Journal of Endocrinological Investigation

, Volume 41, Issue 5, pp 539–547 | Cite as

The effects of add-on exenatide to insulin on glycemic variability and hypoglycemia in patients with type 1 diabetes mellitus

  • L.-l. Jiang
  • S.-q. Wang
  • B. Ding
  • J. Zhu
  • T. Jing
  • L. Ye
  • K.-O. Lee
  • J.-d. Wu
  • J.-h. Ma
Original Article



To investigate the effect of add-on exenatide to insulin on glycemic excursion and the counter-regulatory hormone in response to hypoglycemia in patients with type 1 diabetes mellitus (T1DM).


30 patients with T1DM were recruited and randomly assigned to exenatide + insulin-treated group (group 1, n = 15) or insulin-only-treated group (group 2, n = 15) for 4 weeks. All patients had continuous glucose monitor system (CGMS) applied at before (week-0) and after (week-4) treatment to evaluate the glycemic variability. All patients had an arginine-stimulated test at before and after treatment. Six patients from each group also had hypoglycemic clamp test to assess counter-regulatory hormone level.


Patients in the exenatide group had significant reductions in body weight, body mass index (BMI), total insulin dose, bolus insulin dose, fructosamine, and glycemic excursion after 4 weeks’ treatment. Compared with patients in group 2, the mean amplitude of glycemic excursion (MAGE) and coefficient of variation (CV) of exenatide group decreased significantly. Similarly, a significant decrease of glucagon (GLC) in the arginine-stimulated test was found in group 1. No significant changes of GLC, growth hormone (GH), cortisol (COR), epinephrine (E), and norepinephrine (NE) were found in both groups during hypoglycemia clamp test. However, patients who had residual islet function in group 1 showed an upward trend of basic C-peptide (C-P) and GLC during the hypoglycemia period.


Although exenatide could inhibit glucagon secretion during euglycemia or hyperglycemia in patients with T1DM, it has no effect on GLC and counter-regulatory hormones during hypoglycemia clamp in patients with no functional residual islet test.


Type 1 diabetes mellitus Exenatide Glycemic excursion 



This study received financial support from the Science Association fund of Nanjing (201303005), JiangSu, China.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts interest to declare.

Ethical approval

The research study was approved by the ethics committee at Nanjing First Hospital, Nanjing, China.

Informed consent

Our research involved human participants who had obtained informed consent.

Supplementary material

40618_2017_765_MOESM1_ESM.doc (136 kb)
Supplementary material 1 (DOC 135 kb)


