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

NCT03965000 | Unknown

• 1 other identifier: 20190121-1930
• Study Type: observational
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Familial Renal Glucosuria; Diabetes Mellitus; Cardiovascular Diseases

Keywords

SGLT2; SLC5A2; glucose metabolism; glucagon; incretin

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (2)

Patients

Patients carrying one or both mutations.

Other: Mixed-meal-tolerance-test

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

Interventions

Mixed-meal-tolerance-test OTHER

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

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

• Impaired glucose tolerance
• Diabetes mellitus

Sponsors & Collaborators

• Medical University Innsbruck: lead

Study Sites (1)

Medical University Innsbruck

Innsbruck, Tyrol, 6020, Austria

RECRUITING

Related Publications (6)

• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.

  PMID: 26378978 BACKGROUND

• Rosenstein R, Hough A. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016 Mar 17;374(11):1093-4. doi: 10.1056/NEJMc1600827. No abstract available.

  PMID: 26981944 BACKGROUND

• Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016 Mar 17;374(11):1094. doi: 10.1056/NEJMc1600827. No abstract available.

  PMID: 26981940 BACKGROUND

• Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227. Epub 2014 Jan 27.

  PMID: 24463454 BACKGROUND

• Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thevenet J, Beaucamps C, Delalleau N, Popescu I, Malaisse WJ, Sener A, Deprez B, Abderrahmani A, Staels B, Pattou F. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015 May;21(5):512-7. doi: 10.1038/nm.3828. Epub 2015 Apr 20.

  PMID: 25894829 BACKGROUND

• Pedersen MG, Ahlstedt I, El Hachmane MF, Gopel SO. Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells. Sci Rep. 2016 Aug 18;6:31214. doi: 10.1038/srep31214.

  PMID: 27535321 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood samples acquired during the mixed-meal-tolerance-test

MeSH Terms

Conditions

Glycosuria, Renal; Diabetes Mellitus; Cardiovascular Diseases

Condition Hierarchy (Ancestors)

Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Glycosuria; Urination Disorders; Male Urogenital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Design

• Study Type: observational
• Observational Model: FAMILY BASED
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2019
• First Posted: May 28, 2019
• Study Start: January 24, 2019
• Primary Completion: January 1, 2021
• Study Completion: January 1, 2022
• Last Updated: May 29, 2019

Record last verified: 2019-05

Locations

AU (1)