The Incretin Effect in Patients With Kidney Impairment (UREMINC)

This study has been completed.
Sponsor:
Collaborators:
Rigshospitalet, Denmark
University of Copenhagen
Information provided by:
University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier:
NCT01327378
First received: March 29, 2011
Last updated: March 31, 2011
Last verified: June 2010
  Purpose

The current study explores the incretin effect; a central mechanism of sugar metabolism. People with type 2 diabetes have a markedly reduced incretin effect, while the incretin effect never has been studied in patients with severe chronic renal failure. Non-diabetic patients with severe kidney failure and patients with diabetes and normal kidney function share several pathophysiological traits, including decreased sensitivity to insulin, fasting hyperinsulinaemia and impaired beta cell function. The investigators expect the incretin effect to be affected in patients with chronic renal failure without diabetes, which in time can result in therapeutic changes in this group of patients.


Condition
Renal Insufficiency, Chronic

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional
Official Title: The Incretin Effect in Non-diabetic Patients With Severe Renal Impairment Depending on Chronic Dialysis Treatment

Resource links provided by NLM:


Further study details as provided by University Hospital, Gentofte, Copenhagen:

Primary Outcome Measures:
  • Incretin effect [ Time Frame: Minimum 3 days and maximum 3 weeks between the two examination days. Cross-sectional design. No follow up. ] [ Designated as safety issue: No ]

    IE= 100%*(iAUC,OGTT - iAUC,IIGI)/iAUC,OGTT Assessed at two separate examination days. Day 1: Oral glucose tolerance test (OGTT), Day 2: Intravenous isoglycaemic glucose infusion (IIGI).

    Data will be presented when all analyses have been performed. Estimated in May 2011.



Secondary Outcome Measures:
  • Gastric-induced glucose disposal (GIGD) [ Time Frame: Minimum 3 days and maximum 3 weeks between the two examination days. Cross-sectional design. No follow up. ] [ Designated as safety issue: No ]

    GIGD=100%*(glucose,OGTT-glucose,IIGI)/glucose,OGTT) Assessed at two separate examination days. Day 1: Oral glucose tolerance test (OGTT), Day 2: Intravenous isoglycaemic glucose infusion (IIGI).

    Data will be presented when all analyses have been performed. Estimated in May 2011.



Biospecimen Retention:   Samples Without DNA

Plasma (10 ml per participant)


Enrollment: 30
Study Start Date: March 2009
Study Completion Date: October 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Groups/Cohorts
Dialysis, normal glucose tolerance
Chronic dialysis treatment, N=10 OGTT,120 min < 7.8 mmol/L
Dialysis, impaired glucose tolerance
Chronic dialysis treatment, N=10 OGTT,120 min 7.7<11.1 mmol/L
Control, normal glucose tolerance
Healthy Control subjects, N=10 OGTT,120 min <7.8 mmol/L

Detailed Description:

The novel and original aspect of this investigator initiated study is the focus on incretin (patho)physiology in an uraemic milieu. In this first of 5 substudies (separate notification and registration) the investigators explore the incretin effect. Our hypothesis is that it is impaired in non-diabetic patients in chronic dialysis treatment.

The prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide. In addition to reduced insulin sensitivity and beta cell dysfunction, T2DM is characterized by a severely impaired incretin effect. The incretin effect refers to the insulinotropic action of the nutrient-released incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both hormones are secreted from intestinal endocrine mucosal cells. The incretin effect is defined as the difference in insulin secretory responses between oral and isoglycaemic intravenous (iv) glucose challenges. In healthy individuals it accounts for as much as 70% of insulin secreted in response to oral glucose, whereas patients with T2DM exhibit an incretin effect in the range of 0 to 30%. The incretin hormone GLP-1 has a potent blood glucose-lowering effect in patients with T2DM. However, following secretion of GLP-1, the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4) rapidly cleaves the hormone, by which it is completely inactivated. This has formed the basis for new pharmacological agents blocking DPP-4 (DPP-4 inhibitors) or DPP-4 resistant GLP-1 receptor agonists. Long-term treatment has showed positive effect on glycaemic control and risk factors of cardiovascular diseases in patients with T2DM.

These effects may be applicable also in patients with end-stage renal disease (ESRD) because patients with T2DM and normal kidney function and non-diabetic patients with ESRD show several identical characteristics. These include decreased insulin sensitivity, hyperinsulinaemia and impaired beta cell function. The incretin effect has only to a small extent been investigated in patients with ESRD.

The single most frequent cause of ESRD and need of chronic maintenance dialysis is diabetic nephropathy. In the U.S. more than 50% of patients in dialysis have diabetes compared with about 23% in Denmark. The life expectancy of dialysis patients with T2DM is severely reduced with a median survival of 2 to 4 years and there is no treatment documented to significantly improve this poor prognosis. The most common cause of death in this group of patients is related to cardiovascular disease that seems to result from death of causes different from classical atherosclerosis. So far intervention directed towards hypertension, dyslipidaemia and other classical risk factors have showed divergent and primarily negative results.

There is therefore an unmet medical need to find new treatments to protect these patients from cardiovascular disease and premature death.

Improving the glycaemic control using incretin-based therapies has the potential to meet this medical need. The incretin hormones and their metabolites are however to a large extent excreted by the kidneys and this may lead to problems (or benefits!) when administered to patients without kidney function or with severely reduced kidney function. The present knowledge about the incretin effect and incretin hormone physiology as well as pharmacokinetics, clinical effects and side effects of GLP-1 analogues in patients with reduced kidney function is limited and the few studies available are predominantly confined to patients with only mild or moderately reduced kidney function. The investigators will explorer basic and pharmacologic aspects in patients with severe reduced kidney function depending on chronic maintenance dialysis treatment. Before any potential treatment can be initiated, the investigators need basic information on how the incretin system is affected by an uraemic milieu. Current and succeeding substudies will provide us with that information.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

3 groups

  1. Chronic hemodialysis treatment. Normal glucose tolerance (NGT). N=10
  2. Chronic hemodialysis treatment. Impaired glucose tolerance (IGT). N=10
  3. Healthy control subjects. Normal glucose tolerance. N=10

Glucose tolerance is evaluated at the screeningday. A 75 gram oral glucose tolerance test (OGTT) is performed and the 120 minute value sets the glucose tolerance. NGT: < 7.8 mmol/L, IGT: > 7.7 mmol/L and < 11.1 mmol/L (according to WHO guidelines).

Criteria

Inclusion Criteria:

  • Male or female; age: 18 - 90 years
  • CKD stage 5 (CrCL < 15 ml/min) in chronic haemodialysis (minimum 3 months)
  • NGT or IGT (diagnosed according to WHO criteria)
  • Body mass index 18.5 - 28 kg/m2

Exclusion Criteria:

  • Type 1 or 2 diabetes mellitus
  • Pancreatitis
  • Medication with influence on insulin secretion and/or glucose metabolism
  • Previous or actual malignancy
  • Inflammatory bowel disease
  • Congestive heart failure (NYHA III-IV)
  • Previous bowel resection
  • Severe hypertension
  • Impaired liver function
  • Haemoglobin < 6.5 mmol/L
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01327378

Locations
Denmark
Department of Nephrology P 2131, Rigshospitalet
Copenhagen Ø, Denmark, 2100
Sponsors and Collaborators
University Hospital, Gentofte, Copenhagen
Rigshospitalet, Denmark
University of Copenhagen
Investigators
Study Director: Bo Feldt-Rasmussen, Prof, DMSc Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark
  More Information

No publications provided by University Hospital, Gentofte, Copenhagen

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Thomas Idorn/M.D. PhD student, Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark
ClinicalTrials.gov Identifier: NCT01327378     History of Changes
Other Study ID Numbers: H-C-2009-007
Study First Received: March 29, 2011
Last Updated: March 31, 2011
Health Authority: Denmark: Ethics Committee
Denmark: Danish Dataprotection Agency

Additional relevant MeSH terms:
Renal Insufficiency
Renal Insufficiency, Chronic
Kidney Diseases
Urologic Diseases
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 26, 2014