Defining the Physiological Mechanisms of Risk Genes for Hyperglycaemia, Insulin Resistance and Type 2 Diabetes

• Conditions: Type 2 Diabetes
• Interventions: Other: 4 Hour Frequently Sampled Oral Glucose Tolerance Test; Other: Isoglycaemic Clamp

• Registration Number: NCT02723110
• Lead Sponsor: 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.

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).

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2015-06
• Study First Submitted: 2016-02-12
• Study First Submitted QC: 2016-03-29
• Study First Posted: 2016-03-30
• Status Verified: 2016-06
• Last Update Submitted: 2016-06-21
• Last Update Posted: 2016-06-22
• Primary Completion: 2016-07
• Study Completion: 2016-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

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

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
rs78408340 heterozygous carriers	4 Hour Frequently Sampled Oral Glucose Tolerance Test	-
homozygous non-risk allele carriers	Isoglycaemic Clamp	-
homozygous non-risk allele carriers	4 Hour Frequently Sampled Oral Glucose Tolerance Test	-
rs78408340 heterozygous carriers	Isoglycaemic Clamp	-

Primary Outcome Measures

Name	Time	Method
Calculated Incretin Effect	3 months	Will be calculated from the amount of IV glucose required to reproduce OGTT glycaemic profile

Secondary Outcome Measures

Name	Time	Method
Glucose concentrations	3 months
Insulin concentration	3 months
GLP-1 (glucagon-like peptide-1) amidated and unamidated concentration	3 months
PAM enzyme activity assay	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

Trial Locations

Locations (1)

OCDEM, University of Oxford; 🇬🇧 Oxford, Oxfordshire, United Kingdom