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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: LY2409021; Procedure: OGTT; Drug: LY2409021 placebo; Procedure: IIGI; Procedure: Standardised liquid meal

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, DK-2900
    • Center for Diabetes Research, Gentofte Hospital, Copenhagen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: T2D + OGTT + LY2409021; Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.	Drug: LY2409021; Procedure: OGTT
Placebo Comparator: T2D + OGTT + placebo; Type 2 diabetes patients + 50 oral glucose tolerance test 4 hours + placebo comparator to the human antagonist of the glucagon receptor.	Procedure: OGTT; Drug: LY2409021 placebo
Active Comparator: T2D + IIGI + LY2409021; Type 2 diabetes patients + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor.	Drug: LY2409021; Procedure: IIGI
Placebo Comparator: T2D + IIGI + placebo; Type 2 diabetes patients + isoglycaemic iv glucose infusion + placebo comparator to the human antagonist of the glucagon receptor.	Drug: LY2409021 placebo; Procedure: IIGI
Active Comparator: T2D + MEAL + LY2409021; Type 2 diabetes patients + Standardised liquid meal + the human antagonist of the glucagon receptor.	Drug: LY2409021; Procedure: Standardised liquid meal
Placebo Comparator: T2D + MEAL + placebo; Type 2 diabetes patients + Standardised liquid meal + placebo comparator to the human antagonist of the glucagon receptor.	Drug: LY2409021 placebo; Procedure: Standardised liquid meal
Active Comparator: CTRL + OGTT + LY2409021; Healthy controls + 50 oral glucose tolerance test 4 hours + the human antagonist of the glucagon receptor.	Drug: LY2409021; Procedure: OGTT
Placebo Comparator: CTRL + OGTT + placebo; Healthy controls + 50 oral glucose tolerance test 4 hours + placebo comparator of the human antagonist of the glucagon receptor.	Procedure: OGTT; Drug: LY2409021 placebo
Active Comparator: CTRL + IIGI + LY2409021; Healthy controls + isoglycaemic iv glucose infusion + the human antagonist of the glucagon receptor.	Drug: LY2409021; Procedure: IIGI
Placebo Comparator: CTRL + IIGI + placebo; Healthy controls + isoglycaemic iv glucose infusion + placebo comparator the human antagonist of the glucagon receptor.	Drug: LY2409021 placebo; Procedure: IIGI
Active Comparator: CTRL + MEAL + LY2409021; Healthy controls + Standardised liquid meal + the human antagonist of the glucagon receptor.	Drug: LY2409021; Procedure: Standardised liquid meal
Placebo Comparator: CTRL + MEAL + placebo; Healthy controls + Standardised liquid meal + placebo comparator of the human antagonist of the glucagon receptor.	Drug: LY2409021 placebo; Procedure: Standardised liquid meal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in GIGD (%)	GIGD = Gastrointestinal glucose disposal. GIGD (%) = 100% × (glucoseOGTT-glucoseIIGI)/glucoseOGTT.	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	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incretin effect	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
Endogenous glucose production	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.
Lipolysis	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.
Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1.	Insulin, C-peptide, glucagon, GIP and GLP-1 serum/plasma concentrations will be measured in pM.	Time frame: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.
Appetite	Appetite will be evaluated with a visual analogue scale (VAS).	VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.
Energy intake (kcal/kJ)	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
Changes in blood pressure (mmHg)		Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist
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	Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC)	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Free fatty acids	serum values of free fatty acids	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes
Fibroblast growth factor-21	plasma values of FGF-21	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen
• Collaborators: Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: December 14, 2015
• First Submitted That Met QC Criteria: January 27, 2016
• First Posted (Estimate): February 1, 2016

Study Record Updates

• Last Update Posted (Estimate): October 25, 2016
• Last Update Submitted That Met QC Criteria: October 24, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: H-15007312

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED