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

June 21, 2016 updated by: University of Oxford
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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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).

Study Type

Observational

Enrollment (Anticipated)

40

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Oxfordshire
      • Oxford, Oxfordshire, United Kingdom, OX3 7LE
        • Recruiting
        • OCDEM, University of Oxford
        • Contact:
        • Contact:
        • Principal Investigator:
          • Fredrik Karpe
        • Sub-Investigator:
          • Mahesh Umapathysivam
        • Sub-Investigator:
          • Anna Gloyn
        • Sub-Investigator:
          • Mark McCarthy
        • Sub-Investigator:
          • Patrik Rorsman

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Healthy volunteers enrolled in the Oxford Biobank

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • Matched clamp

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Calculated Incretin Effect
Time Frame: 3 months
Will be calculated from the amount of IV glucose required to reproduce OGTT glycaemic profile
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Insulin concentration
Time Frame: 3 months
3 months
Glucose concentrations
Time Frame: 3 months
3 months
GLP-1 (glucagon-like peptide-1) amidated and unamidated concentration
Time Frame: 3 months
3 months
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
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Collaborators

Medical Research Council
University of Exeter

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2015

Primary Completion (Anticipated)

July 1, 2016

Study Completion (Anticipated)

July 1, 2016

Study Registration Dates

First Submitted

February 12, 2016

First Submitted That Met QC Criteria

March 29, 2016

First Posted (Estimate)

March 30, 2016

Study Record Updates

Last Update Posted (Estimate)

June 22, 2016

Last Update Submitted That Met QC Criteria

June 21, 2016

Last Verified

June 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 15/SC/0072

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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