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e-Letters: Observations

Effect of 3 Years of Treatment With Exenatide on Postprandial Glucagon Levels

  1. Mark M. Smits1⇑,
  2. Mathijs C. Bunck1,2,
  3. Michaela Diamant1,†,
  4. Anja Corner3,
  5. Bjorn Eliasson4,
  6. Robert J. Heine1,5,
  7. Ulf Smith4,
  8. Hannele Yki-Järvinen3 and
  9. Daniël H. van Raalte1
  1. 1Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands
  2. 2Eli Lilly and Co., Utrecht, the Netherlands
  3. 3Faculty of Medicine, Helsinki University Central Hospital, Helsinki, Finland
  4. 4Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden
  5. 5Eli Lilly and Co., Indianapolis, IN
  1. Corresponding author: Mark M. Smits, mm.smits1{at}vumc.nl.
  • ↵† Deceased.

Diabetes Care 2016 Mar; 39(3): e42-e43. https://doi.org/10.2337/dc15-2489
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α-Cell dysfunction contributes to hyperglycemia in type 2 diabetes and is characterized by inappropriately increased basal and postprandial glucagon levels (1). The regulation of glucagon secretion remains poorly understood. Glucagon-like peptide 1 (GLP-1), a gut-derived hormone with glucose-dependent insulinotropic effects, has been shown, albeit mostly in short-term studies, to reduce fasting and postprandial glucagon levels. Thus, the glucagonostatic effect of GLP-1 receptor agonists has been considered as one of the key mechanisms by which they improve glycemia (2). However, in a recent 48-week study with the GLP-1 receptor agonist liraglutide, a paradoxical postprandial increase in glucagon levels was observed (3). This study challenged our understanding of the effects of GLP-1 receptor agonists on glucagon.

We assessed the effects of 3-year treatment with the GLP-1 receptor agonist exenatide (EXE) versus insulin glargine (GLAR) on fasting and postprandial glucagon levels. Details of the study design were reported previously (4). In short, 36 metformin-treated patients with type 2 diabetes (25 males, 11 females; mean ± SD age 59 ± 7.9 years and BMI 29.7 ± 4.2 kg/m2) completed the study on EXE (n = 16) or GLAR (n = 20) treatment. Two sequential meal tests (breakfast and lunch: 50 g of fat, 75 g of carbohydrates, and 35 g protein) were performed, where EXE was given prior to breakfast but not before lunch. GLAR was administered the evening before the test meal. Blood was drawn from an intravenous catheter at specified times (Fig. 1) into chilled EDTA tubes containing aprotinin. Plasma glucagon, glucose, and HbA1c concentrations were assessed by a central laboratory (Quintiles, Livingston, U.K.).

Figure 1
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Figure 1

Effects of EXE (circles, dashed line) and GLAR (squares, solid line) on glucagon levels in the fasting state and after two mixed meals. *Statistically significant difference (P < 0.05) between the treatment groups.

Glycemic control was similar for both groups. HbA1c values were 6.6 ± 0.2% for EXE and 6.9 ± 0.2% for GLAR (between-group difference P = 0.186). As a result of the treat-to-target titration, the GLAR group showed a significantly greater reduction in fasting plasma glucose as compared with the EXE group (−2.0 ± 0.4 vs. −0.2 ± 0.5 mmol/L, respectively; P < 0.001). No differences in fasting glucagon levels were observed between EXE and GLAR treatment (Fig. 1). Following breakfast, glucagon levels decreased with EXE treatment and an increase was seen during GLAR treatment. However, following the second meal, glucagon levels increased in the EXE group, whereas a similar response to that following breakfast was seen in the GLAR group.

The lack of effect of EXE on fasting and postlunch glucagon is likely caused by the short half-life of approximately 2.5 h. In line with previous short-term studies, 3-year treatment with EXE reduces postbreakfast glucagon levels in apparent contrast to long-term liraglutide treatment (3). Possibly, prolonged continuous exposure to high GLP-1 levels induces different responses than intermittent GLP-1 receptor stimulation, as has been observed for gastric emptying. The paradoxical increase in glucagon secretion after the second meal corroborates earlier observations in patients with type 2 diabetes following mixed meals (5). Taken together, this study demonstrates that in patients treated with EXE for 3 years the glucagon response to a mixed breakfast remains suppressed.

Article Information

Duality of Interest. This study was sponsored by Amylin Pharmaceuticals, Inc., and Eli Lilly and Co. The study was collectively initiated and designed by the investigators from the study sites. The investigators had full access to the trial data and had control over the statistical analysis and interpretation of the study results.

M.C.B. and R.J.H. are employees and stockholders of Eli Lilly and Co. During the study, M.C.B. and R.J.H. were still employed at the VU University Medical Center. M.D. was a consultant and speaker for Eli Lilly and Co. Through M.D., the VU University Medical Center has received research grants from Amylin Pharmaceuticals, Inc., and Eli Lilly and Co. Through U.S., the Sahlgrenska University Hospital has received research grants from Amylin Pharmaceuticals, Inc., and Eli Lilly and Co. H.Y.-J. serves as a consultant for Amylin Pharmaceuticals, Inc. Through H.Y.-J., the Helsinki University Central Hospital has received research grants from Amylin Pharmaceuticals, Inc., and Eli Lilly and Co. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. All authors contributed to discussion. M.M.S. and D.H.v.R. wrote the manuscript. M.C.B., A.C., B.E., R.J.H., U.S., and H.Y.-J. edited the manuscript. M.M.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Received November 18, 2015.
  • Accepted November 24, 2015.
  • © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

References

  1. ↵
    1. Müller WA,
    2. Faloona GR,
    3. Aguilar-Parada E,
    4. Unger RH
    . Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med 1970;283:109–115
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Lund A,
    2. Bagger JI,
    3. Christensen M,
    4. Knop FK,
    5. Vilsbøll T
    . Glucagon and type 2 diabetes: the return of the alpha cell. Curr Diab Rep 2014;14:555
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  3. ↵
    1. Kramer CK,
    2. Zinman B,
    3. Choi H,
    4. Connelly PW,
    5. Retnakaran R
    . The impact of chronic liraglutide therapy on glucagon secretion in type 2 diabetes: insight from the LIBRA trial. J Clin Endocrinol Metab 2015;100:3702–3709
    OpenUrlCrossRefPubMed
  4. ↵
    1. Bunck MC,
    2. Corner A,
    3. Eliasson B, et al
    . Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 2011;34:2041–2047
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Reaven GM,
    2. Chen YD,
    3. Golay A,
    4. Swislocki AL,
    5. Jaspan JB
    . Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1987;64:106–110
    OpenUrlCrossRefPubMedWeb of Science
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Effect of 3 Years of Treatment With Exenatide on Postprandial Glucagon Levels
Mark M. Smits, Mathijs C. Bunck, Michaela Diamant, Anja Corner, Bjorn Eliasson, Robert J. Heine, Ulf Smith, Hannele Yki-Järvinen, Daniël H. van Raalte
Diabetes Care Mar 2016, 39 (3) e42-e43; DOI: 10.2337/dc15-2489

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Effect of 3 Years of Treatment With Exenatide on Postprandial Glucagon Levels
Mark M. Smits, Mathijs C. Bunck, Michaela Diamant, Anja Corner, Bjorn Eliasson, Robert J. Heine, Ulf Smith, Hannele Yki-Järvinen, Daniël H. van Raalte
Diabetes Care Mar 2016, 39 (3) e42-e43; DOI: 10.2337/dc15-2489
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