A view at postbariatric hypoglycemia by endocrinologist

The obesity epidemic has led to the growing number of bariatric operations and the expansion of indications for this operation as the most effective method of treatment, that’s why endocrinologists are increasingly faced the challenge of late complications, including postbariatric hypoglycemia. Postbariatric hypoglycemia is a rare but severe metabolic disorder that occurs months or years after upper gastrointestinal surgery. Postbariatric hypoglycemia can be accompanied by severe clinical symptoms and lead to disability and decreasing of the life’s quality. It is difficult to assess the prevalence of hypoglycemia after bariatric surgery due to the lack of clear diagnostic criteria, often a hidden clinical picture and ignorance of doctors and patients about this complication. Hypoglycemia in this case has postprandial and hyperinsulinemic nature. The mechanisms of development of this complication have recently been actively discussed. The exchange of incretins and dysregulation of insulin secretion are the subject of constant research in this area. Understanding the mechanisms of development of this condition makes it possible to develop optimal methods of diagnosis and treatment. The issues of pathophysiology, basic principles of diagnosis and treatment of post-bariatric hypoglycemia will be considered in this review.

1. Available at: https://www.who.int/data/gho/data/indicators/indicator-details/GHO/prevalence-of-obesityamong-adults-bmi-=-30-(age-standardized-estimate)-(-)

2. Appolinario J, Bacaltchuk J, Sichieri R, et al. A randomized, double-blind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder. Archives of General Psychiatry. 2003; 60:1109-16. doi: https://doi.org/10.1001/archpsyc.60.11.1109

3. Celio AC, Pories WJ. A History of Bariatric Surgery: The Maturation of a Medical Discipline. Surg Clin North Am. 2016;96(4):655-667. doi: https://doi.org/10.1016/j.suc.2016.03.001

4. Brix JM, Kopp HP, Höllerl F, et al. Frequency of Hypoglycaemia after Different Bariatric Surgical Procedures. Obes Facts. 2019;12(4):397-406. doi: https://doi.org/10.1159/000493735

5. Goldfine AB, Mun EC, 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(12):4678-4685. doi: https://doi.org/10.1210/jc.2007-0918

6. Salehi M, Vella A, McLaughlin, et al. Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies. J Clin Endocrinol Metab. 2018;103(8):2815-2826. doi:10.1210/jc.2018-00528

7. Heber D, Greenway F, Kaplan L, et al. Endocrine and Nutritional Management of the Post-Bariatric Surgery Patient: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(11):4823-43. doi: https://doi.org/10.1210/jc.2009-2128

8. Fried M, Yumuk V, Oppert J, et al. Interdisciplinary European guidelines on metabolic and bariatric surgery. International Federation for the Surgery of Obesity and Metabolic Disorders — European Chapter (IFSO — EC) and European Association for the Study of Obesity (EASO). Obes Surg. 2014;24(1):42-55. doi: https://doi.org/10.1007/s11695-013-1079-8

9. Dedov II, Mel’nichenko GA, Shestakova MV, et al. Russian national clinical recommendations for morbid obesity treatment in adults. 3rd revision (Morbid obesity treatment in adults). Obesity and metabolism. 2018;15(1):53-70. (In Russ.). doi: https://doi.org/10.14341/omet2018153-70

10. Dedov II, Shestakova MV, Melnichenko GA, et al. Interdisciplinary clinical practice guidelines «management of obesity and its comorbidities». Obesity and metabolism. 2021;18(1):5-99. (In Russ.) doi: https://doi.org/10.14341/omet12714

11. Трошина Е.А., Ершова Е.В., Мазурина Н.В. Эндокринологические аспекты бариатрической хирургии // Consilium Medicum. — 2019. — Т. 21. — №4. — С. 50-55. doi: 10.26442/20751753.2019.4.190336

12. Service GJ, Thompson GB, Service FJ, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353(3):249-254. doi: https://doi.org/10.1056/NEJMoa043690

13. Patti ME, McMahon G, Mun EC, et al. Severe hypoglycaemia postgastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005;48:2236-2240. doi: https://doi.org/10.1007/s00125-005-1933-x

