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Defining the Physiological Mechanisms of Risk Genes for Hyperglycaemia, Insulin Resistance and Type 2 Diabetes (DIVA - PAM)

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ClinicalTrials.gov Identifier: NCT02723110
Recruitment Status : Unknown
Verified June 2016 by University of Oxford.
Recruitment status was:  Recruiting
First Posted : March 30, 2016
Last Update Posted : June 22, 2016
Sponsor:
Collaborators:
University of Exeter
Medical Research Council
Information provided by (Responsible Party):
University of Oxford

Brief Summary:
Recent genetic association studies have identified variants in the Peptidyl-Glycine alpha-amidating mono-oxygenase (PAM) gene that increase the risk of diabetes likely through a defect in beta-cell function. This has been followed up and supported by novel kinetic assays and cellular studies. This investigation will recall heterozygous carriers of the risk allele at rs78408340 and age, BMI and gender matched controls from the Oxford Biobank. The study will compare the incretin effect, glucagon-like peptide-1(GLP-1), insulin, glucose levels and PAM protein activity in individuals both with and without the risk variant. The aim of the study is to gain mechanistic insight into the effect of the variant on human physiology and diabetes pathogenesis.

Condition or disease Intervention/treatment
Type 2 Diabetes Other: 4 Hour Frequently Sampled Oral Glucose Tolerance Test Other: Isoglycaemic Clamp

Detailed Description:

Note: The study will utilize an adaptive study design with an interim analysis at 40 volunteers (20 v 20) with the possibility of adding an additional 20 volunteers to the study (10 v 10) if the criteria for futility or clear effect are not met.

The criteria are; stop and reject null hypothesis if t > 2.490 and stop and accept null hypothesis if t < 1.033. If the t falls between these values an additional 20 volunteers (10 v10) will be recruited. The decision to stop or additional volunteers will be based on the incretin effect (primary outcome).


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Study Type : Observational
Estimated Enrollment : 40 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: Defining the Physiological Mechanisms of Risk Genes for Hyperglycaemia, Insulin Resistance and Type 2 Diabetes
Study Start Date : June 2015
Estimated Primary Completion Date : July 2016
Estimated Study Completion Date : July 2016

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
rs78408340 heterozygous carriers Other: 4 Hour Frequently Sampled Oral Glucose Tolerance Test
Blood glucose level(BGL) every 5 min, blood for hormone, biochemical analysis at -15,0,15,30,45,60,90,120,180, 240
Other Name: OGTT

Other: Isoglycaemic Clamp
Glucose infusion over 4 hours to reproduce OGTT glucose curve to allow measurement of incretin effect. BGL every 5 min, blood for hormone, biochemical analysis at -15,0,15,30,45,60,90,120,180, 240
Other Name: Matched clamp

homozygous non-risk allele carriers Other: 4 Hour Frequently Sampled Oral Glucose Tolerance Test
Blood glucose level(BGL) every 5 min, blood for hormone, biochemical analysis at -15,0,15,30,45,60,90,120,180, 240
Other Name: OGTT

Other: Isoglycaemic Clamp
Glucose infusion over 4 hours to reproduce OGTT glucose curve to allow measurement of incretin effect. BGL every 5 min, blood for hormone, biochemical analysis at -15,0,15,30,45,60,90,120,180, 240
Other Name: Matched clamp




Primary Outcome Measures :
  1. Calculated Incretin Effect [ Time Frame: 3 months ]
    Will be calculated from the amount of IV glucose required to reproduce OGTT glycaemic profile


Secondary Outcome Measures :
  1. Insulin concentration [ Time Frame: 3 months ]
  2. Glucose concentrations [ Time Frame: 3 months ]
  3. GLP-1 (glucagon-like peptide-1) amidated and unamidated concentration [ Time Frame: 3 months ]
  4. PAM enzyme activity assay [ Time Frame: 3 months ]
    This assay is based off the protocol in the published literature, and is based on the turnover of radio-labelled substrate to quantify the amidating ability of the PAM enzyme


Biospecimen Retention:   Samples With DNA
EDTA plasma, serum, lithium heparin


Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Healthy volunteers enrolled in the Oxford Biobank
Criteria

Inclusion Criteria:

  • Adult, age 30-65 inclusive, healthy, appropriate genotype
  • Mental capacity to consent

Exclusion Criteria:

  • Demographics: <30 and >65 years old
  • Medical history: Bariatric surgery, surgery on gut/ stomach; history of recent significant weight loss (>10% of weight in last year); known cardiovascular disease
  • Medications: Currently prescribed glucose-lowering medication, oral/IV corticosteroid treatment, any medication effecting gastric motility or glucose metabolism

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): NCT02723110


Contacts
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Contact: Fredrik Karpe 01865 857222 fredrik.karpe@ocdem.ox.ac.uk
Contact: Mahesh M Umapathysivam 01865857261 mahesh.umapathysivam@spc.ox.ac.uk

Locations
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United Kingdom
OCDEM, University of Oxford Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 7LE
Contact: Fredrik Karpe    01865 857222    fredrik.karpe@ocdem.ox.ac.uk   
Contact: Mahesh M Umapathysivam       mahesh.umapathysivam@spc.ox.ac.uk   
Principal Investigator: Fredrik Karpe         
Sub-Investigator: Mahesh Umapathysivam         
Sub-Investigator: Anna Gloyn         
Sub-Investigator: Mark McCarthy         
Sub-Investigator: Patrik Rorsman         
Sponsors and Collaborators
University of Oxford
University of Exeter
Medical Research Council

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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT02723110     History of Changes
Other Study ID Numbers: 15/SC/0072
First Posted: March 30, 2016    Key Record Dates
Last Update Posted: June 22, 2016
Last Verified: June 2016

Keywords provided by University of Oxford:
Type 2 Diabetes Risk

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Insulin Resistance
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperinsulinism