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

Type 2 Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02669524
• Other study ID #: H-15007312
• Status: Completed
• Phase: N/A
• First received: December 14, 2015
• Last updated: October 24, 2016
• Start date: October 2015
• Est. completion date: August 2016

Study information

• Verified date: October 2016
• Source: University Hospital, Gentofte, Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Dataprotection AgencyDenmark: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 35 Years to 80 Years

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• LY2409021

• LY2409021 placebo

Procedure:
• OGTT

• IIGI

• Standardised liquid meal

Locations

Country	Name	City	State
Denmark	Center for Diabetes Research, Gentofte Hospital, Copenhagen University	Hellerup

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Gentofte, Copenhagen	Eli Lilly and Company

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Primary	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.	No
Secondary	Incretin effect	The incretin effect (100% × [ß-cell secretory response to oral glucose tolerance test - intravenous ß-cell secretory response]/ß-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	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	No
Secondary	Changes in blood pressure (mmHg)		Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist	No
Secondary	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	No
Secondary	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	No
Secondary	Free fatty acids	serum values of free fatty acids	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes	No
Secondary	Fibroblast growth factor-21	plasma values of FGF-21	-30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes	No