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Human Solute Carrier Family 5 Member 2 (SLC5A2) Deficiency and the Glucagon-Incretin Axis

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ClinicalTrials.gov Identifier: NCT03965000
Recruitment Status : Recruiting
First Posted : May 28, 2019
Last Update Posted : May 29, 2019
Sponsor:
Information provided by (Responsible Party):
Medical University Innsbruck

Brief Summary:

Sodium-glucose-cotransporter 2 (SGLT2) are a new type of oral antidiabetic drugs. SGLT2 inhibitors increase the urinary glucose excretion and thereby decrease blood glucose levels. Beside their glucose lowering effects SGLT2 inhibitors showed beneficial effects on the cardiovascular health. But several studies in cell culture and mice showed that the physiological inhibition of glucagon after meal consumption is impaired when using SGLT2 inhibitors.

The patients carry a rare genetical disease called Familial renal glucosuria (FRG), a human model of life long SGLT2 inhibition. To elucidate the effects of partial and complete SGLT2 inhibition in humans the investigators perform a mixed-meal tolerance test (MMTT), the gold standard for elucidation of insulin and glucagon dynamics.


Condition or disease Intervention/treatment
Familial Renal Glucosuria Diabetes Mellitus Cardiovascular Diseases Other: Mixed-meal-tolerance-test

Detailed Description:

The index patient was referred to the Department of Internal Medicine I at the Medical University of Innsbruck for evaluation of unclear glucosuria in combination with normal blood glucose levels. The patient suffered from recurrent urinary tract infections and increased urinary frequency, showed a physiological hemoglobin A1c and no further signs of renal dysfunction. Sequencing of the SLC5A2 coding region confirmed that the patient was compound heterozygous for two SLC5A2 mutations. The patient is a mother of five healthy children which are willing to take part in the test. The children show a 50/50 distribution of the mother's mutations. The MMTT will take place after 48 hours of alcohol, sport abstinence and an overnight fasting period. The patients will be given 6 ml/kg body weight of a standardized liquid meal. Blood samples will be collected 10 minutes before consumption of the meal, at the time point of consumption and 15, 30, 60, 120, 150, 180, 210 and 240 minutes after consumption. At each time point six blood tubes will be taken, except at time point -10 and 240 minutes, there is one sample more collected. The investigators aim to assess glucagon, insulin, c-peptide, gastric inhibitory polypeptide (GIP), Glucagon-like peptide-1 (GLP-1), Glucagon-like peptide-2 (GLP-2) levels.

Glucose tolerance will be assessed by using the 4 hours area under the curve (AUC) for glucose. To evaluate the beta-cell function the 4h-AUC's for insulin, c-peptide and the 4h-AUC insulin:glucose ratio will be calculated and compared. The calculation of the alpha-cell function will be performed with the AUC of glucagon and the AUC glucagon/glucose ratio. GIP, GLP-1 and GLP-2 will be determined using the AUC. The AUC's will be calculated by the trapezoidal method.

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Study Type : Observational
Estimated Enrollment : 10 participants
Observational Model: Family-Based
Time Perspective: Prospective
Official Title: Human SLC5A2 Deficiency and the Glucagon-Incretin Axis: A Pilot Study
Actual Study Start Date : January 24, 2019
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Glucagon

Group/Cohort Intervention/treatment
Patients
Patients carrying one or both mutations.
Other: Mixed-meal-tolerance-test
To assess the dynamics of the glucagon-incretin axis we need to perform the MMTT. Thereby the patients need to consume a body weight adjusted, standardized meal and we draw blood at fixed time points over 4 hours.

Controls
Patients not carrying a mutation Familial renal glucosuria causing mutation in the SLC5A2 gene and without impaired glucose tolerance and type 1 or 2 diabetes mellitus.
Other: Mixed-meal-tolerance-test
To assess the dynamics of the glucagon-incretin axis we need to perform the MMTT. Thereby the patients need to consume a body weight adjusted, standardized meal and we draw blood at fixed time points over 4 hours.




Primary Outcome Measures :
  1. Changes in the glucagon-incretin axis. [ Time Frame: 18 months ]

    Glucose tolerance will be assessed by using the 4 hours area under the curve (AUC) for glucose.

    Beta-cell function will be assessed by the 4h-AUC's for insulin, c-peptide and the 4h-AUC insulin:glucose ratio will be calculated and compared. The calculation of the alpha-cell function will be performed with the AUC of glucagon and the AUC glucagon/glucose ratio. GIP, GLP-1 and GLP-2 will be determined using the AUC. The AUC's will be calculated by the trapezoidal method


  2. Changes in the gene expression [ Time Frame: 18 months ]
    By collecting blood samples for gene expression analysis before and after the test and comparing it to our healthy controls.


Biospecimen Retention:   Samples With DNA
Whole blood samples acquired during the mixed-meal-tolerance-test


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
One compound heterozygous female index patient and four heterozygous children. The control group consists of age, sex and BMI matched participants from nearly the same area to avoid environmental factors.
Criteria

Inclusion Criteria:

  • At least 18 years
  • Capable of giving consent
  • One or more SLC5A2 mutations leading to FRG
  • Written consent

Exclusion Criteria:

  • Impaired glucose tolerance
  • Diabetes mellitus

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03965000


Locations
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Austria
Medical University Innsbruck Recruiting
Innsbruck, Tyrol, Austria, 6020
Contact: Christoph Ebenbichler, MD, Prof.    +43 512 504 81394    mui-sponsor@i-med.ac.at   
Principal Investigator: Christoph Ebenbichler, MD, Prof.         
Sub-Investigator: Clemens Engler, MD         
Sponsors and Collaborators
Medical University Innsbruck
Publications:

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Responsible Party: Medical University Innsbruck
ClinicalTrials.gov Identifier: NCT03965000    
Other Study ID Numbers: 20190121-1930
First Posted: May 28, 2019    Key Record Dates
Last Update Posted: May 29, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Medical University Innsbruck:
SGLT2
SLC5A2
glucose metabolism
glucagon
incretin
Additional relevant MeSH terms:
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Glycosuria, Renal
Cardiovascular Diseases
Glycosuria
Urination Disorders
Urologic Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn