Abstract
Aims/hypothesis
Type 2 diabetes is associated with hypersecretion of glucagon during an OGTT, whereas i.v. glucose suppresses glucagon levels. This suggests that type 2 diabetic hyperglucagonaemia may result from glucose stimulation of the gastrointestinal tract. We evaluated glucagon responses to increasing amounts of glucose given orally and corresponding isoglycaemic i.v. glucose infusions (IIGIs) in patients with type 2 diabetes and in healthy controls.
Methods
Plasma glucagon responses were measured during three 4 h OGTTs with increasing loads of glucose (25 g, 75 g and 125 g) and three corresponding IIGIs in eight patients with type 2 diabetes (age [mean ± SEM] 57 ± 4 years; BMI 29.5 ± 1.0 kg/m2; HbA1c 7.0 ± 0.3% [53 ± 2 mmol/mol]) and eight healthy individuals (age 57 ± 4 years; BMI 28.9 ± 0.7 kg/m2; HbA1c 5.4 ± 0.1% [36 ± 1 mmol/mol]).
Results
In healthy controls no difference in glucagon suppression during the first 45 min of the 25 g OGTT and the corresponding IIGI (−153 ± 35 vs −133 ± 24 min × pmol/l; p = NS) was observed, whereas patients with type 2 diabetes only exhibited significant glucagon suppression following IIGI (29 ± 27 vs −144 ± 20 min × pmol/l; p = 0.005). At higher oral glucose loads this difference increased and also became evident in healthy controls.
Conclusions/interpretation
In patients with type 2 diabetes increasing amounts of oral glucose elicit hypersecretion of glucagon, whereas corresponding IIGIs result in significant glucagon suppression; a phenomenon that is also observed in healthy individuals when larger glucose loads are ingested orally. This suggests that the hyperglucagonaemic response to oral glucose in type 2 diabetes may represent a pathological version of a gut-derived physiological phenomenon.
Trial registration: ClinicalTrials.gov NCT00529048
Similar content being viewed by others
Abbreviations
- GIP:
-
Glucose-dependent insulinotropic polypeptide
- GLP:
-
Glucagon-like peptide
- iAUC:
-
Incremental AUC
- IIGI:
-
Isoglycaemic i.v. glucose infusion
- PC1/3:
-
Prohormone convertase 1/3
- PC2:
-
Prohormone convertase 2
- rmANOVA:
-
Repeated measures ANOVA
References
Unger RH, Orci L (1975) The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1:14–16
Mitrakou A, Kelley D, Veneman T et al (1990) Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39:1381–1390
Ipp E (2000) Impaired glucose tolerance: the irrepressible alpha-cell? Diabetes Care 23:569–570
Knop FK, Vilsbøll T, Madsbad S et al (2007) Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia 50:797–805
Meier J, Deacon C, Schmidt W et al (2007) Suppression of glucagon secretion is lower after oral glucose administration than during intravenous glucose administration in human subjects. Diabetologia 50:806–813
Bagger JI, Knop FK, Lund A et al (2011) Impaired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 96:737–745
Holst JJ, Pedersen JH, Baldissera F, Stadil F (1983) Circulating glucagon after total pancreatectomy in man. Diabetologia 25:396–399
Christensen M, Vedtofte L, Holst JJ et al (2011) Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 60:3103–3109
Lund A, Vilsbøll T, Bagger JI et al (2011) The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes. Am J Physiol Endocrinol Metab 300:E1038–E1046
Chia CW, Carlson OD, Kim W et al (2009) Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 58:1342–1349
Jackson RS, Creemers JWM, Farooqi IS et al (2003) Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 112:1550–1560
Acknowledgements
We are grateful to our volunteers whose availability made this work possible and to laboratory technician L. Bagger (University of Copenhagen, Copenhagen, Denmark) for measurement of plasma glucagon concentrations. Some of the data were presented as abstracts at the scientific sessions of the American Diabetes Association in 2009 (New Orleans, LA, USA) and at the Annual Scientific Meeting of the European Association for the Study of Diabetes in 2009 (Vienna, Austria).
Funding
The study was supported by an unrestricted research grant (no. 34851) from the Investigator-Initiated Studies Program of Merck & Co. Inc. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck & Co. Inc. The funding source had no involvement in the study design; in the collection, analysis or interpretation of the data; or in the decision to submit the paper for publication. The study was presented in 2011 at the American Diabetes Association 69th Scientific Session (abstract P-1421).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
Contribution statement
All the persons listed as authors fulfil all three of the following criteria: (1) substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published. F. K. Knop is responsible for the integrity of the work as a whole and is the guarantor of this work.
Author information
Authors and Affiliations
Corresponding author
Additional information
J. I. Bagger and F. K. Knop contributed equally to this study.
Rights and permissions
About this article
Cite this article
Bagger, J.I., Knop, F.K., Lund, A. et al. Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Diabetologia 57, 1720–1725 (2014). https://doi.org/10.1007/s00125-014-3264-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00125-014-3264-2