Type 2 Diabetes
Conditions
Brief summary
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.
Interventions
DRUGLY2403021
Glucagon receptor antagonist
DRUGLY2403021 placebo
PROCEDUREStandardised liquid meal
DRUGLinagliptin
DPP-4-inhibitor
DRUGEmpagliflozin
SGLT2-inhibitor
Sponsors
Eli Lilly and Company
University Hospital, Gentofte, Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Caucasians above 30 years of age with diet or metformin treated type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization) * Normal haemoglobin * Informed consent
Exclusion criteria
* Inflammatory bowel disease * Intestinal resections * Nephropathy (serum creatinine above normal range and/or albuminuria) * Liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) \>2×normal values) * Treatment with medicine that cannot be paused for 12 hours * Pregnancy and/or breastfeeding * Family history of pancreatic islet tumours * Age above 75 years * Treatment with loop-diuretics (applies only to arms with empagliflozin or empagliflozin placebo) * Chronic heart failure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in postprandial glucose excursions (linagliptin) | 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 (measured as incremental (baseline substracted) area under the curve (AUC) values). |
| Difference in postprandial glucose excursions | 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) | Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1. | : 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes | — |
| Appetite | VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes. | Appetite will be evaluated with a visual analogue scale (VAS). |
| Energy intake (kcal/kJ) | At time 240 to 270, the participants will eat an ad libitum meal. | 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 |
| Changes in blood pressure (mmHg) | Measured at time 0 and time 210 minutes. | — |
| Endogenous glucose production | 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. | Glucose rate of appearance will be calculated by the non-steady state equation using double tracer technique. |
| Differences in gastric emptying | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes | Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC) |
| Free fatty acids | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes | Serum values of free fatty acids |
| Plasma Fibroblast growth factor-21 | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes | — |
| Resting energy expenditure | -60 to -50 and 35 to 45 | Resting energy expenditure evaluated by 10 minutes of indirect calorimetry. |
| Changes in pulse rate (beat per minute) | Measured at time 0 and at time 210 minutes. | — |
| Lipolysis | 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. | Glycerol disappearance will be calculated by the non-steady state equation using double tracer technique. |
Countries
Denmark
Outcome results
None listed