Type 2 Diabetes
Conditions
Keywords
Type 2 Diabetes Risk
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).
Interventions
OTHER4 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
OTHERIsoglycaemic 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
Sponsors
University of Exeter
Medical Research Council
University of Oxford
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
30 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Calculated Incretin Effect | 3 months | Will be calculated from the amount of IV glucose required to reproduce OGTT glycaemic profile |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin concentration | 3 months | — |
| Glucose concentrations | 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 |
Countries
United Kingdom
Contacts
Primary ContactFredrik Karpe
Backup ContactMahesh M Umapathysivam
Outcome results
None listed