Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals
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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.
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]).
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.
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
KeywordsGlucagon Glucose Intravenous i.v. Oral Type 2 diabetes
Glucose-dependent insulinotropic polypeptide
Isoglycaemic i.v. glucose infusion
Prohormone convertase 1/3
Prohormone convertase 2
Repeated measures ANOVA
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).
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.
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.