The Incretin Effect in Patients With Kidney Impairment
Condition: Renal Insufficiency, Chronic
MeSH terms: Renal Insufficiency; Renal Insufficiency, Chronic
Study type: Observational

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.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
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).
      
Biospecimen description: 
      Plasma (10 ml per participant)