Skip to main content

Advertisement

SpringerLink
Log in

Distal Gastrectomy in Pancreaticoduodenectomy is Associated with Accelerated Gastric Emptying, Enhanced Postprandial Release of GLP-1, and Improved Insulin Sensitivity

  • 2013 SSAT Plenary
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Objective

This study aims to investigate the relationship between gastric emptying, postprandial GLP-1 and insulin sensitivity after pancreaticoduodenectomy (PD).

Background

Abnormal glucose regulation is highly prevalent in patients with pancreatic neoplasm and resolves in some after PD, the cause of which is unclear. The procedure is carried out with pylorus preservation (PPPD) or with distal gastrectomy (Whipple procedure). Accelerated gastric emptying and ensuing enhanced release of glucagon-like peptide-1 (GLP-1) conceivably play a role in glucose metabolism after PD. It was the purpose of this study to shed light on the relationship between gastric emptying, GLP-1 and glycemic control after PPPD and the Whipple procedure.

Methods

A 75-g oral glucose tolerance test was carried out in 13 patients having undergone PPPD and in 13 after the Whipple procedure, median age 61 (range, 32–70) years, following an interval of 23 (range, 5–199) months. Gastric emptying was measured by the paracetamol absorption method. Plasma concentrations of glucose, insulin, GLP-1 and paracetamol were measured at baseline, 10, 20, 30 60, 90, 120, 150 and 180 min. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) and oral glucose insulin sensitivity were calculated from glucose and insulin concentrations.

Results

Patients with Whipple procedure as compared to PPPD had accelerated gastric emptying (p = 0.01) which correlated with early (0–30 min) integrated GLP-1 (AUC30; r 2 = 0.61; p = 0.02) and insulin sensitivity (r 2 = 0.41; p = 0.026) and inversely with HOMA-IR (r 2 = 0.17; p = 0.033). Two of 13 Whipple patients (15 %) as compared to seven of 13 after PPPD (54 %) had postload glucose concentrations (i.e. 120 min postmeal) ≥200 mg/dl (p < 0.05). None of 13 (0 %) after Whipple procedure but four of 13 patients (31 %) after PPPD had fasting glucose concentrations ≥126 mg/dl (p < 0.05)

Conclusions

Gastric emptying was accelerated after Whipple procedure as compared to patients who have undergone PPPD, resulting in higher postprandial GLP-1 concentrations and insulin sensitivity and improved glycemic control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of Vater. Ann Surg 1935;102:763-779.

    Article  CAS  PubMed  Google Scholar 

  2. Are C, Dhir M, Ravipati L. History of pancreaticoduodenectomy: early misconceptions, initial milestones and the pioneers. HPB (Oxford) 2011;13:377-384.

    Article  Google Scholar 

  3. Traverso LW, Longmire WP Jr. Preservation of the pylorus in pancreaticoduodenectomy. Surg Gynecol Obstet 1978; 146: 959-962.

    CAS  PubMed  Google Scholar 

  4. Tran KT, Smeenk HG, van Eijck CH, Kazemier G, Hop WC, Greve JW, Terpstra OT, Zijlstra JA, Klinkert P, Jeekel H. Pylorus preserving pancreaticoduodenectomy versus standard Whipple procedure: a prospective, randomized, multicenter analysis of 170 patients with pancreatic and periampullary tumors. Ann Surg 2004; 240:738-745.

    Article  PubMed  Google Scholar 

  5. Diener MK, Knaebel HP, Heukaufer C, Antes G, Büchler MW, Seiler CM. A systematic review and meta-analysis of pylorus-preserving versus classical pancreaticoduodenectomy for surgical treatment of periampullary and pancreatic carcinoma. Ann Surg 2007; 245:187-200.

