The Incretin Effect in Patients With Kidney Impairment

NCT ID: NCT01327378

Last Updated: 2011-04-01

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 30 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2010-10-31

Brief Summary

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.

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.

Conditions

Renal Insufficiency, Chronic

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Dialysis, normal glucose tolerance

Chronic dialysis treatment, N=10 OGTT,120 min \< 7.8 mmol/L

No interventions assigned to this group

Dialysis, impaired glucose tolerance

Chronic dialysis treatment, N=10 OGTT,120 min 7.7\<11.1 mmol/L

No interventions assigned to this group

Control, normal glucose tolerance

Healthy Control subjects, N=10 OGTT,120 min \<7.8 mmol/L

No interventions assigned to this group

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: collaborator

University of Copenhagen

OTHER

Sponsor Role: collaborator

University Hospital, Gentofte, Copenhagen

OTHER

Sponsor Role: lead

Responsible Party

Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark

Principal Investigators

Bo Feldt-Rasmussen, Prof, DMSc

Role: STUDY_DIRECTOR

Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark

Locations

Department of Nephrology P 2131, Rigshospitalet

Copenhagen Ø, , Denmark

Countries

Denmark

References

Wewer Albrechtsen NJ, Hartmann B, Veedfald S, Windelov JA, Plamboeck A, Bojsen-Moller KN, Idorn T, Feldt-Rasmussen B, Knop FK, Vilsboll T, Madsbad S, Deacon CF, Holst JJ. Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels? Diabetologia. 2014 Sep;57(9):1919-26. doi: 10.1007/s00125-014-3283-z. Epub 2014 Jun 3.

Reference Type: DERIVED

PMID: 24891019 (View on PubMed)

Idorn T, Knop FK, Jorgensen M, Holst JJ, Hornum M, Feldt-Rasmussen B. Gastrointestinal factors contribute to glucometabolic disturbances in nondiabetic patients with end-stage renal disease. Kidney Int. 2013 May;83(5):915-23. doi: 10.1038/ki.2012.460. Epub 2013 Jan 16.

Reference Type: DERIVED

PMID: 23325073 (View on PubMed)

Other Identifiers

H-C-2009-007

Identifier Type: -

Identifier Source: org_study_id