  1. 1.
    Kramer CK, Borgono CA, Van Nostrand P et al (2014) Glucagon response to oral glucose challenge in type 1 diabetes: lack of impact of euglycemia. Diabetes Care 37(4):1076–1082CrossRefPubMedGoogle Scholar
  2. 2.
    Cryer PE (2008) Hypoglycemia: still the limiting factor in the glycemic management of diabetes. Endocr Pract 14:750–756CrossRefPubMedGoogle Scholar
  3. 3.
    Russell-Jones D, Khan R (2007) Insulin-associated weight gain in diabetes–causes, effects and coping strategies. Diabetes Obes Metab 9:799–812CrossRefPubMedGoogle Scholar
  4. 4.
    Wood JR, Miller KM, Maahs DM et al (2013) Most youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes clinical guidelines. Diabetes Care 36(7):2035–2037CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Downie E, Craig ME, Hing S et al (2011) Continued reduction in the prevalence of retinopathy in adolescents with type 1 diabetes: role of insulin therapy and glycemic control. Diabetes Care 34(11):2368–2373CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Monami M, Nreu B, Scatena A, Giannini S, Andreozzi F, Sesti G, Mannucci E (2017) Glucagon-like peptide-1 receptor agonists and atrial fibrillation: a systematic review and meta-analysis of randomised controlled trials. J Endocrinol Invest. doi: 10.1007/s40618-017-0698-7 Google Scholar
  7. 7.
    Traina AN, Lull ME, Hui AC et al (2014) Once-weekly exenatide as adjunct treatment of type 1 diabetes mellitus in patients receiving continuous subcutaneous insulin infusion therapy. Can J Diabetes 38(4):269–272CrossRefPubMedGoogle Scholar
  8. 8.
    Sarkar G, Alattar M, Brown RJ et al (2014) Exenatide treatment for 6 months improves insulin sensitivity in adults with type 1 diabetes. Diabetes Care 37(3):666–670CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ghazi T, Rink L, Sherr JL, Herold KC (2014) Acute metabolic effects of exenatide in patients with type 1 diabetes with and without residual insulin to oral and intravenous glucose challenges. Diabetes Care 37(1):210–216CrossRefPubMedGoogle Scholar
  10. 10.
    Kielgast U, Asmar M, Madsbad S, Holst JJ (2010) Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients. J Clin Endocrinol Metab 95(5):2492–2496CrossRefPubMedGoogle Scholar
  11. 11.
    Pieber TR, Deller S, Korsatko S et al (2015) Counter-regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: a randomized, placebo- controlled, double-blind, crossover trial. Diabetes Obes Metab 17(8):742–750CrossRefPubMedGoogle Scholar
  12. 12.
    Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15(7):539–553CrossRefPubMedGoogle Scholar
  13. 13.
    Abumrad NN, Rabin D, Diamond MP et al (1981) Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism 30(9):936–940CrossRefPubMedGoogle Scholar
  14. 14.
    McGee P, Steffes M, Nowicki M et al (2014) Short report: pathophysiology Insulin secretion measured by stimulated C-peptide in long-established Type 1 diabetes in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort: a pilot Study. Diabet Med 31:1264–1268CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Garber AJ, Abrahamson MJ, Barzilay JI et al (2013) AACE comprehensive diabetes management algorithm 2013. Endocr Pract 19(2):327–336CrossRefPubMedGoogle Scholar
  16. 16.
    Dupré J, Behme MT, McDonald TJ (2004) Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab 89(7):3469–3473CrossRefPubMedGoogle Scholar
  17. 17.
    D’Alessio D, Vahl T, Prigeon R (2004) Effects of glucagon-like peptide 1 on the hepatic glucose metabolism. Horm Metab Res 36:837–841CrossRefPubMedGoogle Scholar
  18. 18.
    Dardevet D, Moore MC, DiCostanzo CA et al (2005) Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors. Am J Physiol Gastrointest Liver Physiol 289:G806–G814CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Seghieri M, Rebelos E, Gastaldelli A et al (2013) Direct effect of GLP-1 infusion on endogenous glucose production in humans. Diabetologia 56:156–161CrossRefPubMedGoogle Scholar
  20. 20.
    Ohlsson L, Alsalim W, Carr RD et al (2013) Glucose-lowering effect of the DPP-4 inhibitor sitagliptin after glucose and non-glucose macronutrient ingestion in nondiabetic subjects. Diabetes Obes Metab 15:531–537CrossRefPubMedGoogle Scholar
  21. 21.
    Jun LS, Millican RL, Hawkins ED et al (2015) Absence of glucagon and insulin action reveals a role for the GLP-1 receptor in endogenous glucose production. Diabetes 64:819–827CrossRefPubMedGoogle Scholar
  22. 22.
    Tremblay AJ, Lamarche B, Kelly I et al (2014) Effect of sitagliptin therapy on triglyceride-rich lipoprotein kinetics in patients with type 2 diabetes. Diabetes Obes Metab 16(12):1223–1229CrossRefPubMedGoogle Scholar
  23. 23.
    Velija-Asimi Z, Izetbegovic S, Karamehic J et al (2013) The effects of dipeptidyl peptidase-4 inhibitors in treatment of obese patients with type 2 diabetes. Med Arch 67(5):365–367CrossRefPubMedGoogle Scholar
  24. 24.
    Drews G, Krippeit-Drews P, Düfer M (2010) Oxidative stress and beta-cell dysfunction. Pflugers Arch 460(4):703–718CrossRefPubMedGoogle Scholar
  25. 25.
    Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Varanasi A, Bellini N, Rawal D et al (2011) Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 165(1):77–84CrossRefPubMedGoogle Scholar
  27. 27.
    Sherr J, Xing D, Ruedy KJ et al (2013) Lack of association between residual insulin production and glucagon response to hypoglycemia in youth with short duration of type 1 diabetes. Diabetes Care 36(6):1470–1476CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Siafarikas A, Johnston RJ, Bulsara MK, O’Leary P, Jones TW, Davis EA (2012) Early loss of the glucagon response to hypoglycemia in adolescents with type 1 diabetes. Diabetes Care 35(8):1757–1762CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kuhadiya ND, Malik R, Bellini NJ et al (2013) Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. Endocr Pract 19(6):963–967CrossRefPubMedGoogle Scholar
  30. 30.
    Farngren J, Persson M, Schweizer A, Foley JE, Ahrén B (2012) Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counterregulation during hypoglycemia in type 1 diabetes. J Clin Endocrinol Metab 97(10):3799–3806CrossRefPubMedGoogle Scholar
  31. 31.
    Schopman JE, Hoekstra JB, Frier BM et al (2015) Effects of sitagliptin on counter-regulatory and incretin hormones during acute hypoglycaemia in patients with type 1 diabetes: a randomized double-blind placebo-controlled crossover study. Diabetes Obes Metab 17(6):546–553CrossRefPubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2017

Authors and Affiliations

  1. 1.Department of EndocrinologyNanjing First Hospital, Nanjing Medical UniversityNanjingChina
  2. 2.Department of NephrologyNanjing Pukou Central HospitalNanjingChina
  3. 3.National Heart Centre SingaporeNational Heart Research Institute SingaporeSingaporeSingapore
  4. 4.Department of MedicineNational University of SingaporeSingaporeSingapore

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