    Article  PubMed  Google Scholar 

  6. Wang F, Herrington M, Larsson J, Permert J. The relationship between diabetes and pancreatic cancer. Mol Cancer 2003; 2:4.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, Petersen GM. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008;134:95-101.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Permert J, Adrian TE, Jacobsson P, Jorfelt L, Fruin AB, Larsson J. Is profound peripheral insulin resistance in patients with pancreatic cancer caused by a tumor-associated factor? Am J Surg 1993;165:61-67.

    Article  CAS  PubMed  Google Scholar 

  9. Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 2008;134:981-987.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409-1439.

    Article  CAS  PubMed  Google Scholar 

  11. Miholic J, Orskov C, Holst JJ, Kotzerke J, Meyer HJ. Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy. Dig Dis Sci 1991;36:1361-1370.

    Article  CAS  PubMed  Google Scholar 

  12. Peterli R, Wolnerhanssen B, Peters T, Devaux N, Kern B, Christoffel-Courtin C, Drewe J, von Flue M, Beglinger C. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial. Ann Surg 2009;250:234-241.

    Article  PubMed  Google Scholar 

  13. Larsson H, Holst JJ, Ahren B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand 1997;160:413-422.

    Article  CAS  PubMed  Google Scholar 

  14. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 2008;60:470-512.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Lee W, Ahn SH, Lee JH, Park do J, Lee HJ, Kim HH, Yang HK. Comparative study of diabetes mellitus resolution according to reconstruction type after gastrectomy in gastric cancer patients with diabetes mellitus. Obes Surg 2012;22:1238-1243.

    Article  PubMed  Google Scholar 

  16. Kashyap SR, Daud S, Kelly KR, Gastaldelli A, Win H, Brethauer S, Kirwan JP, Schauer PR. Acute effects of gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes. Int J Obes (Lond) 2010;34:462-471.

    Article  CAS  Google Scholar 

  17. Kawai M, Tani M, Hirono S, Miyazawa M, Shimizu A, Uchiyama K, Yamaue H. Pylorus ring resection reduces delayed gastric emptying in patients undergoing pancreatoduodenectomy: a prospective, randomized, controlled trial of pylorus-resecting versus pylorus-preserving pancreatoduodenectomy. Ann Surg 2011; 253: 495-501.

    Article  PubMed  Google Scholar 

  18. Lukaski HC, Bolonchuk WW, Hall CB, Siders WA. Validation of tetrapolar bioelectrical impedance method to assess human body composition. J Appl Physiol 1986;60:1327-1332.

    CAS  PubMed  Google Scholar 

  19. Miholic J, Reilmann L, Meyer HJ, Korber H, Kotzerke J, Hecker H. Extracellular space, blood volume, and the early dumping syndrome after total gastrectomy. Gastroenterology 1990;99:923-929.

    CAS  PubMed  Google Scholar 

  20. Willems M, Quartero AO, Numans ME. How useful is paracetamol absorption as a marker of gastric emptying? A systematic literature study. Dig Dis Sci 2001;46:2256-2262.

    Article  CAS  PubMed  Google Scholar 

  21. Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 2001;24:539-548.

    Article  CAS  PubMed  Google Scholar 

  22. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-419.

    Article  CAS  PubMed  Google Scholar 

  23. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: WHO Document Production Services, 2006, pp21.

  24. Vijan S. Type 2 diabetes. Ann Intern Med 2010;152: ITC31-15; quiz ITC316.

  25. Cryer PE. Hypoglycemia. In: Jefferson L, Cherrington A, Goodman H (eds) for the American Physiological Society. Handbook of physiology,vol 2, 1st edn. New York: Oxford University Press, 2001, pp. 1057–1092

  26. Miholic J, Hoffmann M, Holst JJ, Lenglinger J, Mittlbock M, Bergmann H, Stacher G. Gastric emptying of glucose solution and associated plasma concentrations of GLP-1, GIP, and PYY before and after fundoplication. Surg Endosc 2007;21:309-314.

    Article  CAS  PubMed  Google Scholar 

  27. Laferrere B. Diabetes remission after bariatric surgery: is it just the incretins? Int J Obes (Lond) 2011;35Suppl3:22-25.

