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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Human SLC5A2 Deficiency and the Glucagon-Incretin Axis: A Pilot Study

Conditions
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Familial Renal Glucosuria, Diabetes Mellitus, Cardiovascular Diseases

Intervention / Treatment
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* Other: Mixed-meal-tolerance-test


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients carrying one or both mutations. | Other: Mixed-meal-tolerance-test<br>* 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.<br>|
| Controls<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the glucagon-incretin axis. | 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 | 18 months | 
| Changes in the gene expression | By collecting blood samples for gene expression analysis before and after the test and comparing it to our healthy controls. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGLT2, SLC5A2, glucose metabolism, glucagon, incretin