Type 2 Diabetes
Conditions
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.
Interventions
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
35 Years to 80 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differences in GIGD (%) | Comparison between experimental days with and without the glucagon receptor antagonist . The glucose disposal at time 240 minutes will be used. | GIGD = Gastrointestinal glucose disposal. GIGD (%) = 100% × (glucoseOGTT-glucoseIIGI)/glucoseOGTT. |
| 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 and without the glucagon receptor antagonist. | Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. | Insulin, C-peptide, glucagon, GIP and GLP-1 serum/plasma concentrations will be measured in pM. |
| 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. Comparison between experimental days with and without the glucagon receptor antagonist | At the end of the clamp experiment food intake will be examined with an ad libitum meal. The weight of the food will be measured i grams and calculated to the energy intake in kcal/kJ. |
| Incretin effect | 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 | The incretin effect (100% × \[β-cell secretory response to oral glucose tolerance test - intravenous β-cell secretory response\]/β-cell secretory response to oral glucose tolerance test) |
| Changes in pulse rate (beat per minute) | Measured at time 0 and at time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist | — |
| 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 |
| Fibroblast growth factor-21 | -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes | plasma values of FGF-21 |
| Changes in blood pressure (mmHg) | Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist | — |
| 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. |
Countries
Denmark
Outcome results
None listed