14. Vella A, Service FJ. Incretin hypersecretion in postgastric bypass hypoglycemia: primary problem or red herring? J Clin Endocrinol Metab. 2007; 92: 4563-4565. doi:10.1210/jc.2007-2260

15. Kellogg TA, Bantle JP, Leslie DB, et al. Postgastric bypass hyperinsulinemic hypoglycemia syndrome: characterization and response to a modified diet. Surg Obes Relat Dis. 2008;4(4):492-499. doi: https://doi.org/10.1016/j.soard.2008.05.005

16. Roslin M, Damani T, Oren J, et al. Abnormal glucose tolerance testing following gastric bypass demonstrates reactive hypoglycemia. Surg Endosc. 2011;25(6):1926-1932. doi: https://doi.org/10.1007/s00464-010-1489-9

17. Bernard B, Kline GA, Service FJ. Hypoglycaemia following upper gastrointestinal surgery: case report and review of the literature. BMC Gastroenterol. 2010;10:77. doi: https://doi.org/10.1186/1471-230X-10-77

18. Abrahamsson N, Edén Engström B, Sundbom M, et al. Hypoglycemia in everyday life after gastric bypass and duodenal switch. Eur J Endocrinol. 2015;173(1):91-100. doi: https://doi.org/10.1530/EJE-14-0821.

19. Marsk R, Jonas E, Rasmussen F, et al. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986-2006 in Sweden. Diabetologia. 2010;53(11):2307-2311. doi: https://doi.org/10.1007/s00125-010-1798-5

20. Frankhouser SY, Ahmad AN, Perilli GA, et al. Post-gastric-bypass hypoglycemia successfully treated with alpha-glucosidase inhibitor therapy. Endocr Pract. 2013;19(3):511-514. doi: https://doi.org/10.4158/EP12281.RA

21. Sarwar H, Chapman WH 3rd, Pender JR, et al. Hypoglycemia after Roux-en-Y gastric bypass: the BOLD experience. Obes Surg. 2014;24(7):1120-1124. doi: https://doi.org/10.1007/s11695-014-1260-8

22. Affinati AH, Esfandiari NH, Oral EA, et al. Bariatric Surgery in the Treatment of Type 2 Diabetes. Curr Diab Rep. 2019;19(12):156. doi:10.1007/s11892-019-1269-4

23. Zilberstein B, Santo MA, Carvalho MH. Critical analysis of surgical treatment techniques of morbid obesity. Arq Bras Cir Dig. 2019;32(3):e1450. doi: https://doi.org/10.1590/0102-672020190001e1450

24. Komatsu M, Takei M, Ishii H, et al. Glucose-stimulated insulin secretion: A newer perspective. J Diabetes Investig. 2013;4(6):511-516. doi: https://doi.org/10.1111/jdi.12094

25. Röder PV, Wu B, Liu Y, et al. Pancreatic regulation of glucose homeostasis. Exp Mol Med. 2016;48(3):e219. doi: https://doi.org/10.1038/emm.2016.6

26. Patti ME, Goldfine AB, Hu J, et al. Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass. Acta Diabetol. 2017;54(8):737-747. doi: https://doi.org/10.1007/s00592-017-1001-2

27. Meier JJ, Butler AE, Galasso R, et al. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care. 2006;29(7):1554-1559. doi: https://doi.org/10.2337/dc06-0392

28. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131-2157. doi: https://doi.org/10.1053/j.gastro.2007.03.054

29. Vilsbøll T, Krarup T, Madsbad S, et al. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003;114(2-3):115-121. doi: https://doi.org/10.1016/s0167-0115(03)00111-3

30. Salehi M, Woods SC, D’Alessio DA. Gastric bypass alters both glucose-dependent and glucose-independent regulation of islet hormone secretion. Obesity (Silver Spring). 2015;10:2046-2052. doi: https://doi.org/10.1002/oby.21186

31. Salehi M, Gastaldelli A, D’Alessio DA. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146(3):669-680. doi: https://doi.org/10.1053/j.gastro.2013.11.044

