Clinical trial NCT02792400: The Role of Glucagon in the Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-glucose Co-transporter-2 Inhibitors
Official title: The Role of Glucagon in the Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-glucose Co-transporter-2 Inhibitors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
First posted: 2016-06-07
Enrollment: 24
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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

Primary outcomes:
measure: Difference in postprandial glucose excursions (linagliptin)
timeFrame: 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)
measure: Difference in postprandial glucose excursions
timeFrame: 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)
Secondary outcomes:
measure: Endogenous glucose production
timeFrame: 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.
measure: Lipolysis
timeFrame: 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.
measure: Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1.
timeFrame: : 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes
measure: Appetite
timeFrame: VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.
measure: Energy intake (kcal/kJ)
timeFrame: At time 240 to 270, the participants will eat an ad libitum meal.
measure: Changes in blood pressure (mmHg)
timeFrame: Measured at time 0 and time 210 minutes.
measure: Changes in pulse rate (beat per minute)
timeFrame: Measured at time 0 and at time 210 minutes.
measure: Differences in gastric emptying
timeFrame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
measure: Free fatty acids
timeFrame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
measure: Plasma Fibroblast growth factor-21
timeFrame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
measure: Resting energy expenditure
timeFrame: -60 to -50 and 35 to 45
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Center for Diabetes Research, Gentofte Hospital, Copenhagen University
Study officials:
References:
citation: Haedersdal S, Lund A, Nielsen-Hannerup E, Maagensen H, van Hall G, Holst JJ, Knop FK, Vilsboll T. The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition. Diabetes. 2020 Dec;69(12):2619-2629. doi: 10.2337/db20-0369. Epub 2020 Oct 1.
citation: Cox AR, Chernis N, Bader DA, Saha PK, Masschelin PM, Felix JB, Sharp R, Lian Z, Putluri V, Rajapakshe K, Kim KH, Villareal DT, Armamento-Villareal R, Wu H, Coarfa C, Putluri N, Hartig SM. STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity. Diabetes. 2020 Dec;69(12):2630-2641. doi: 10.2337/db20-0384. Epub 2020 Sep 29.