Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes
- Conditions
- Type 2 Diabetes
- Interventions
- Drug: LY2409021 placeboProcedure: IIGIProcedure: OGTTProcedure: Standardised liquid meal
- Registration Number
- NCT02669524
- Lead Sponsor
- University Hospital, Gentofte, Copenhagen
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 20
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
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description CTRL + OGTT + LY2409021 LY2409021 Healthy controls + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor. CTRL + IIGI + LY2409021 IIGI Healthy controls + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor. T2D + IIGI + LY2409021 IIGI Type 2 diabetes patients + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor. T2D + OGTT + LY2409021 OGTT Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor. T2D + OGTT + placebo LY2409021 placebo Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + placebo comparator to the human antagonist of the glucagon receptor. T2D + MEAL + LY2409021 Standardised liquid meal Type 2 diabetes patients + Standardised liquid meal + the human antagonist of the glucagon receptor. CTRL + MEAL + placebo Standardised liquid meal Healthy controls + Standardised liquid meal + placebo comparator of the human antagonist of the glucagon receptor. T2D + OGTT + LY2409021 LY2409021 Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor. CTRL + OGTT + placebo OGTT Healthy controls + 50 oral glucose tolerance test 4 hours + placebo comparator of the human antagonist of the glucagon receptor. CTRL + IIGI + placebo LY2409021 placebo Healthy controls + isoglycaemic iv glucose infusion + placebo comparator the human antagonist of the glucagon receptor. CTRL + MEAL + placebo LY2409021 placebo Healthy controls + Standardised liquid meal + placebo comparator of the human antagonist of the glucagon receptor. T2D + OGTT + placebo OGTT Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + placebo comparator to the human antagonist of the glucagon receptor. T2D + IIGI + placebo LY2409021 placebo Type 2 diabetes patients + isoglycaemic iv glucose infusion + placebo comparator to the human antagonist of the glucagon receptor. T2D + IIGI + placebo IIGI Type 2 diabetes patients + isoglycaemic iv glucose infusion + placebo comparator to the human antagonist of the glucagon receptor. T2D + MEAL + placebo LY2409021 placebo Type 2 diabetes patients + Standardised liquid meal + placebo comparator to the human antagonist of the glucagon receptor. T2D + MEAL + placebo Standardised liquid meal Type 2 diabetes patients + Standardised liquid meal + placebo comparator to the human antagonist of the glucagon receptor. CTRL + OGTT + LY2409021 OGTT Healthy controls + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor. CTRL + OGTT + placebo LY2409021 placebo Healthy controls + 50 oral glucose tolerance test 4 hours + placebo comparator of the human antagonist of the glucagon receptor. CTRL + IIGI + LY2409021 LY2409021 Healthy controls + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor. CTRL + IIGI + placebo IIGI Healthy controls + isoglycaemic iv glucose infusion + placebo comparator the human antagonist of the glucagon receptor. CTRL + MEAL + LY2409021 Standardised liquid meal Healthy controls + Standardised liquid meal + the human antagonist of the glucagon receptor. T2D + IIGI + LY2409021 LY2409021 Type 2 diabetes patients + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor. T2D + MEAL + LY2409021 LY2409021 Type 2 diabetes patients + Standardised liquid meal + the human antagonist of the glucagon receptor. CTRL + MEAL + LY2409021 LY2409021 Healthy controls + Standardised liquid meal + the human antagonist of the glucagon receptor.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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)
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.
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.
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.
Changes in blood pressure (mmHg) Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist 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
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).
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)
Trial Locations
- Locations (1)
Center for Diabetes Research, Gentofte Hospital, Copenhagen University
🇩🇰Hellerup, Denmark