    Google Scholar 

  28. Gebhard B, Holst JJ, Biegelmayer C, Miholic J. Postprandial GLP-1, norepinephrine, and reactive hypoglycemia in dumping syndrome. Dig Dis Sci 2001;46:1915-1923.

    Article  CAS  PubMed  Google Scholar 

  29. Fischer CP, Hong JC. Method of pyloric reconstruction and impact upon delayed gastric emptying and hospital stay after pylorus-preserving pancreaticoduodenectomy. J Gastrointest Surg 2006;10:215-219.

    Article  PubMed  Google Scholar 

  30. Uravic M, Zelic M, Petrosic N, Tokmadzic VS, Stimac D, Sustic A. Effect of pyloric dilatation on gastric emptying after pylorus-preserving pancreaticoduodenectomy. Hepatogastroenterology 2011;58:2144-2147.

    Article  PubMed  Google Scholar 

  31. Manes K, Lytras D, Avgerinos C, Delis S, Dervenis C. Antecolic gastrointestinal reconstruction with pylorus dilatation. Does it improve delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy? HPB (Oxford) 2008;10:472-476.

    Article  Google Scholar 

  32. Holt S, Heading RC, Clements JA, Tothill P, Prescott LF. Acetaminophen absorption and metabolism in celiac disease and Crohn’s disease. Clin Pharmacol Ther 1981;30:232-238.

    Article  CAS  PubMed  Google Scholar 

  33. Steinert RE, Poller B, Castelli MC, Friedman K, Huber AR, Drewe J, Beglinger C. Orally administered glucagon-like peptide-1 affects glucose homeostasis following an oral glucose tolerance test in healthy male subjects. Clin Pharmacol Ther 2009;86:644-650.

    Article  CAS  PubMed  Google Scholar 

  34. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007;132:2131-2157.

    Article  CAS  PubMed  Google Scholar 

  35. Niskanen L, Uusitupa M, Sarlund H, Siitonen O, Paljarvi L, Laakso M. The effects of weight loss on insulin sensitivity, skeletal muscle composition and capillary density in obese non-diabetic subjects. Int J Obes Relat Metab Disord 1996;20:154-160.

    CAS  PubMed  Google Scholar 

  36. Salinari S, Bertuzzi A, Guidone C, Previti E, Rubino F, Mingrone G. Insulin sensitivity and secretion changes after gastric bypass in normotolerant and diabetic obese subjects. Ann Surg. 2013;257:462-468.

    Article  PubMed  Google Scholar 

  37. Ranganath LR, Beety JM, Morgan LM, Wright JW, Howland R, Marks V. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996;38:916-919.

    Article  CAS  PubMed  Google Scholar 

  38. Verdich C, Toubro S, Buemann B, Lysgard Madsen J, Holst JJ, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction. Int J Obes Relat Metab Disord 2001;25:1206-1214.

    Article  CAS  PubMed  Google Scholar 

  39. Michaud DS, Giovannucci E, Willett WC, Colditz GA, Stampfer MJ, Fuchs CS. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 2001;286:921-929.

    Article  CAS  PubMed  Google Scholar 

  40. Yalniz M, Pour PM. Diabetes mellitus: a risk factor for pancreatic cancer? Langenbecks Arch Surg 2005;390:66-72.

    Article  CAS  PubMed  Google Scholar 

  41. McWilliams RR, Matsumoto ME, Burch PA, Kim GP, Halfdanarson TR, de Andrade M, Reid-Lombardo K, Bamlet WR. Obesity adversely affects survival in pancreatic cancer patients. Cancer 2010;116:5054-5062.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Becker S, Dossue L, Kaaks R: Obesity related hyperinsulinemia and hyperglycemia and cancer development. Arch Physiol Biochem 2009; 115: 86-96.

    Article  CAS  PubMed  Google Scholar 

  43. Butler PC, Matveyenko AV, Dry S, Bhushan A, Elashoff R. Glucagon-like peptide-1 therapy and the exocrine pancreas: innocent bystander or friendly fire? Diabetologie 2010; 53: 1-6.

    CAS  Google Scholar 

  44. Gale EAM. GLP-1-based therapies and the exocrine pancreas: more light, or just more heat? Diabetes 2012; 61: 986-988.

    Article  CAS  PubMed  Google Scholar 

  45. Gale EAM. GLP-1 based agents and acute pancreatitis. BMJ 2013; 346:f1304.

    Article  Google Scholar 

  46. Labuzek K, Kozlowski M, Szkudlapski D, Sikorska P, Kozlowska M, Okopien B. Incretin-based therapies in the treatment of type 2 diabetes—more than meets the eye? Eur J Int Med 2013; 24: 207-212.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Allgemeines Krankenhaus (AKH), Medical University of Vienna, Währinger Gürtel 18, 1090, Vienna, Austria

    Stefan Harmuth, Romina Nemecek, Klaus Sahora, Michael Gnant & Johannes Miholić

  2. Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

    Marlene Wewalka

  3. Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark

    Jens Juul Holst

  4. Department of Surgery, Kaiser Franz-Josef-Krankenhaus (KFJ), Vienna, Austria

    Sabine Thalhammer

  5. Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria

    Rainer Schmid

Authors
  1. Stefan Harmuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlene Wewalka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jens Juul Holst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Romina Nemecek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sabine Thalhammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rainer Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Klaus Sahora
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Gnant
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Johannes Miholić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johannes Miholić.

Additional information

Discussant

Dr. David McFadden (Farmington, Connecticut): Thank you for that excellent presentation, Dr. Miholic, and for the opportunity of reading your manuscript in advance. Your study introduced me to two unknown concepts; one is that patients undergoing pancreaticoduodenectomy have increased gastric emptying, and the second is that glucose tolerance is improved and diabetes may be cured by this operation. You attribute this to increased GLP-1 secretion, and demonstrate here that it is much more pronounced postprandially in patients undergoing antrectomy with their Whipple versus the pylorus preserving variant. I have two questions and one criticism.

First, given their rapid gastric emptying, and their low body mass index, were any of your study patients symptomatic?

Second, although statistically insignificant, the length of time postoperatively in your antrectomy group was much longer (31 vs. 19 months) and may have contributed to your findings. Could this be a Type II error?

Finally, I believe this study would be strengthened by the addition of a control group, i.e. unoperated normal volunteers, to eliminate inter-assay variations. Your fasting GLP-1 levels seem low to me from the values I am familiar with, and I would expect them to be higher given your findings.

Again, thank you and congratulations on an excellent contribution to the scientific literature.

Closing Discussant

Dr. Johannes Miholic: Dr. McFadden, although in patients with accelerated gastric emptying after pancreaticoduodenectomy dumping may be expected, we did not look at postprandial symptoms during our tests. Dumping symptoms had not been reported spontaneously by the subjects during the screening visit at the outpatient clinic. Reactive hypoglycemia (late dumping) may be a concern in some subjects, particularly after rapid gastric emptying, and be considered in future trials.

Recruitment of patients who have undergone Whipple procedure was a demanding task since the operation has become sort of antiquity. The somewhat longer intervals since operation in Whipple subjects may thus be explained. The interval since operation was of no statistical association with the insulin sensitivity in simple and in multivariate statistics.

I agree that a control group of healthy volunteers would have helped to elucidate the results, and controls shall be included in future studies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harmuth, S., Wewalka, M., Holst, J.J. et al. Distal Gastrectomy in Pancreaticoduodenectomy is Associated with Accelerated Gastric Emptying, Enhanced Postprandial Release of GLP-1, and Improved Insulin Sensitivity. J Gastrointest Surg 18, 52–59 (2014). https://doi.org/10.1007/s11605-013-2283-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-013-2283-5

Keywords

Search

Navigation