal GLP-1 release.

Effects of Manipulating Circulating Bile Acid Concentrations on Postprandial GLP-1 Secretion and Glucose Metabolism After Roux-en-Y Gastric Bypass

“…Notable, bile acids have been suggested to be involved in the pathogenesis of postprandial hypoglycemia via the bile acids-GLP-1-insulin-axis or indirectly via stimulation of FGF-19. Subjects developing postprandial hypoglycemia have been shown to have higher postprandial bile acids levels coinciding with augmented GLP-1 and insulin responses during a mixed meal (44). However, the present study does not support a role for acutely altered intestinal bile acids concentrations for the development of postprandial hypoglycemia as no differences in nadir or in time to nadir of plasma glucose concentrations were found between the four days w i t h m i x e d m e al an d d i ff e r e n c e s i n p l a s m a b i l e acid concentrations.…”

Colesevelam‐induced hypoglycaemia in a patient with type 1 diabetes mellitus

“…It has been proposed that the inhibition of SGLT‐1 sodium‐glucose transport in the alimentary limb could be induced by the deprivation of sodium load present in bile 11 ; moreover, SGLT‐1 inhibition leads to increased GLP‐1 secretion. 13 , 14 …”

“…This finding demonstrates that in an intestinal segment where bile acid absorption does not take place, glucose absorption is also inhibited, introducing a potential correlation between bile acid sequestration and decreased intestinal glucose absorption. It has been proposed that the inhibition of SGLT‐1 sodium‐glucose transport in the alimentary limb could be induced by the deprivation of sodium load present in bile 11 ; moreover, SGLT‐1 inhibition leads to increased GLP‐1 secretion 13,14 …”

Study protocol for a randomised, double-blind, placebo-controlled crossover trial assessing the impact of the SGLT2 inhibitor empagliflozin on postprandial hypoglycaemia after gastric bypass

“…10 Additional factors such as diminished insulin clearance, alterations in postprandial bile acid kinetics, and blunted neuro-endocrine counterregulation may be further contributors. [11][12][13][14] In the absence of approved pharmacotherapies for PBH, dietary modification, mainly carbohydrate restriction is first-line therapy. 15 Second-line approaches include off-label use of acarbose and other systemic acting drugs such as somatostatin analogues, diazoxide and/or calcium channel blockers.…”

“…While the underlying physiology is incompletely understood, inappropriately high postprandial insulin exposure, caused by both accelerated glucose absorption from the gut and increased insulinotropic hormones such as GLP-1, are well established 10. Additional factors such as diminished insulin clearance, alterations in postprandial bile acid kinetics, and blunted neuro-endocrine counter-regulation may be further contributors 11–14…”