The Effect of the Incretin Hormones on the Endocrine Pancreatic Function During Hyperglycemia in End-stage Renal Disease

Patients with end-stage renal disease (ESRD) have a high prevalence of impaired glucose metabolism. The pathophysiological cause is uncertain, but disturbances in the secretion, elimination and effect of glucagon, insulin and the two incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), probably play important roles. Our research group has previously found that dialysis patients without type 2 diabetes mellitus (T2DM) have a reduced incretin effect and an inability to suppress glucagon after a meal - two early pathophysiological characteristics of patients with T2DM and normal kidney function.

The aim of the project is to provide a detailed description of the mechanisms underlying the (patho)physiological effects of the incretin hormones in patients with ESRD. We plan to investigate the above mentioned disturbances during fasting and hyperglycaemic conditions using incretin infusions during glucose clamping. Furthermore, stable isotopic tracers will be used to determine the effect of the incretin hormones on the endogenous glucose handling.

We hypothesise that the effects of the incretin hormones in ESRD will be reduced in respect to healthy control subjects.

Study Overview

• Status: Completed
• Conditions: End-stage Renal Disease
• Intervention / Treatment: Other: Eu- and hyperglycemic clamp; Other: Arginine test

Detailed Description

The effect of the incretin hormones on the endocrine pancreatic function in a uremic environment will be explored during fasting and hyperglycemic conditions in three randomised examination days.

At a preceding screening day, an oral glucose tolerance test (OGTT) and a dual energy x-ray absorptiometry (DXA) scan will be performed to determine glucose tolerance and the distribution of muscle and adipose tissue. The study will be carried out on three separate days differing with respect to the hormones infused: GLP-1, GIP or placebo (saline) which are double blinded. The patients will meet from an overnight fast and an infusion of one of the hormones is initiated. At the same time labeled glucose will be infused to determine the endogenous hepatic glucose production. A glucose infusion is adjusted according to frequent plasma glucose measurements to maintain fasting glucose level. After 2 hours a steady state of the tracer is achieved and a 2 hour hyperglycemic clamp, 3 mmol/l above fasting glucose concentration will be started. The tracer infusions are continued during the hyperglycemia. After the 4 hour clamp an arginine bolus will be administered to measure the ability to increase the secretion of insulin and glucagon.

• Study Type: Observational
• Enrollment (Actual): 24

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Department of Nephrology, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

1. End-stage renal disease patients receiving chronic hemodialysis treatments
2. Healthy control subjects

Description

Inclusion Criteria (End-stage renal disease):

• Chronic hemodialysis-dependent uremia in more than 3 months

Inclusion Criteria (Healthy controls):

• Normal kidney function

Exclusion Criteria:

• Fasting plasma glucose ≥ 6.1 mmol/l
• 2h plasma glucose ≥ 7.8 after ingestion of 75 grams of glucose
• Admittance to a hospital
• Anemia (Hb < 6.0 mmol/l)
• Ongoing treatment with drugs interfering with glucose metabolism including steroids and calcineurin inhibitors
• Bowel resection or any other large abdominal surgery

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
End-stage renal disease; Patients with normal glucose tolerance and end-stage renal disease	Other: Eu- and hyperglycemic clamp; Eu- and hyperglycemic clamp with concomitant infusion of the natural occurring hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) or placebo along with stable glucose isotope infusion to measure the effects of the incretins.; Other: Arginine test; Bolus infusion of the natural occurring amino acid arginine to measure the ability to increase the secretion of insulin and glucagon
Controls; Healthy controls with normal kidney function and normal glucose tolerance	Other: Eu- and hyperglycemic clamp; Eu- and hyperglycemic clamp with concomitant infusion of the natural occurring hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) or placebo along with stable glucose isotope infusion to measure the effects of the incretins.; Other: Arginine test; Bolus infusion of the natural occurring amino acid arginine to measure the ability to increase the secretion of insulin and glucagon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of GLP-1 and GIP on insulin response during hyperglycemia between groups	Average plasma insulin concentrations during hyperglycemia	Average during the last 2 hours of each examination day. Blood samples are collected at time 122, 124, 126, 130, 210, 225 and 240 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of GLP-1 and GIP on insulin, glucagon and endogenous glucose production during euglycemia	Average plasma insulin and glucagon concentrations as well as glucose rate of appearance during euglycemia.	Average during the first 2 hours of each examination day. Blood samples are collected at time 90, 105 and 120 minutes
The effect of GLP-1 and GIP on early and late phase of insulin, glucagon and endogenous glucose production during hyperglycemia	Average plasma insulin and glucagon concentrations as well as glucose rate of appearance during the first 10 minutes and last 30 minutes of hyperglycemia.	Averages during the last 2 hours of each examination day. Blood samples are collected at time 122, 124, 126, 130, 210, 225 and 240 minutes
The effect of GLP-1 and GIP on insulin and glucagon response to arginine	Average plasma insulin and glucagon concentrations 10 minutes following arginine bolus at the end of the examination.	Average following ariginine bolus. Blood samples are collected at time 242, 244, 246 and 250 minutes
The effect of GLP-1 and GIP on the peripheral glucose handling	Average glucose infusion rate during both euglycemia (the first 2 hours) and hyperglycemia (the last 2 hours).	Average during the first 4 hours of each examination day. Blood samples are collected at 5-15 minutes interval from time 0 to time 240 minutes
The effect of GLP-1 and GIP on potassium concentrations during euglycemia	Average plasma potassium concentrations during euglycemia	Average during the first 2 hours of each examination day. Blood samples are collected at time 30, 60, 90 and 120 minutes

Collaborators and Investigators

• Sponsor: Bo Feldt-Rasmussen
• Investigators: Principal Investigator: Morten B Jørgensen, MD, Department of Nephrology, Rigshospitalet

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): April 28, 2016
• Study Completion (Actual): April 28, 2016

Study Registration Dates

• First Submitted: August 29, 2014
• First Submitted That Met QC Criteria: September 9, 2014
• First Posted (Estimate): September 11, 2014

Study Record Updates

• Last Update Posted (Actual): May 22, 2017
• Last Update Submitted That Met QC Criteria: May 19, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Insulin; GLP-1; ESRD; End-stage renal disease; Incretin hormones; Glucagon; GIP
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic
• Other Study ID Numbers: H-2-2014-021