In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and in response to ingestion of glucose or a mixed meal.glucagon, glucagon concentrations fail to decrease appropriately and may even increase. This diabetic hyperglucagonaemia may therefore contribute importantly to the hyperglycaemia of the patients. Several glucose-lowering treatment modalities have been shown to affect glucagon levels in patients with type 2 diabetes, but the role of glucagon in the glucose-lowering effects of these treatment modalities has been difficult to discern. By using a glucagon receptor antagonist (GRA) the investigators will exploit glucagon receptor antagonism to delineate the role of glucagon during treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to increase and decrease plasma glucagon levels, respectively.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
24
Glucagon receptor antagonist
DPP-4-inhibitor
SGLT2-inhibitor
Center for Diabetes Research, Gentofte Hospital, Copenhagen University
Hellerup, Denmark
Difference in postprandial glucose excursions (linagliptin)
Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values).
Time frame: Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with linagliptin (A1, A2, A3, A4)
Difference in postprandial glucose excursions
Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve
Time frame: Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with empagliflozin (B1, B2, B3, B4)
Endogenous glucose production
Glucose rate of appearance will be calculated by the non-steady state equation using double tracer technique.
Time frame: Plasma concentration of 6,6^2 H2-glucose and U-13C^6-glucose at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.
Lipolysis
Glycerol disappearance will be calculated by the non-steady state equation using double tracer technique.
Time frame: Plasma concentration of 1,1,2,3,3-^2-H5 - glycerol measured at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.
Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1.
Time frame: : 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes
Appetite
Appetite will be evaluated with a visual analogue scale (VAS).
Time frame: VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.
Energy intake (kcal/kJ)
At the end of the standardised liquid meal test, food intake will be examined with an ad libitum meal. The weight of the food will be measured in grams and calculated to the energy intake in kcal/kJ
Time frame: At time 240 to 270, the participants will eat an ad libitum meal.
Changes in blood pressure (mmHg)
Time frame: Measured at time 0 and time 210 minutes.
Changes in pulse rate (beat per minute)
Time frame: Measured at time 0 and at time 210 minutes.
Differences in gastric emptying
Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC)
Time frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Free fatty acids
Serum values of free fatty acids
Time frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Plasma Fibroblast growth factor-21
Time frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Resting energy expenditure
Resting energy expenditure evaluated by 10 minutes of indirect calorimetry.
Time frame: -60 to -50 and 35 to 45
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