32. Shah M, Law JH, Micheletto F, et al. Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass. Diabetes. 2014;63(2):483-493. doi: https://doi.org/10.2337/db13-0954

33. Shah A, Holter MM, Rimawi F, et al. Insulin Clearance After Oral and Intravenous Glucose Following Gastric Bypass and Gastric Banding Weight Loss. Diabetes Care. 2019;42(2):311-317. doi: https://doi.org/10.2337/dc18-1036

34. Salehi M, Gastaldelli A, D’Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99(6):2008-2017. doi: https://doi.org/10.1210/jc.2013-2686

35. Patti ME, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity (Silver Spring). 2009;17:1671-1677. doi: https://doi.org/10.1038/oby.2009.102

36. Abrahamsson N, Borjesson JL, Sundbom M, et al. Gastric bypass reduces symptoms and hormonal responses in hypoglycemia. Diabetes 2016;9:2667-2675. doi: https://doi.org/10.2337/db16-0341

37. Meier JJ, Gallwitz B, Siepmann N, et al. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia. 2003;46(6):798-801. doi: https://doi.org/10.1007/s00125-003-1103-y

38. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287(2):E199-206. doi: https://doi.org/10.1152/ajpendo.00545.2003

39. Meehan S, Beck CR, Mair-Jenkins J, et al. 6. Glycemic Targets: Standards of Medical Care in Diabetes — 2021. Diabetes Care. 2021;44(S1):S73-S84. doi: https://doi.org/10.2337/dc21-S006

40. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94(3):709-728. doi: https://doi.org/10.1210/jc.2008-1410

41. Heller SR. Glucose Concentrations of Less Than 3.0 mmol/L (54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2017;40(1):155-157. doi: https://doi.org/10.2337/dc16-2215

42. Rodríguez Flores M, Cruz Soto RC, Vázquez Velázquez V, et al. Continuous glucose monitoring in the management of patients after gastric bypass. Endocrinol Diabetes Metab Case Rep. 2019;2019(1):1-6. doi: https://doi.org/10.1530/EDM-18-0155

43. Scarpellini E, Arts J, Karamanolis G, et al. International consensus on the diagnosis and management of dumping syndrome. Nat Rev Endocrinol. 2020;6:448-466. doi: https://doi.org/10.1038/s41574-020-0357-5

44. Halperin F, Patti ME, Skow M, et al. Continuous Glucose Monitoring for Evaluation of Glycemic Excursions after Gastric Bypass. J Obes. 2011;2011:1-7. doi: https://doi.org/10.1155/2011/869536

45. Lobato CB, Pereira SS, Guimarães M, et al. Use of flash glucose monitoring for post-bariatric hypoglycaemia diagnosis and management. Sci Rep. 2020;10(1):11061. doi: https://doi.org/10.1038/s41598-020-68029-8

46. Eisenberg D, Azagury DE, Ghiassi S, et al. ASMBS Position Statement on Postprandial Hyperinsulinemic Hypoglycemia after Bariatric Surgery. Surg Obes Relat Dis. 2017;13(3):371-378. doi: https://doi.org/10.1016/j.soard.2016.12.005

47. Nadelson J, Epstein A. A Rare Case of Noninsulinoma Pancreatogenous Hypoglycemia Syndrome. Case Rep Gastrointest Med. 2012;2012:1-3. doi: https://doi.org/10.1155/2012/164305

48. Laurenius A, Olbers T, Näslund I, et al. Dumping syndrome following gastric bypass: validation of the dumping symptom rating scale. Obes Surg. 2013;23(6):740-755. doi: https://doi.org/10.1007/s11695-012-0856-0

49. Banerjee A, Ding Y, Mikami DJ, et al. The role of dumping syndrome in weight loss after gastric bypass surgery. Surg Endosc. 2013;27(5):1573-1578. doi: https://doi.org/10.1007/s00464-012-2629-1

