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

Type 2 Diabetes Clinical Trial

— DIVA - PAM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02723110
• Other study ID #: 15/SC/0072
• Status: Recruiting
• Phase: N/A
• First received: February 12, 2016
• Last updated: June 21, 2016
• Start date: June 2015
• Est. completion date: July 2016

Study information

• Verified date: June 2016
• Source: University of Oxford
• Contact: Fredrik Karpe
• Phone: 01865 857222
• Email: fredrik.karpe[@]ocdem.ox.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics Committee
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: July 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 30 Years to 65 Years

Eligibility

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 Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Hyperglycemia
• Insulin Resistance
• Type 2 Diabetes

Intervention

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
• 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

Locations

Country	Name	City	State
United Kingdom	OCDEM, University of Oxford	Oxford	Oxfordshire

Sponsors (3)

Lead Sponsor	Collaborator
University of Oxford	Medical Research Council, University of Exeter

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Calculated Incretin Effect	Will be calculated from the amount of IV glucose required to reproduce OGTT glycaemic profile	3 months	No
Secondary	Insulin concentration		3 months	No
Secondary	Glucose concentrations		3 months	No
Secondary	GLP-1 (glucagon-like peptide-1) amidated and unamidated concentration		3 months	No
Secondary	PAM enzyme activity assay	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	No