Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes

Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes

Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes - the Role of Glucagon

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.

Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.

Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + placebo comparator to the human antagonist of the glucagon receptor.

Type 2 diabetes patients + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor.

Type 2 diabetes patients + isoglycaemic iv glucose infusion + placebo comparator to the human antagonist of the glucagon receptor.

Type 2 diabetes patients + Standardised liquid meal + placebo comparator to the human antagonist of the glucagon receptor.

Healthy controls + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.

Healthy controls + 50 oral glucose tolerance test 4 hours + placebo comparator of the human antagonist of the glucagon receptor.

Healthy controls + isoglycaemic iv glucose infusion + placebo comparator the human antagonist of the glucagon receptor.

Healthy controls + Standardised liquid meal + placebo comparator of the human antagonist of the glucagon receptor.

Comparison between experimental days with and without the glucagon receptor antagonist . The glucose disposal at time 240 minutes will be used.

Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values).

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.

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)

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

Glucose rate of appearance will be calculated by the non-steady state equation using double tracer technique.

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.

Glycerol disappearance will be calculated by the non-steady state equation using double tracer technique.

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.

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.

At time 240 to 270, the participants will eat an ad libitum meal. Comparison between experimental days with and without the glucagon receptor antagonist

Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist

Measured at time 0 and at time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist

Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC)

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