50. Papamargaritis D, Koukoulis G, Sioka E, et al. Dumping Symptoms and Incidence of Hypoglycaemia After Provocation Test at 6 and 12 Months After Laparoscopic Sleeve Gastrectomy. Obes Surg. 2012;22(10):1600-1606. doi: https://doi.org/10.1007/s11695-012-0711-3

51. Malik S, Mitchell JE, Steffen K, et al. Recognition and management of hyperinsulinemic hypoglycemia after bariatric surgery. Obes Res Clin Pract. 2016;10(1):1-14. doi: https://doi.org/10.1016/j.orcp.2015.07.003

52. Zagury L, Moreira RO, Guedes EP, et al. Insulinoma misdiagnosed as dumping syndrome after bariatric surgery. Obes Surg. 2004;14(1):120-123. doi: https://doi.org/10.1381/096089204772787419

53. Suhl E, Anderson-Haynes SE, Mulla C, et al. Medical nutrition therapy for post-bariatric hypoglycemia: practical insights. Surg Obes Relat Dis. 2017;13(5):888-896. doi: https://doi.org/10.1016/j.soard.2017.01.025

54. Botros N, Rijnaarts I, Brandts H, et al. Effect of carbohydrate restriction in patients with hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. Obes Surg. 2014;24(11):1850-1855. doi: https://doi.org/10.1007/s11695-014-1319-6

55. Vilarrasa N, Goday A, Rubio MA, et al. Hyperinsulinemic Hypoglycemia after Bariatric Surgery: Diagnosis and Management Experience from a Spanish Multicenter Registry. Obes Facts. 2016;9(1):41-51. doi: https://doi.org/10.1159/000442764

56. Ames A, Lago-Hernandez CA, Grunvald E. Hypoglycemia After Gastric Bypass Successfully Treated With Calcium Channel Blockers: Two Case Reports. J Endocr Soc. 2019;3(7):1417-1422. doi: https://doi.org/10.1210/js.2019-00097

57. Mordes JP, Alonso LC. Evaluation, Medical Therapy, and Course of Adult Persistent Hyperinsulinemic Hypoglycemia After Roux-en-Y Gastric Bypass Surgery: A Case Series. Endocr Pract. 2015;21(3):237-46. doi: 10.4158/EP14118

58. Ng CM, Tang F, Seeholzer SH, et al. Population pharmacokinetics of exendin-(9-39) and clinical dose selection in patients with congenital hyperinsulinism. Br J Clin Pharmacol. 2018;84(3):520-532. doi: https://doi.org/10.1111/bcp.13463

59. Craig CM, Liu LF, Deacon CF, et al. Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia. Diabetologia. 2017;60(3):531-540. doi: https://doi.org/10.1007/s00125-016-4179-x

60. Johnson KW, Neale AC, Gordon A, et al. Activity of Xoma 358, an Inhibitor of Insulin Action Following Short-Term Administration to Congenital Hyperinsulinism Patients. Endocrine Rev June. 2017;38(3).

61. Corbin JA, Bhaskar V, Goldfine ID, et al. Inhibition of insulin receptor function by a human, allosteric monoclonal antibody: a potential new approach for the treatment of hyperinsulinemic hypoglycemia. MAbs. 2014;6:262-272 doi: https://doi.org/10.4161/mabs.26871

62. Johnson KW, Neale A, Gordon A, et al. Attenuation of insulin action by an allosteric insulin receptor antibody in healthy volunteers. J Clin Endocrinol Metab. 2017;102:3021-3028. doi: https://doi.org/10.1210/jc.2017-00822

63. Patel P, Charles L, Corbin J, et al. A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1-/- mouse model of KATP hyperinsulinism. MAbs. 2018;10(5):796-802. doi: https://doi.org/10.1080/19420862.2018.1457599

64. Craig CM, Lamendola C, Holst JJ, et al. The Use of Gastrostomy Tube for the Long-Term Remission of Hyperinsulinemic Hypoglycemia After Roux-en-y Gastric Bypass: A Case Report. AACE Clin Case Reports. 2015;1(2):e84-e87. doi: https://doi.org/10.4158/EP14218.CR