Clinical trial NCT02723110: Defining the Physiological Mechanisms of Risk Genes for Hyperglycaemia, Insulin Resistance and Type 2 Diabetes
Official title: Defining the Physiological Mechanisms of Risk Genes for Hyperglycaemia, Insulin Resistance and Type 2 Diabetes
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Type 2 Diabetes
Keywords: Type 2 Diabetes Risk
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: University of Exeter
name: Medical Research Council
First posted: 2016-03-30
Enrollment: 40
Sex: ALL
Minimum age (years): 30
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Healthy volunteers enrolled in the Oxford Biobank

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).

Eligibility 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

Primary outcomes:
measure: Calculated Incretin Effect
timeFrame: 3 months
Secondary outcomes:
measure: Insulin concentration
timeFrame: 3 months
measure: Glucose concentrations
timeFrame: 3 months
measure: GLP-1 (glucagon-like peptide-1) amidated and unamidated concentration
timeFrame: 3 months
measure: PAM enzyme activity assay
timeFrame: 3 months
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: OCDEM, University of Oxford
state: Oxfordshire
Study officials:
References: