Original article| Volume 17, ISSUE 1, P55-63, January 2021

Counterregulatory responses to postprandial hypoglycemia after Roux-en-Y gastric bypass

Published:September 03, 2020DOI:


      • Minor counterregulatory responses to postprandial hypoglycemia after bariatric surgery
      • Aggravated hypoglycemia can increase counterregulatory hormone responses
      • Recurrent hypoglycemia may explain altered counterregulation after bariatric surgery



      Postbariatric hypoglycemia (PBH) is a potentially serious complication after Roux-en-Y gastric bypass (RYGB), and impaired counterregulatory hormone responses have been suggested to contribute to the condition.


      We evaluated counterregulatory responses during postprandial hypoglycemia in individuals with PBH who underwent RYGB.


      University hospital.


      Eleven women with documented PBH who had RYGB underwent a baseline liquid mixed meal test (MMT) followed by 5 MMTs preceded by treatment with (1) acarbose 50 mg, (2) sitagliptin 100 mg, (3) verapamil 120 mg, (4) liraglutide 1.2 mg, and (5) pasireotide 300 μg. Blood was collected at fixed time intervals. Plasma and serum were analyzed for glucose, insulin, glucagon, epinephrine, norepinephrine, pancreatic polypeptide (PP), and cortisol.


      During the baseline MMT, participants had nadir blood glucose concentrations of 3.3 ± .2 mmol/L. At the time of nadir glucose, there was a small but significant increase in plasma glucagon. Plasma epinephrine concentrations were not increased at nadir glucose but were significantly elevated by the end of the MMT. There were no changes in norepinephrine, PP, and cortisol concentrations in response to hypoglycemia. After treatment with sitagliptin, 8 individuals had glucose nadirs <3.2 mmol/L (versus 4 individuals at baseline), and significant increases in glucagon, PP, and cortisol responses were observed.


      In response to postprandial hypoglycemia, individuals with PBH who underwent RYGB only had minor increases in counterregulatory hormones, while larger hormone responses occurred when glucose levels were lowered during treatment with sitagliptin. The glycemic threshold for counterregulatory activation could be altered in individuals with PBH, possibly explained by recurrent hypoglycemia.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery for Obesity and Related Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Madsbad S.
        • Dirksen C.
        • Holst J.J.
        Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery.
        Lancet Diabetes Endocrinol. 2014; 2: 152-164
        • Salehi M.
        • Vella A.
        • McLaughlin T.
        • Patti M.E.
        Hypoglycemia after gastric bypass surgery: current concepts and controversies.
        J Clin Endocrinol Metab. 2018; 103: 2815-2826
        • Tharakan G.
        • Behary P.
        • Wewer Albrechtsen N.J.
        • et al.
        Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass.
        Eur J Endocrinol. 2017; 177: 455-464
        • Marsk R.
        • Jonas E.
        • Rasmussen F.
        • Näslund E.
        Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986–2006 in Sweden.
        Diabetologia. 2010; 53: 2307-2311
        • Goldfine A.B.
        • Patti M.E.
        How common is hypoglycemia after gastric bypass?.
        Obesity. 2016; 24: 1210-1211
        • Halperin F.
        • Patti M.E.
        • Skow M.
        • Bajwa M.
        • Goldfine A.B.
        Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass.
        J Obes. 2011; 2011: 1-7
        • Abrahamsson N.
        • Edén Engstrom B.
        • Sundbom M.
        • Karlsson F.A.
        Hypoglycemia in everyday life after gastric bypass and duodenal switch.
        Eur J Endocrinol Eur Fed Endocr Soc. 2015; 173: 91-100
        • Cryer P.E.
        Glucose counterregulation: prevention and correction of hypoglycemia in humans.
        Am J Physiol-Endocrinol Metab. 1993; 264: E149-E155
        • Goldfine A.B.
        • Mun E.C.
        • Devine E.
        • et al.
        Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal.
        J Clin Endocrinol Metab. 2007; 92: 4678-4685
        • Valderas J.P.
        • Ahuad J.
        • Rubio L.
        • Escalona M.
        • Pollak F.
        • Maiz A.
        Acarbose improves hypoglycaemia following gastric bypass surgery without increasing glucagon-like peptide 1 levels.
        Obes Surg. 2012; 22: 582-586
        • Tack J.
        • Aberle J.
        • Arts J.
        • et al.
        Safety and efficacy of pasireotide in dumping syndrome—results from a phase 2, multicentre study.
        Aliment Pharmacol Ther. 2018; 47: 1661-1672
        • Moreira R.O.
        • Moreira R.B.M.
        • Machado N.A.M.
        • Gonçalves T.B.
        • Coutinho W.F.
        Post-prandial hypoglycemia after bariatric surgery: pharmacological treatment with verapamil and acarbose.
        Obes Surg. 2008; 18: 1618-1621
        • Abrahamsson N.
        • Engstrom B.E.
        • Sundbom M.
        • Karlsson F.A.
        GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?.
        Eur J Endocrinol. 2013; 169: 885-889
        • Øhrstrøm C.C.
        • Worm D.
        • Kielgast U.L.
        • Holst J.J.
        • Hansen D.L.
        Evidence for relationship between early dumping and postprandial hypoglycemia after Roux-en-Y gastric bypass.
        Obes Surg. 2020; 30: 1038-1045
        • Orskov C.
        • Jeppesen J.
        • Madsbad S.
        • Holst J.J.
        Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine.
        J Clin Invest. 1991; 87: 415-423
        • Dirksen C.
        • Jørgensen N.B.
        • Bojsen-Møller K.N.
        • et al.
        Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass.
        Int J Obes (Lond). 2013; 37: 1452-1459
        • Bergmann M.L.
        • Schmedes A.
        Highly sensitive LC-MS/MS analysis of catecholamines in plasma.
        Clin Biochem. 2020; 82: 51-57
        • Øhrstrøm C.C.
        • Worm D.
        • Højager A.
        • et al.
        Postprandial hypoglycaemia after Roux-en-Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide.
        Diabetes Obes Metab. 2019; 21: 2142-2151
        • Mehagnoul-Schipper D.J.
        • Lenders J.W.
        • Willemsen J.J.
        • Hopman W.P.
        Sympathoadrenal activation and the dumping syndrome after gastric surgery.
        Clin Auton Res. 2000; 10: 301-308
        • Clutter W.E.
        • Bier D.M.
        • Shah S.D.
        • Cryer P.E.
        Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man.
        J Clin Invest. 1980; 66: 94-101
        • Davis S.N.
        • Shavers C.
        • Costa F.
        Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds.
        Am J Physiol Endocrinol Metab. 2000; 279: E1054-E1063
        • Mulla C.M.
        • Zavitsanou S.
        • Laguna Sanz A.J.
        • et al.
        A randomized, placebo-controlled double-blind trial of a closed-loop glucagon system for post-bariatric hypoglycemia.
        J Clin Endocrinol Metab. 2020; 105: e1260-e1271
        • Abrahamsson N.
        • Börjesson J.L.
        • Sundbom M.
        • Wiklund U.
        • Karlsson F.A.
        • Eriksson J.W.
        Gastric bypass reduces symptoms and hormonal responses in hypoglycemia.
        Diabetes. 2016; 65: 2667-2675
        • Svane M.S.
        • Bojsen-Møller K.N.
        • Nielsen S.
        • et al.
        Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery.
        Am J Physiol Endocrinol Metab. 2016; 310: E505-E514
        • Harris A.G.
        Somatostatin and somatostatin analogues: pharmacokinetics and pharmacodynamic effects.
        Gut. 1994; 35: S1-S4
        • Heller S.R.
        • Cryer P.E.
        Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans.
        Diabetes. 1991; 40: 223-226
        • Caduff A.
        • Lutz H.U.
        • Heinemann L.
        • Benedetto G.D.
        • Talary M.S.
        • Theander S.
        Dynamics of blood electrolytes in repeated hyper- and/or hypoglycaemic events in patients with type 1 diabetes.
        Diabetologia. 2011; 54: 2678-2689
        • Heller S.R.
        • Robinson R.T.C.E.
        Hypoglycaemia and associated hypokalaemia in diabetes: mechanisms, clinical implications and prevention.
        Diabetes Obes Metab. 2000; 2: 75-82
        • Ritzel R.
        • Ørskov C.
        • Holst J.J.
        • Nauck M.A.
        Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7–36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships.
        Diabetologia. 1995; 38: 720-725
        • Toft-Nielsen M.
        • Madsbad S.
        • Holst J.J.
        Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia.
        Diabetologia. 1998; 41: 1180-1186