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

University Hospital, Gentofte, Copenhagen

Status: Completed

Conditions: Type 2 Diabetes

Treatments: Drug: LY2409021 placebo; Procedure: Standardised liquid meal; Drug: LY2409021; Procedure: OGTT; Procedure: IIGI

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02669524

H-15007312

Details and patient eligibility

About

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.

Enrollment: 20 patients

Sex: All

Ages: 35 to 80 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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20 participants in 12 patient groups, including a placebo group

T2D + OGTT + LY2409021

Active Comparator group

Description:

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

Treatment:

Procedure: OGTT

Drug: LY2409021

T2D + OGTT + placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: OGTT

Drug: LY2409021 placebo

T2D + IIGI + LY2409021

Active Comparator group

Description:

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

Treatment:

Procedure: IIGI

Drug: LY2409021

T2D + IIGI + placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: IIGI

Drug: LY2409021 placebo

T2D + MEAL + LY2409021

Active Comparator group

Description:

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

Treatment:

Drug: LY2409021

Procedure: Standardised liquid meal

T2D + MEAL + placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: LY2409021 placebo

CTRL + OGTT + LY2409021

Active Comparator group

Description:

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

Treatment:

Procedure: OGTT

Drug: LY2409021

CTRL + OGTT + placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: OGTT

Drug: LY2409021 placebo

CTRL + IIGI + LY2409021

Active Comparator group

Description:

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

Treatment:

Procedure: IIGI

Drug: LY2409021

CTRL + IIGI + placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: IIGI

Drug: LY2409021 placebo

CTRL + MEAL + LY2409021

Active Comparator group

Description:

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

Treatment:

Drug: LY2409021

Procedure: Standardised liquid meal

CTRL + MEAL + placebo

Placebo Comparator group

Description:

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

Treatment:

Procedure: Standardised liquid meal

Drug: LY2409021 placebo