Clinical trial NCT02669524: Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes
Official title: Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes - the Role of Glucagon
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: 2016-02-01
Enrollment: 20
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: In patients with type 2 diabetes, the incretin effect is markedly reduced contributing to the relative insulin deficiency that characterizes these patients. This defect is believed to be due to a decreased effect of GLP-1 and an almost ceased effect of GIP. Nevertheless, the impact of the defect on glucose tolerance is not fully understood. The so-called gastrointestinal-mediated glucose disposal (GIGD) is a measure of glucose handling, which includes the incretin effect, but also other factors affecting glucose disposal (e.g. glucagon secretion). Interestingly, patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and glucagon concentrations fail to decrease appropriately and may even increase in response to ingestion of glucose and show exaggerated increases after a mixed meal. With the current project the investigators wish to elucidate how this paradoxical glucagon response observed in patients with type 2 diabetes affects the GIGD, the incretin effect and postprandial glucose excursions.

Ten patients with type 2 diabetes and 10 healthy matched control subjects will be enrolled in this randomised, placebo-controlled, double-blinded study. The aim is to examine the effect of a glucagon receptor antagonist (GRA) on gastrointestinal-mediated glucose disposal (GIGD), incretin effect and postprandial glucose excursions in patients with type 2 diabetes and healthy controls. Participants will attend two oral glucose tolerance tests (OGTT), two isoglycaemic iv glucose infusion (IIGI) and two standardised liquid meals.


Eligibility criteria: Inclusion Criteria:

Patients with type 2 diabetes

* Caucasians above 35 years of age with diet or metformin treated type 2 diabetes for at least 3 month (diagnosed according to the criteria of the World Health Organization (WHO)
* Normal haemoglobin
* Informed consent

Healthy subjects

* Normal fasting plasma glucose (FPG) \<6.1 mmol/l and HbA1c \<42 mmol/mol (6.0%)
* Normal haemoglobin
* Age above 35 years
* Informed consent

Exclusion Criteria:

Patients with type 2 diabetes

* 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 80 years

Healthy subjects

* Diabetes or prediabetes with reduced glucose tolerance: FPG \>6.0 mmol/l and/or HbA1c \>42 mmol/mol
* First degree relatives with type 2 diabetes
* Inflammatory bowel disease
* Intestinal resections
* Treatment with medicine that cannot be paused for 12 hours
* Pregnancy and/or breastfeeding
* Age above 80 years

Primary outcomes:
measure: Differences in GIGD (%)
timeFrame: Comparison between experimental days with and without the glucagon receptor antagonist . The glucose disposal at time 240 minutes will be used.
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 and without the glucagon receptor antagonist.
Secondary outcomes:
measure: Incretin effect
timeFrame: Insulin AUC time frame: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes. Comparison between experimental days with and without the glucagon receptor antagonist
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: Time frame: 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. Comparison between experimental days with and without the glucagon receptor antagonist
measure: Changes in blood pressure (mmHg)
timeFrame: Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist
measure: Changes in pulse rate (beat per minute)
timeFrame: Measured at time 0 and at time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist
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: Fibroblast growth factor-21
timeFrame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Center for Diabetes Research, Gentofte Hospital, Copenhagen University
Study officials:
References: